Seronegative Spondyloarthropathies Dr.

osama sayed daifallh

Back to basics
The skeleton

Axial skeleton

Skull Vertebral column

Vertebrae Sacrum Coccyx

Ribs Sternum Girdles Extremities

Appendicular skeleton

Back to basics
Articulations

Diarthrosis (moveable)

Majority of articulations Contiguous bones are covered by cartilage, connected by ligaments, and have an interposing synovial sac

Synarthrosis (immoveable)

Contiguous bones are in direct contact without cartilage, syovium, or ligaments

Characteristics of both diarthrosis and synarthrosis Contiguous surfaces are either:

Amphiarthrosis (sort of moveable)

Connected by fibrocartiganeous disks (vertebral joint) Covered by fibrocartilage and partial synovium, and attached by external ligaments (sacroiliac joint)

Back to basics
Enthesis

Enthesis is the site of bony attachment of

Tendon Ligament Cartilage Joint capsule Fascia

Comprise these conditions

Seronegative spondyloarthropathies

Ankylosing spondylitis (the prototype) Psoriatic arthritis Reactive arthritis

Formerly called Reiters syndrome)

Enteropathic arthritis Undifferentiated spondyloarthropathy

Well, because they share these characteristics

Why are these diseases classified together?

HLA-B27 association Enthesitis (both juxtarticular and extrarticular) Axial skeleton arthritis (generally secondary to juxtarticular enthesitis)

Spondylitis (inflammation of vertebral bodies) Sacroiliitis (inflammation of sacroiliac joint)

Asymmetric (cf rheumatoid arthritis)

Peripheral arthritis (generally a synovitis)

Extrarticular manifestations (besides enthesitis) Seronegativity

Rheumatoid factor and ANA negative

Why are these diseases classified together?

HLA-B27 association

Ankylosing spondylitis: 95%

Ethnically matched controls: 8%

Reactive arthritis: 70% Enteropathic arthritis: 50% Psoriatic arthritis: 35%

Why are these diseases classified together?

Enthesitis

Inflammation of an enthesis It is the Principal pathogenetic mechanism in spondyloarthropathy Pathogenesis

CD8 T cells infiltrate entheses Activated macrophages release cytokines (eg TNF) Fibroblasts synthesize new collagen (cf rhematoid arthritis!!) New bone formation results Axial skeleton arthritis (see later) Enthesopathy at other sites

Clinical

Calcaneal spurs at plantar fascia insertion Spurs at Achilles tendon insertion Manifests as extrarticular or juxtarticular bony tenderness

Why are these diseases classified together?

Axial skeleton arthritis

Arises from enthesitis Includes spondylitis and sacroiliitis Spondylitis

CD8 T cells invade the junction of the annulus fibrosis and the vertebral body (an enthesis) Annulus fibrosis is replaced by bone (syndesmophytosis) Vertebral bodies assume a square shape, and ultimately a bamboo spine

Sacroiliitis

CD8 T cells invades the subchondral area at the junction of the bones and the cartilage (an enthesis) Cartilage on iliac side is replaced by bone, obliterating the jont space and hardening the joint

Ankylosing spondylitis

AS: Characteristic Pathologic Features

Chronic inflammation in:
Axial structures (sacroiliac joint, spine, anterior chest wall, shoulder and hip) Possibly large peripheral joints, mainly at the lower limbs (oligoarthritis)

Entheses (enthesitis)
Bone formation particularly in the axial joints

Inflammation
Disease activity

Structural damage
Syndesmophytes formation

Sieper J. Arthritis Res Ther 2009;11:208 Elewaut D & Matucci MC. Rheumatology 2009;48:1029-1035

AS: Signs and Symptoms

Axial manifestations:

Inflammation

Disease activity

Chronic low back pain

MRI sacro-iliac joint

With or without buttock pain

Inflammatory characteristics:

