SpondyloarthropathiesSpondyloarthropathies

Ori Elkayam M.DOri Elkayam M.D

Tel Aviv Medical CenterTel Aviv Medical Center

SpondyloarthropathiesSpondyloarthropathies

Ankylosing spondylitisAnkylosing spondylitis Psoriatic arthritisPsoriatic arthritis Reactive arthritis Reactive arthritis Entheropathic arthritis Entheropathic arthritis

Spondyloarthropathies (1)Spondyloarthropathies (1)

Inflammatory spinal pain or synovitis Inflammatory spinal pain or synovitis mainly in the lower limbsmainly in the lower limbs

One or more of the following:One or more of the following:

European Spondyloarthropathy StudyGroup Criteria for Spondyloarthropathy

Spondyloarthropathy (2)Spondyloarthropathy (2)

Positive family historyPositive family history Inflammatory bowel diseaseInflammatory bowel disease Urethritis, cervicitis or acute diarrhea Urethritis, cervicitis or acute diarrhea

within one month before arthritiswithin one month before arthritis Buttock pain alternating between right and Buttock pain alternating between right and

left gluteal areasleft gluteal areas EnthesopathyEnthesopathy Sacroiliitis Sacroiliitis

EnthesitisEnthesitis

Inflammation at the sites of attachment of Inflammation at the sites of attachment of tendons, fascia, ligament or joint capsule tendons, fascia, ligament or joint capsule to bone to bone

EnthesisEnthesis

Lateral malleoli and head of fibulaLateral malleoli and head of fibula Tendon of quadriceps tendon to patellaTendon of quadriceps tendon to patella Muscle attachments to greater and Muscle attachments to greater and

lesser trochanter,iliac crests, ischial lesser trochanter,iliac crests, ischial tuberosities, pubistuberosities, pubis

Insertions on the humeral medial and Insertions on the humeral medial and lateral epicondyleslateral epicondyles

Insertions of flexor carpi radialis Insertions of flexor carpi radialis Achilles tendon etc Achilles tendon etc

Common pathophysiologyCommon pathophysiology

Genetic factors – HLA-B27 related and Genetic factors – HLA-B27 related and othersothers

Enthesopathy seems to be the primary Enthesopathy seems to be the primary event event

Increased incidence of histologic evidence Increased incidence of histologic evidence of inflammatory lesion in ileocolonoscopy of inflammatory lesion in ileocolonoscopy

Low Back PainLow Back Pain

Low Back PainLow Back Pain The most frequent disorder of The most frequent disorder of

mankind after the common cold mankind after the common cold Between 65% and 80% of the world's Between 65% and 80% of the world's

population develop back pain at population develop back pain at some point during their lives.some point during their lives.

Over 50% of all patients with back Over 50% of all patients with back pain improve after 1 week, while pain improve after 1 week, while more than 90% are better at 8 weeks more than 90% are better at 8 weeks

Mechanical Back PainMechanical Back Pain 90% of patients with back pain have 90% of patients with back pain have

a 'mechanical' reason a 'mechanical' reason Secondary to overuse of a normal Secondary to overuse of a normal

anatomic structure, to trauma or to anatomic structure, to trauma or to deformity of an anatomic structure. deformity of an anatomic structure.

The remaining 10% of adults with The remaining 10% of adults with back pain have the symptom as a back pain have the symptom as a manifestation of a systemic illness manifestation of a systemic illness

Inflammatory back painInflammatory back pain

Onset before age 40Onset before age 40 Insidious onsetInsidious onset Persistence for at least 3 monthsPersistence for at least 3 months Associated with morning stiffnessAssociated with morning stiffness Improvement with exerciseImprovement with exercise

Case 1Case 1

A 30 year old man A 30 year old man Back pain since age 25 Back pain since age 25 Irradiation to both legsIrradiation to both legs Operation for herniated disc L5-S1Operation for herniated disc L5-S1 No improvementNo improvement Referral to rheumatologistReferral to rheumatologist

Case 1Case 1

Inflammatory Back PainInflammatory Back Pain Arthritis of the left hipArthritis of the left hip Bilateral sacroiliitisBilateral sacroiliitis Involvement of the left hipInvolvement of the left hip Diagnosis of Ankylosing SpondylitisDiagnosis of Ankylosing Spondylitis Treatment and left total hip replacement. Treatment and left total hip replacement.