Occurs at night (second part) Sleep disturbance Morning stiffness

Inflammatory back pain (IBP) = Characteristic symptom

Limited lumbar motion

Onset before age of 40 years

Ankylosing spondylitis
Inflammatory back pain

Inflammatory back pain requires 4 of these 5 criteria (serves as a screening tool for AS)

Young onset ( 40 years) Morning stiffness ( 30 minutes) Chronic ( 3 months) Activity improves the pain (rest does not) and rapide response to NSAIDS within 24 hrs Insidious (not acute) (mnemonic is YMCA-I)

Diffuse lumbar or gluteal, not focal or radicular

Cf focal pain of disk herniation

Structural damage

AS: Structural Damage

Syndesmophytes formation

Most striking feature of AS = New bone formation in the spine with:

Spinal
X-ray showing syndesmophytes

syndesmophytes

Ankylosis

Even in patients with longerstanding disease, syndesmophytes are present in 50% patients and a smaller percentage will develop ankylosis

Both can be seen on Bamboo spine and conventional radiography bilateral sacroiliitis
Sieper J. Arthritis Res Ther 2009;11:208

AS: Signs and Symptoms Peripheral manifestations

Enthesitis Peripheral arthritis Dactylitis

50% patients with enthesitis1

Up to 58% patients ever had arthritis1

Much smaller number of patients2

1Cruyssen

2Sidiropoulos

BV et al. Ann Rheum Dis 2007;66:1072-1077 PI et al. Rheumatology 2008;47:355-361

Why are Dactylitis and Enthesitis Important?

Likelihood of erosions is higher for digits with dactylitis than those without1

The first abnormality to appear in swollen joints associated with spondyloarthropathies is an enthesitis2

1Brockbank.

2McGonagle

Ann Rheum Dis 2005;62:188-90; et al. The Lancet 1998;352.

Ankylosing spondylitis
Other clinical (besides back pain)

Restriction of lumbar movement

Shobers test mark the patients back at the level of the posterior iliac spine. Place one finger 5 cm below this mark and a 2nd finger 10 cm above this mark. Patient is instructed to touch his toes. If the distance between finegrs increases < 5 cm, lumbar flexion is limited. Acute eye pain Increased lacrimation Photophobia Blurred vision Aortic insufficiency Third degree heart block (5%)

Anterior uveitis (iritis or iridocyclitis) (25%)

Aortitis with fibrosis

AS: Extra-articular Manifestations (EAM)

EAM Prevalence in AS Patients (%) 30-50 5-10 25-49 1-33 1-10 10-20 10-35 40-88 82 47-65 9-35 11-18 39-59
Elewaut D & Matucci MC. Rheumatology 2009;48:1029-1035 Terminal ileitis

Anterior uveitis IBD

Anterior uveitis

Subclinical inflammation of the gut Cardiac abnormalities Conduction disturbances Aortic insufficiency Psoriasis Renal abnormalities Lung abnormalities Airways disease Interstitial abnormalities Emphysema Bone abnormalities Osteoporosis Osteopenia

Cardiac abnormalities

AS: Extra-skeletal Signs and Symptoms Other common symptoms seen during the early stages of disease
include:

Anorexia Malaise Low grade fever Weight loss Fatigue

Fatigue is a frequent complaint of patients with AS1

B. et al. Ann Readapt Med Phys 2006;49:305-8, 389-391 Linden VD et al. Chapter 10. In: Firestein, Budd, Harris, McInnes, Ruddy and Sergent, eds. Kelleys Textbook of Rheumatology: Spondyloarthropathies. 8th ed. Saunders Elsevier;2009:p.1176

1Missaoui

Laboratory tests
ESR CRP CBC HLA-B27

Radiographic and imaging

Sacroiliitis Whiskering at enthesis (calcaneous, ischial tuberosities, femoral trochanters) Squaring of vertebrae Syndesmophytes Spinal osteoporosis Hip, shoulder

Ankylosing spondylitis
Radiographic evaluation
Sacroiliac joints
Grade 0
Grade 1 Grade 2

Normal
Suspicious changes Minimal abnormality small localized areas with erosion or sclerosis without alterations in joint width

Grade 3

Unequivocal abnormality moderate or advanced sacroiliitis with 1 of the following: erosions, sclerosis, widening, narrowing, or partial ankylosis
Severe abnormality total ankylosis

Grade 4

Marginal erosions and new bone formation

Sacroiliitis

Unilateral sacroiliitis

Ossification of SI joint space

Bamboo spine

Enthesopathy of heels

Ankylosing Spondylitis
Classification

Ankylosing spondylitis
Modified New York Diagnostic Criteria

Low back pain 3 months improved by exercise and not relieved by rest Limitation of lumbar spine in sagittal and frontal planes Chest expansion reduction relative to normal values corrected for age and sex (costovertebral ankylosis, 25%) Radiographic criteria of sacroiliitis

Bilateral grade 2-4 OR Unilateral grade 3-4

Ankylosing spondylitis is defined by the presence of either radiographic criterion PLUS any clinical criterion

Diagnostic Standard for AS: Modified NY Classification Criteria (1984)1

Clinical components:

Low back pain and stiffness for more than 3 months which improves with exercise, but is not relieved by rest

Old criteria Limitation of motion of the lumbar spine in both the sagittal Defined before TNF blockers and frontal planes Sacroiliitis detectable by X-ray occurs
lately expansion relative to normal values Limitation of chest for No magnetic resonance imaging (MRI) correlated age and sex

Used for clinical trial Radiological component:

Sacroiliitis Grade >2 bilaterally or Grade 3-4 unilaterally

Definite AS if the radiological criterion is associated with at least one clinical criterion2 Probable AS if three clinical criteria present or radiologic criteria present without clinical criteria2 1
2Rudwaleit

Linden VD et al. Arthritis Rheum 1984;27:361-368 M et al. Arthritis Rheum 2005;52:1000-1008

ASAS Classification Criteria for Axial SpA

In patients with back pain 3 months and age at onset <45 years Sacroiliitis* on imaging plus HLA-B27

OR

plus

1SpA feature**
*Sacroiliitis on imaging:

2 other SpA features**

**SpA features: Inflammatory back pain Arthritis Enthesitis (heel) Uveitis Dactylitis Psoriasis Crohns disease/ulcerative colitis Good response to NSAIDs Family history for SpA HLA-B27 Elevated CRP
Rudwaleit M et al. Ann Rheum Dis 2009;68(6):770-6

Active (acute) inflammation on MRI highly suggestive of sacroiliitis associated with SpA
or

Definite radiographic sacroiliitis according to modified New York criteria

Psoriatic arthritis
Inflammatory polyarthritis associated with psoriasis May occur prior to the onset of skin disease Usually seronegative M=F Prevalence rate 0.1%

Psoriatic arthritis is an enthesitis

DIP joint disease Spinal inflammation Dactylitis-sausage finger

Psoriatic Arthritis
Clinical Variants
Inflammatory DIP disease Asymmetic oligoarthritis with large and small joints Symmetric polyarthritis Arthritis mutilans Spondyloarthropathy

Spondylitis and sacroiliitis

Psoriatic Arthritis
Other Features
Nail pitting Skin disease Pitting edema Inflammatory eye disease

Radiological features of PsA

Lack of juxta-articular osteopenia Pencil-in cup change Ankylosis Periostal reaction Asymmetric sacroiliitis Coarse syndesmophytes

Erosive psoriatic arthritis

Psoriatic Arthritis
Treatment
NSAIDs Little role for systemic steroids, but IA steroids can be very helpful Methotrexate TNF inhibitors

Management of PsA
NSAIDs Methotrexate Sulphasalazine Leflunomide Azathioprine Cyclosporine Anti TNF therapies Intra articular injections of corticosteroids

Methotrexate
Efficacy in PsA 1st demonstrated in 1964. Placebo controlled study of 21 patients with active skin disease and peripheral arthritis observation 3 months. Improvement in skin and joint involvement.