Ankylosing spondylitisAnkylosing spondylitis

Ankylosing spondylitisAnkylosing spondylitis“Marie-Strumpell disease ” “Von Bechterew disease”

Ankylos: bent, fusion

Spondylos: vertebral disc

Prevalence & IncidencePrevalence & Incidence

Prevalence : from 67.7/100000 to Prevalence : from 67.7/100000 to 197/100000197/100000

Incidence : 7.3 per 100,000 person-years Incidence : 7.3 per 100,000 person-years More common in malesMore common in males Familial predominanceFamilial predominance

Genetics and ankylosing spondylitisGenetics and ankylosing spondylitis

Strong association with HLA-B27Strong association with HLA-B27 Prevalence of AS – associated with wild Prevalence of AS – associated with wild

world distribution of HLA-B27 world distribution of HLA-B27 90-98% of patients with AS are HLA-B27 90-98% of patients with AS are HLA-B27

positivepositive Only 1-2% of HLA-B27 positive adults may Only 1-2% of HLA-B27 positive adults may

develop AS develop AS

HLA B 27HLA B 27

HLA-B27 encompasses 40 different alleles HLA-B27 encompasses 40 different alleles encoding 40 different proteins encoding 40 different proteins

HLA-B27O5 –most widespread HLA-B27O5 –most widespread HLA-B27 contributes only part of the HLA-B27 contributes only part of the

genetic risksgenetic risks

Genetic factors involved in ASGenetic factors involved in AS

ARTS1 gene (26%)ARTS1 gene (26%) IL23R (9%)IL23R (9%) HLA-class IIHLA-class II Low molecular proteasomeLow molecular proteasome Polymorphisms of TNFPolymorphisms of TNFαα Major histocompatibility complex class II –MICAMajor histocompatibility complex class II –MICA Genes encoding IL-1RA,IL-6,IL-10,CYP2D6 Genes encoding IL-1RA,IL-6,IL-10,CYP2D6

Environmental factorsEnvironmental factors

Transgenic B27 mice maintained in germ Transgenic B27 mice maintained in germ free condition do not develop ASfree condition do not develop AS

MHCI related to pedptide (microbial) MHCI related to pedptide (microbial) presentation presentation

Clinical featuresClinical features

Inflammatory back painInflammatory back pain

Onset before age 40Onset before age 40 Insidious onsetInsidious onset Persistence for at least 3 monthsPersistence for at least 3 months Associated with morning stiffnessAssociated with morning stiffness Improvement with exerciseImprovement with exercise

EnthesitisEnthesitis

Costosternal junctions producing chest Costosternal junctions producing chest painpain

Spinous processes, iliac crests, greater Spinous processes, iliac crests, greater trochanters, ischial tuberosities, tibial trochanters, ischial tuberosities, tibial tubercles tubercles

Heels – achilles tendinitis, plantar fasciitis Heels – achilles tendinitis, plantar fasciitis

Plantar fasciitisPlantar fasciitis

Peripheral jointsPeripheral joints

Girdle joints – hips and shoulders (35%)Girdle joints – hips and shoulders (35%) KneesKnees TMJTMJ

Extraskeletal manifestationsExtraskeletal manifestations

Constitutional symptomsConstitutional symptoms Acute anterior uveitis Acute anterior uveitis Cardiovascular diseaseCardiovascular disease Pulmonary diseasePulmonary disease Neurologic involvementNeurologic involvement Renal involvement Renal involvement

UveitisUveitis

AnteriorAnterior Acute and unilateralAcute and unilateral Red and painful eyeRed and painful eye Photophobia, lacrimationPhotophobia, lacrimation Attacks usually subside in 4-8 weeksAttacks usually subside in 4-8 weeks Without sequelaeWithout sequelae More common in HLA-B27 positive More common in HLA-B27 positive

CardiovascularCardiovascular

May be clinically silent although clinically May be clinically silent although clinically importantimportant

Ascending aortitisAscending aortitis Aortic valve incompetenceAortic valve incompetence Conduction abnormalitiesConduction abnormalities CardiomegalyCardiomegaly PericarditisPericarditis

Pulmonary diseasePulmonary disease

Progressive fibrosis of the upper lobes Progressive fibrosis of the upper lobes Eventual secondary colonization with Eventual secondary colonization with

aspergillusaspergillus Impaired pulmonary ventilation due to Impaired pulmonary ventilation due to

involvement of thoracic jointsinvolvement of thoracic joints Restrictive lung disease Restrictive lung disease

Neurologic involvementNeurologic involvement

Fracture, instability or compression of Fracture, instability or compression of vertebraevertebrae

Atlanto-axial subluxationAtlanto-axial subluxation Ossification of the posterior longitudinal Ossification of the posterior longitudinal

ligament resulting in compressive ligament resulting in compressive myelopathymyelopathy

Cauda equina synd :lumbosacral roots, Cauda equina synd :lumbosacral roots, pain , sensory loss, urinary&bowel pain , sensory loss, urinary&bowel symptomssymptoms

Renal involvementRenal involvement

Immunoglobulin A (IgA) nephropathyImmunoglobulin A (IgA) nephropathy Secondary amyloidosisSecondary amyloidosis High incidence of prostatitis High incidence of prostatitis

Physical examinationPhysical examination

Evidence of sacroiliitisEvidence of sacroiliitis Expansion of the lumbar spine –Schober Expansion of the lumbar spine –Schober

testtest Chest expansion < below 5 cmChest expansion < below 5 cm Enthesitis Enthesitis Posture –forward sloop of the neck, Posture –forward sloop of the neck,

stiffness of the spine , loss of lumbar stiffness of the spine , loss of lumbar lordosis, thoracic kyphosis lordosis, thoracic kyphosis

Normal pelvisNormal pelvis

SacroiliitisSacroiliitis

SacroiliitisSacroiliitis

SacroiliitisSacroiliitis

Elbow enthesopathyElbow enthesopathy

Enthesopathy of heelsEnthesopathy of heels

Radiographic and imagingRadiographic and imaging

Sacroiliitis Sacroiliitis Whiskering at enthesis (calcaneous, Whiskering at enthesis (calcaneous,

ischial tuberosities, femoral trochanters)ischial tuberosities, femoral trochanters) Squaring of vertebraeSquaring of vertebrae SyndesmophytesSyndesmophytes Spinal osteoporosisSpinal osteoporosis Hip, shoulder Hip, shoulder

Laboratory testsLaboratory tests

ESRESR CRPCRP CBCCBC HLA-B27HLA-B27

Criteria of ankylosing spondylitisCriteria of ankylosing spondylitis

Low back pain of at least 3 months Low back pain of at least 3 months duration improved by exercise, not duration improved by exercise, not relieved by restrelieved by rest

Limitation of lumbar spine in sagittal and Limitation of lumbar spine in sagittal and frontal planesfrontal planes

Reduced chest expansionReduced chest expansion Bilateral sacroiliitis, grade2-4Bilateral sacroiliitis, grade2-4 Unilateral sacroiliitis, grade3-4Unilateral sacroiliitis, grade3-4

Definite ankylosing spondylitisDefinite ankylosing spondylitis

Unilateral grade 3 or 4 or

Bilateral grade 2-4 sacroiliitis and any clinical criterion

Probable ankylosing spondylitis

a.The three clinical criteria are present b.The radiologic criteria is present without clinical criteria

Conventional Medical treatment for Conventional Medical treatment for ASAS

PhysiotherapyPhysiotherapy NSAIDsNSAIDs Sulfasalazine–peripheral arthritis, acute Sulfasalazine–peripheral arthritis, acute

phase responsephase response MethotrexateMethotrexate Corticosteroids (p.o, IA, IV)Corticosteroids (p.o, IA, IV) PamidronatePamidronate Anti-TNF α therapies Anti-TNF α therapies

Dougados M, Ann Rheum Dis 2002;61:40iii-50

5555

Key Actions Attributed to TNFKey Actions Attributed to TNF

Mouse(Binding site for TNF)

Human (IgG1)

Fc region ofFc region ofhuman IgG1human IgG1

Extracellular domain ofExtracellular domain ofhuman p75 TNF receptorhuman p75 TNF receptor

CCHH33 CCHH22

SSSS

SSSS

SSSS

SSSS

SSSS

SSSS

SSSS

InfliximabEtanercept

Adalimumab

ENBREL Inhibits Activationof Cell-Surface Receptors

ENBREL

TNF

TNF INHIBITION WITH ENBREL® (etanercept)

Reference: 1. Data on file, Immunex Corporation, Seattle, Wash.

ENBREL has been designed tocomplement the body’s naturalinhibition of TNF 1

ENBREL

TNF

Etanercept: soluble receptor of TNFα

Side effectsSide effects

Good tolerabilityGood tolerability The most frequent was injection site reaction The most frequent was injection site reaction

in37%in37% Infection in 35% and headache 17 %Infection in 35% and headache 17 %

Post marketing : severe infections including TB Post marketing : severe infections including TB and fatalities, demyelinative disorders, and fatalities, demyelinative disorders, lymphoma, rare cases of pancytopenia including lymphoma, rare cases of pancytopenia including aplastic anemia,vasculitis, drug induced lupus aplastic anemia,vasculitis, drug induced lupus