Sulfasalazine
5 controlled studies 221 patients treated with 2 g/day over 36 week course. Improvement in tender and swollen joints. Its actions appears to be confined to peripheral arthritis with no benefit in axial disease Rare reports of cutaneous improvement.

Leflunomide (ARAVA)
A selective pyrimidine synthesis inhibitor that targets activated T cells lacking a salvage pathway. Randomised double blind, placebo controlled study in 188 patients with active PsA and active rash. After 6 months 59% met primary efficacy. Compared with 30% of placebo.

Other options ?
Gold Cyclosporine A Azathioprine and 6-mercaptopurine Antimalarial agents Colchicine

Biological treatment of PsA

Etanercept
SS SS
S S S S S S S S

Infliximab
Mouse (Binding site for TNF) Human (IgG1)

SS

C H3

C H2

Fc region of human IgG1

Extracellular domain of human p75 TNF receptor

Adalimumab

Why target TNF

Increased serum levels of TNF in PsA. Increased levels of TNF in synovial fluid of PsA

TNF I NHI BI TI ON WI TH ENBREL (et an er c ept )

Etanercept: soluble receptor of TNF

ENBREL Inhibits Activation of Cell-Surface Receptors

ENBREL has been designed to complement the bodys natural inhibition of TNF 1
TNF TNF

ENBREL ENBREL

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

Etanercept in PsA A phase III clinical trial

Stratification (N -205 PsA, active dis.) - Etanercept 25 mg twice weekly (n=101) as either Etanercept (n=59) or Etanercept+MTX (n=42) - Placebo (n=104) or either placebo alone (n=61) or Placebo +MTX (n=43)

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

Percentage of patients achieving ACR 20

60 50 40 30 20 10 0 1 3 Months 6 Etanercept Placebo

Gottlieb A. Ann Rheum Dis 2002;61(Suppl1

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

Measure
Phys. Assess. Patient assess.

Placebo n=104
0 0

Etanercept n= 101 50
33.3

P value
<.0001 <.0001

Pain ( VAS)
Morning stiffness

0
25

50
68.3

<.0001
<.0001

CRP
PASI

-6.3
9

74.2
46

<.0001
<.0001

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Infliximab (Remicade)
Chimeric monoclonal antibody 104 , PsA, 5 mg/kg O, 2 weeks, 6 weeks, thereafter every 8 weeks. Week 16: ACR 20 of 65% in infliximabtreated pts vs 10% in controls Impressive improvement in skin lesions

Adalimumab (Humira)
Fully human anti-TNF monoclonal antibody, SC, 40 mg e.o.w 315 patients with PsA At week 12, ACR 20 in 58% of the adalimumab-treated patients vs 14% of the placebo-treated patients . 59% achieved a 75% PASI improvement response at 24 weeks

T cell activators blocking

Alefacept (Amevive)

Fully human fusion protein binds CD2 on memory T cells and blocks interaction with LFA-3 on the antigen presenting cells. Humanised antibody to the CD11 subunit of LFA1

Efalizumab (Raptiva)

PsA Treatment Guidelines

Establish Diagnosis of Psoriatic Arthritis
Peripheral Arthritis Skin & Nail Disease

Axial Disease

Dactylitis

Enthesitis

Education Physiotherapy
Analgesia NSAID (continous) Biologics(anti-TNF) +/- Corticosteroid inj

Reassess Response to Therapy and Toxicity

PsA 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

Respond

Anti TNF

Reactive arthritis
Interesting historical backdrop

In 1916, Hans Reiter reported Reiters syndrome: a triad of nongonococcal urethritis, conjunctivitis, and arthritis that occurred in a young German officer following an episode of bloody dysentery Subseqently, more cases were reported following enteric infections OR venereally acquired genitourinary infections. In 1967, the term reactive arthritis was applied to similar cases following Yersinia gastroenteritis The two terms should be considered synonomous