5959

6060RA1301a

REMICADEREMICADE®® ( (infliximabinfliximab)) SafetySafety

Hypersensitivity reactions Hypersensitivity reactions Sepsis, pneumocystosis, histoplasmosis, Sepsis, pneumocystosis, histoplasmosis,

and listeriosis have been reportedand listeriosis have been reportedRare cases of lymphoma, demyelinating Rare cases of lymphoma, demyelinating

diseases and drug induced lupus diseases and drug induced lupus Increased incidence of TB Increased incidence of TB

ASAS consensus statement for the ASAS consensus statement for the use of anti-TNF agents in patients use of anti-TNF agents in patients

with ankylosing spondylitiswith ankylosing spondylitis..A diagnosis of definitive ankylosing spondylitis A diagnosis of definitive ankylosing spondylitis Active disease for at least four weeks:Active disease for at least four weeks:

- Bath ankylosing spondylitis disease activity - Bath ankylosing spondylitis disease activity index (BASDAI) of > or =4index (BASDAI) of > or =4

- Expert opinion based on clinical findings- Expert opinion based on clinical findings Failure of at least two NSAIDs, 3 month periodFailure of at least two NSAIDs, 3 month period Failure of SZPin patients with peripheral Failure of SZPin patients with peripheral

arthritisarthritis Application of the usual precautions and Application of the usual precautions and

contraindications for biological treatment. contraindications for biological treatment.

Case history (2)Case history (2)

A 22 year old man A 22 year old man A 5 month history of recurrent low back A 5 month history of recurrent low back

pain and stiffness pain and stiffness An attack of anterior uveitis 5 months agoAn attack of anterior uveitis 5 months ago Episodes of pain in his shouldersEpisodes of pain in his shoulders Clinical examination : severe restriction of Clinical examination : severe restriction of

forward and lateral flexions, tenderness forward and lateral flexions, tenderness over SIJ over SIJ

Case History (2)Case History (2)

Normocytic, normochromic anemiaNormocytic, normochromic anemia Increased ESR OF 40 mm/h Increased ESR OF 40 mm/h Increased sclerosis of the SIJIncreased sclerosis of the SIJ HLA-B27 positive HLA-B27 positive Treated with NSAIDS and physiotherapyTreated with NSAIDS and physiotherapy SalazopyrineSalazopyrine Anti-TNFAnti-TNFαα therapy therapy

Diagnostic problems of Case 1Diagnostic problems of Case 1

Low back painLow back pain A detailed history and clinical examination A detailed history and clinical examination

is mandatoryis mandatory Presence of sacroiliitis Presence of sacroiliitis HLA-B27?HLA-B27?

Psoriatic arthritisPsoriatic arthritis

Case History (3)Case History (3)

A 25 year old womanA 25 year old woman 5 years history of psoriasis 5 years history of psoriasis Oligoarthritis involving the knee and ankle Oligoarthritis involving the knee and ankle Increased ESR, negative RFIncreased ESR, negative RF Treated with NSAIDS and intra-articular Treated with NSAIDS and intra-articular

corticosteroid injectionscorticosteroid injections Polyarticular coursePolyarticular course Methotrexate Methotrexate

Historical backgroundHistorical background

1882 : 1882 : Bourdillon – first study on Bourdillon – first study on psoriatic arthritispsoriatic arthritis

1956 : Wright – first definition of psoriatic 1956 : Wright – first definition of psoriatic arthritis as “an inflammatory arthritis arthritis as “an inflammatory arthritis associated with psoriasis usually with an associated with psoriasis usually with an absence of rheumatoid factor in the absence of rheumatoid factor in the serum” serum”

1970 : Wright and Moll : clinical 1970 : Wright and Moll : clinical classification of psoriatic arthritis classification of psoriatic arthritis

EpidemiologyEpidemiology

7-42% of patients with psoriasis7-42% of patients with psoriasis Estimated prevalence of 1 %Estimated prevalence of 1 % Annual incidence of 6.1 per 100000Annual incidence of 6.1 per 100000 Mild predominance in males Mild predominance in males

PathogenesisPathogenesis

Familial predispositionFamilial predisposition HLA-B13, 17,38,Cw6, DR4 and DR7HLA-B13, 17,38,Cw6, DR4 and DR7 HLA-B27 related to axial involvement HLA-B27 related to axial involvement

Immunologic factorsImmunologic factors

Imbalance of T cell activity Imbalance of T cell activity Increased proliferative activity of Increased proliferative activity of

fibroblasts and synoviafibroblasts and synovia Activated T cells in both skin and joints Activated T cells in both skin and joints Inflammatory mediators : TNF, Inflammatory mediators : TNF,

IL,prostaglandins, leukotrienesIL,prostaglandins, leukotrienes

Skin lesionsSkin lesions

Link between skin and joint diseaseLink between skin and joint disease

Skin involvement precedes arthritis in 70 Skin involvement precedes arthritis in 70 %%

Simultaneous onset in 15%Simultaneous onset in 15% Psoriatic arthritis sine psoriasis in 10-15%Psoriatic arthritis sine psoriasis in 10-15% Loose correlation between joint and skin Loose correlation between joint and skin

activityactivity Different genetic background Different genetic background Increased nail involvement Increased nail involvement

Moll and Wright clinical Moll and Wright clinical classificationclassification

Arthritis of the distal interphalangeal jointsArthritis of the distal interphalangeal joints Arthritis mutilansArthritis mutilans Symmetric polyarthritis (28-78)Symmetric polyarthritis (28-78) Asymmetric oligoarthritis (16-53%)Asymmetric oligoarthritis (16-53%) Spondyloarthropathy (20-40%)Spondyloarthropathy (20-40%)

DIP involvementDIP involvement

Psoriatic arthritis is an enthesitisPsoriatic arthritis is an enthesitis

DIP joint diseaseDIP joint disease Spinal inflammationSpinal inflammation Dactylitis-sausage finger Dactylitis-sausage finger

Sausage fingerSausage finger

Extra-articular features of psoriatic Extra-articular features of psoriatic arthritisarthritis

Psoriatic skin lesionsPsoriatic skin lesions IritisIritis Mouth ulcersMouth ulcers Urethritis Urethritis

Radiological features of PsARadiological features of PsA

Lack of juxta-articular osteopeniaLack of juxta-articular osteopenia Pencil-in cup changePencil-in cup change AnkylosisAnkylosis Periostal reactionPeriostal reaction Asymmetric sacroiliitisAsymmetric sacroiliitis Coarse syndesmophytes Coarse syndesmophytes

Erosive psoriatic arthritisErosive psoriatic arthritis

Prognosis of psoriatic arthritisPrognosis of psoriatic arthritis

Increased risk of progression in patients Increased risk of progression in patients who present with > 5 swollen jointswho present with > 5 swollen joints

HLA-B27 + DR-7, B-39, DQw3- bad HLA-B27 + DR-7, B-39, DQw3- bad prognostic signsprognostic signs

Hla-b22 - protectiveHla-b22 - protective Increased risk of death Increased risk of death

CASPAR criteriaCASPAR criteria

Inflammatory musculoskeletal disease (joint, spine, or Inflammatory musculoskeletal disease (joint, spine, or entheseal)entheseal)

With 3 or more of the followingWith 3 or more of the following::

1. Current psoriasis1. Current psoriasis

2. Personal history of psoriasis (if current psoriasis not present)2. Personal history of psoriasis (if current psoriasis not present)

3. Family history of psoriasis (if personal history of psoriasis or3. Family history of psoriasis (if personal history of psoriasis or

current psoriasis is not present) current psoriasis is not present)

4. Psoriatic nail dystrophy4. Psoriatic nail dystrophy

5. A negative test for rheumatoid factor5. A negative test for rheumatoid factor

6. Current dactylitis6. Current dactylitis

7. History of dactylitis (if current dactylitis is not present)7. History of dactylitis (if current dactylitis is not present)

8. Radiological evidence of juxta-articular new bone formation8. Radiological evidence of juxta-articular new bone formation

Management of PsAManagement of PsA

NSAID’sNSAID’s MethotrexateMethotrexate SulphasalazineSulphasalazine LeflunomideLeflunomide AzathioprineAzathioprine CyclosporineCyclosporine Anti TNFAnti TNFαα therapies therapies Intra articular injections of corticosteroids Intra articular injections of corticosteroids

MethotrexateMethotrexate

Efficacy in PsA 1Efficacy in PsA 1stst demonstrated in 1964. demonstrated in 1964. Placebo controlled study of 21 patients Placebo controlled study of 21 patients

with active skin disease and peripheral with active skin disease and peripheral arthritis – observation 3 months.arthritis – observation 3 months.

Improvement in skin and joint involvement.Improvement in skin and joint involvement.

SulfasalazineSulfasalazine

5 controlled studies5 controlled studies 221 patients treated with 2 g/day over 36 221 patients treated with 2 g/day over 36

week course. Improvement in tender and week course. Improvement in tender and swollen joints.swollen joints.

Its actions appears to be confined to Its actions appears to be confined to peripheral arthritis with no benefit in axial peripheral arthritis with no benefit in axial disease disease

Rare reports of cutaneous improvement.Rare reports of cutaneous improvement.

Leflunomide (ARAVA)Leflunomide (ARAVA)

A selective pyrimidine synthesis inhibitor A selective pyrimidine synthesis inhibitor that targets activated T cells lacking a that targets activated T cells lacking a salvage pathway.salvage pathway.