The term reactive arthritis is increasingly preferred

Reactive arthritis
Pathogenesis

Clinical syndrome triggered by specific etiologic agents in a genetically susceptible host Follows 1-4 weeks after a

Urogenital infection (affects principally men)

Usually C. trachomatis Salmonella Shigella Campylobacter Yersinia

Enteric infection (affects both genddrs equally)

Reactive arthritis
Clinical

Peripheral arthritis

Asymmetric additive oligoarthritis (usually) Synovitis

Warm Edematous Tender Pain with active or passive movement

Usually lower extremity joints (knee, ankle, subtalar)

Conjunctivitis

Reactive arthritis
Clinical

Nongonococcal urethritis

Occurs in postenteric or postvenereal disease

When it occurs in postvenereal disease, C. trachomatis is often the etiology

When present, is usally the first symptom In men

Mild dysuria Mucopurulent urethral discharge May present as prostatitis or epididymitis Dysuria Purulent vaginitis or cervicitis with vaginal discharge

In women

Asymptomatic urethritis often features sterile pyuria

Reactive arthritis
Clinical (continued)

Keratoderma blenorrhagica

A papulosquamous skin rash Comprises vesicles that become hyperkeratotic, forming crusts before disappearing

Palms/soles Penis (causing circinate balanitis

Oral ulcers (ususally shallow and painless) Inflammatory back pain (50% of patients) Enthesitis (40%) Dactylitis (40%) Anterior uveitis (20% of patients)

Reactive arthritis
Keratoderma blenorrhagica

Reactive arthritis
Evaluation

Synovial fluid analysis

Pleocytosis (5 000 to 50 000 WBC/mcL) with polymorphonuclear cell predominance Protein levels Glucose normal

Cf reduced glucose level in true septic arthritis

Gram stain and culture are sterile

Urethral or cervical smears in patients with clinical urethritis

C. trachomatis N. gonorrhoeae

Enteropathic Arthritis
Clinical

Affects 10-20% of patients with inflammatory bowel disease (IBD) Peripheral arthritis affects 10-20% of IBD patients

Generally affects knees, ankles, and feet Always indicates active IBD

Radiographic axial arthritis affects 10% of IBD patients

Frequently asymptomatic Independent of bowel inflammation

Why are these diseases classified together?

Treatment

Physical therapy and exercise Nonsteroidal antiinflammatory agents

Indamethacin

Disease modifying anti-rheumatic drugs (DMARDs)

Methotrexate: inhibits recruitment of CD4 and CD8 T cells

Tumor necrosis factor antagonists

Infliximab: a monoclonal antibody that binds to TNF and inhibits binding of TNF to its receptor Etanercept: similar emchanism to infliximab

Key Actions Attributed to TNFa

75

Etanercept
SS SS
S S S S S S S S

Infliximab
Mouse (Binding site for TNF) Human (IgG1)

SS

C H3

C H2

Fc region of human IgG1

Extracellular domain of human p75 TNF receptor

Adalimumab

TNF I NHI BI TI ON WI TH ENBREL (et an er c ept )

Etanercept: soluble receptor of TNF

ENBREL Inhibits Activation of Cell-Surface Receptors

ENBREL has been designed to complement the bodys natural inhibition of TNF 1
TNF TNF

ENBREL ENBREL

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

Side effects

Good tolerability The most frequent was injection site reaction in37% Infection in 35% and headache 17 %
Post marketing : severe infections including TB and fatalities, demyelinative disorders, lymphoma, rare cases of pancytopenia including aplastic anemia,vasculitis, drug induced lupus

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REMICADE (infliximab) Safety

Hypersensitivity

reactions Sepsis, pneumocystosis, histoplasmosis, and listeriosis have been reported Rare cases of lymphoma, demyelinating diseases and drug induced lupus Increased incidence of TB
80 RA1301a