Randomised double blind, placebo Randomised double blind, placebo controlled study in 188 patients with active controlled study in 188 patients with active PsA and active rash. PsA and active rash.

After 6 months 59% met primary efficacy. After 6 months 59% met primary efficacy. Compared with 30% of placebo.Compared with 30% of placebo.

Other options ?Other options ?

GoldGold Cyclosporine ACyclosporine A Azathioprine and 6-mercaptopurineAzathioprine and 6-mercaptopurine Antimalarial agentsAntimalarial agents ColchicineColchicine

Biological treatment of PsABiological treatment of PsA

Mouse(Binding site for TNF)

Human (IgG1)

Fc region ofFc region ofhuman IgG1human IgG1

Extracellular domain ofExtracellular domain ofhuman p75 TNF receptorhuman p75 TNF receptor

CCHH33 CCHH22

SSSS

SSSS

SSSS

SSSS

SSSS

SSSS

SSSS

InfliximabEtanercept

Adalimumab

Increased serum Increased serum levels of TNFlevels of TNFαα in in PsA.PsA.

Increased levels of Increased levels of TNFTNFαα in synovial fluid in synovial fluid of PsA of PsA

Why target TNFWhy target TNFαα

ENBREL Inhibits Activationof Cell-Surface Receptors

ENBREL

TNF

TNF INHIBITION WITH ENBREL® (etanercept)

Reference: 1. Data on file, Immunex Corporation, Seattle, Wash.

ENBREL has been designed tocomplement the body’s naturalinhibition of TNF 1

ENBREL

TNF

Etanercept: soluble receptor of TNFα

Stratification (N -205 PsA, active dis.)Stratification (N -205 PsA, active dis.)

- Etanercept 25 mg twice weekly (n=101) - Etanercept 25 mg twice weekly (n=101) as either Etanercept (n=59) or as either Etanercept (n=59) or Etanercept+MTX (n=42)Etanercept+MTX (n=42)

- Placebo (n=104) or either placebo alone - Placebo (n=104) or either placebo alone (n=61) or Placebo +MTX (n=43)(n=61) or Placebo +MTX (n=43)

Gottlieb A. Ann Rheum Dis 2002;61(Suppl1)

Etanercept in PsAEtanercept in PsAA phase III clinical trialA phase III clinical trial

0

10

20

30

40

50

60

1 3 6

Etanercept

Placebo

MonthsGottlieb A. Ann Rheum Dis 2002;61(Suppl1

Percentage of patients achieving Percentage of patients achieving ACR 20ACR 20

MeasureMeasure Placebo Placebo n=104n=104

EtanerceptEtanercept

n= 101n= 101

P valueP value

Phys. AssessPhys. Assess . .00 5050 .>.>00010001

Patient assessPatient assess..00 33.333.3 .>.>00010001

Pain ( VAS)Pain ( VAS) 00 5050 .>.>00010001

Morning stiffnessMorning stiffness2525 68.368.3 .>.>00010001

CRPCRP --6.36.3 74.274.2 .>.>00010001

PASIPASI 99 4646 .>.>00010001

Measures of arthritis activity (median Measures of arthritis activity (median improvement from baseline to 3 months)improvement from baseline to 3 months)

101101

Infliximab (Remicade)Infliximab (Remicade)

Chimeric monoclonal antibodyChimeric monoclonal antibody 104 , PsA, 5 mg/kg104 , PsA, 5 mg/kg O, 2 weeks, 6 weeks, thereafter every O, 2 weeks, 6 weeks, thereafter every

8 weeks.8 weeks. Week 16: ACR 20 of 65% in infliximab-Week 16: ACR 20 of 65% in infliximab-

treated pts vs 10% in controls treated pts vs 10% in controls Impressive improvement in skin Impressive improvement in skin

lesionslesions

Adalimumab (Humira)Adalimumab (Humira)

Fully human anti-TNF monoclonal Fully human anti-TNF monoclonal antibody, SC, 40 mg e.o.w antibody, SC, 40 mg e.o.w

315 patients with PsA315 patients with PsA At week 12, ACR 20 in 58% of the At week 12, ACR 20 in 58% of the

adalimumab-treated patients vs 14% of adalimumab-treated patients vs 14% of the placebo-treated patients .the placebo-treated patients .

59% achieved a 75% PASI improvement 59% achieved a 75% PASI improvement response at 24 weeks response at 24 weeks

T cell activators blockingT cell activators blocking

Alefacept (Amevive)Alefacept (Amevive) Fully human fusion protein binds CD2 on Fully human fusion protein binds CD2 on

memory T cells and blocks interaction with memory T cells and blocks interaction with LFA-3 on the antigen presenting cells.LFA-3 on the antigen presenting cells.

Efalizumab (Raptiva)Efalizumab (Raptiva) Humanised antibody to the CD11 subunit Humanised antibody to the CD11 subunit

of LFA1of LFA1

PsA Treatment GuidelinesPsA Treatment Guidelines

Establish Diagnosis of Psoriatic ArthritisEstablish Diagnosis of Psoriatic Arthritis

Reassess Response to Therapy and Toxicity

EducationPhysiotherapyAnalgesiaNSAID (continous)Biologics(anti-TNF)+/- Corticosteroid inj

Axial DiseasePeripheral Arthritis

Skin & Nail Disease

Dactylitis Enthesitis

PsA Treatment GuidelinesPsA Treatment Guidelines

Mild PsA Severe and moderate PsA (oliygo-polyarthritis?).

Poor prognosis PsA

Respond NSAIDs and/or IA steroids

Early DMARD(MTX,SZP, LEF)

Adequate therapeutic trial of 2 DMARD

Anti TNF αα

Respond

Case history (4)Case history (4)

A 37 year old man- positive family of A 37 year old man- positive family of psoriasispsoriasis

Synovitis in the knee and swelling of the Synovitis in the knee and swelling of the calf and lower thighcalf and lower thigh

Resolved with steroid injection in the kneeResolved with steroid injection in the knee 6 year later, a similar episode+ sausage 6 year later, a similar episode+ sausage

finger of the right great toefinger of the right great toe 11 years later, synovitis of the knee, 11 years later, synovitis of the knee,

ankle , toe and psoriasis ankle , toe and psoriasis

Clinical clues to the diagnosis of Clinical clues to the diagnosis of Psoriatic arthritis sine PsoriasisPsoriatic arthritis sine Psoriasis

Positive family history of psoriasisPositive family history of psoriasis Sausage digitsSausage digits Asymmetric, oligoarticular involvementAsymmetric, oligoarticular involvement DIP involvementDIP involvement Waxing and waning course with frequent Waxing and waning course with frequent

remissionsremissions Absent RFAbsent RF Absence of rheumatoid nodules Absence of rheumatoid nodules

Reactive arthritisReactive arthritis

Case 5Case 5

A 20 year old soldierA 20 year old soldier High fever with bloody diarrhea High fever with bloody diarrhea Two weeks later, arthritis of the right kneeTwo weeks later, arthritis of the right knee Joint aspiration: inflammatory sterile fluidJoint aspiration: inflammatory sterile fluid Resolution after 3 months Resolution after 3 months

Reiter syndromeReiter syndrome

ArthritisArthritis Nongonococcal urethritisNongonococcal urethritis ConjunctivitisConjunctivitis

Reactive arthritisReactive arthritis

An acute arthritis developing soon after an An acute arthritis developing soon after an infection elsewhereinfection elsewhere

Different from septic arthritis although Different from septic arthritis although component of the infective organism may component of the infective organism may be presentbe present

Increased frequency of HLA-B27Increased frequency of HLA-B27 Increased association with HIVIncreased association with HIV

Role of bacteriaRole of bacteria

Chlamydia trachomatisChlamydia trachomatis Shigella flexneriShigella flexneri Salmonella typhimuriumSalmonella typhimurium Yersinia enterocolitica Yersinia enterocolitica Yersinia pseudotuberculosisYersinia pseudotuberculosis Campylobacter jejuniCampylobacter jejuni MycoplasmaMycoplasma

Pathogenesis of Reactive Pathogenesis of Reactive arthritisarthritis

Clinical featuresClinical features

Symptoms 1-3 weeks after the inciting Symptoms 1-3 weeks after the inciting episodeepisode

Mild constitutional symptomsMild constitutional symptoms Joint stiffness, inflammatory low back painJoint stiffness, inflammatory low back pain OligoarthritisOligoarthritis Predominant involvement of lower limbs-Predominant involvement of lower limbs-

knees, ankles, feetknees, ankles, feet EnthesitisEnthesitis

Extra-articular manifestations (1)Extra-articular manifestations (1)

UrethritisUrethritis Meatal erythema and edema – balanitis circinataMeatal erythema and edema – balanitis circinata Keratoderma blennorhagicaKeratoderma blennorhagica Oral ulcersOral ulcers Erythema nodosum (yersinia)Erythema nodosum (yersinia) Conjunctivitis, uveitisConjunctivitis, uveitis Increased gut involvementIncreased gut involvement

Extra articular manifestationsExtra articular manifestations

Conjunctivitis, uveitisConjunctivitis, uveitis Increased gut involvementIncreased gut involvement Conduction defectsConduction defects Aortic regurgitationAortic regurgitation

Extra articular manifestationsExtra articular manifestations

Laboratory and radiologic findingsLaboratory and radiologic findings

Increased ESR and CRPIncreased ESR and CRP Inflammatory synovial fluid Inflammatory synovial fluid Erosions, asymmetric sacroiliitisErosions, asymmetric sacroiliitis Coarse ossification Coarse ossification

Course and prognosisCourse and prognosis

Single episode or recurrent symptomatic Single episode or recurrent symptomatic attacks lasting up to 6 monthsattacks lasting up to 6 months

The 10- to 20 year prognosis of The 10- to 20 year prognosis of postdysenteric syndrome better than post-postdysenteric syndrome better than post-chlamydiachlamydia

TreatmentTreatment

NSAID’sNSAID’s Intraarticular injectionsIntraarticular injections SulfasalazineSulfasalazine MethotrexateMethotrexate Controversial effect of antibiotics Controversial effect of antibiotics

Entheropathic arthritisEntheropathic arthritis

Entheropathic arthritisEntheropathic arthritis

Inflammatory bowel diseaseInflammatory bowel disease Bypass arthritis dermatitis syndromeBypass arthritis dermatitis syndrome Gluten-sensitive entheropathyGluten-sensitive entheropathy Whipple diseaseWhipple disease

Case 6Case 6

A 30 year old man A 30 year old man Crohn at age of 25Crohn at age of 25 Treatment with Imuran, Remicade Treatment with Imuran, Remicade Clinical remission of CrohnClinical remission of Crohn Low back PainLow back Pain Pain in the Right hipPain in the Right hip Sacroiliitis , Rt hip arthritisSacroiliitis , Rt hip arthritis

Inflammatory bowel diseasesInflammatory bowel diseases

Peripheral arthritis, seronegative , large Peripheral arthritis, seronegative , large joints, more frequent in Crohn’sjoints, more frequent in Crohn’s

Ankylosing spondylitis like – clearly related Ankylosing spondylitis like – clearly related with HLA-B27with HLA-B27

Association between peripheral arthritis Association between peripheral arthritis and gut activityand gut activity

Extra intestinal manifestationsExtra intestinal manifestations

Skin involvement: erythema nodosum, Skin involvement: erythema nodosum, pyoderma gangrenosum, erythema pyoderma gangrenosum, erythema multiformemultiforme

Aphtous ulcerationsAphtous ulcerations Liver disease Liver disease Eye inflammation Eye inflammation Amyloidosis Amyloidosis

TreatmentTreatment

Treat the underlying IBDTreat the underlying IBD SulphasalazineSulphasalazine MethotrexateMethotrexate AntiTNFAntiTNFαα therapies therapies

Be careful with NSAIDS Be careful with NSAIDS

Bypass arthritis-dermatitis Bypass arthritis-dermatitis syndromesyndrome

Within 1 year of bypassWithin 1 year of bypass Oligoarthritis, sacroiliitis Oligoarthritis, sacroiliitis Pustular rashPustular rash Erythema nodosumErythema nodosum Related to BOGRelated to BOG

Gluten sensitive enteropathyGluten sensitive enteropathy

Asymmetric oligoarthritis, sacroiliitisAsymmetric oligoarthritis, sacroiliitis Often GI asymptomaticOften GI asymptomatic Anti endomysial Ab, anti gliadin AbAnti endomysial Ab, anti gliadin Ab Typical intestine biopsy Typical intestine biopsy

Whipple diseaseWhipple disease

Due to tropheryma whippleiiDue to tropheryma whippleii Seronegative oligoarthritis, sacroiliitis Seronegative oligoarthritis, sacroiliitis DiarrheaDiarrhea Cardiac involv-endocarditis,aortic insuff.Cardiac involv-endocarditis,aortic insuff. Lymphadenopathy,uveitis, rash Lymphadenopathy,uveitis, rash Prolonged treatment with penicillin or Prolonged treatment with penicillin or

tetracycline tetracycline

SAPHOSAPHO

SSynovitisynovitis AAcne cne PPalmo-plantaralmo-plantar ppustulosisustulosis HHyperostosisyperostosis OOsteitis steitis

SAPHOSAPHO

Musculoskeletal complains related to the Musculoskeletal complains related to the anterior chest wall anterior chest wall

Synovial involvementSynovial involvement Skin involvementSkin involvement

Bull’s HeadBull’s Head

Sternocostoclavicular Sternocostoclavicular hyperostosis: chest (CT hyperostosis: chest (CT

scan)scan)

The rheumatologistThe rheumatologist