oligoarthritis in young male 17 yowm 3 mos. of b/l knee swelling and pain pain/swelling began...

Oligoarthritis in Young Male

17 yoWM 3 mos. of B/L knee swelling and pain

Pain/swelling began during hockey workouts. Warmth and

swelling persisted despite rest, mildly improved w/ “coxib”

Also c/o neck and low back pain and “funky nails”

PMHx: ADD, tarsal coalition, Achilles tendinitis

Meds: Adderall, Aleve OTC

Family Hx: mother with psoriasis, father with degenerative

disc disease.

ROS: denies GU, GI, ocular complaints. + hx heel pain

Oligoarthritis in Young Male

Neck: no mass or LN

Chest/CVS; normal

MS: B/L knee effusions;

LOM ankles, + heel pain

Skin: no rash, no psoriasis;

+onycholysis finger nails

LABS: nl CBC, SMA14

ESR 20; CRP: 1.75 mg/dl

HLA-B27 (+)

Diagnosis?

Spondyloarthropathies: Objectives

Understand the unifying features of Spondyloarthropathies

Recognize key presentations for AS, reactive arthritis,

Psoriatic arthritis and enteropathic arthritis

Recognize the importance of HLA-B27 genotype

Describe conventional and new therapies for SpA

Spondyloarthropathies

Seronegative Spondyloarthropathy: a misnomer !! Historically, these disorders were thought to be “variants”

of rheumatoid arthritis, hence the term “seronegative”

SpA definition: A group of inflammatory arthropathies that

share distinctive clinical, radiographic and genetic features.

These diagnoses include: Ankylosing spondylitis Reiter's syndrome (reactive arthritis) Psoriatic arthritis Enteropathic arthritis (Crohns, Ulcerative colitis, Whipples)

Patients not fulfilling criteria for these individually may be

classifed more generally as having a “spondyloarthropathy”

Family of Spondyloarthropathies

AS Undifferentiated

Spondylo-arthropathy

JuvenileSpondylitis

IBD Associated

Arthritis

PsoriaticArthritis

ReactiveArthritis

SAPHOAcute Ant.

Uveitis

Many patients do not fulfill criteria for AS, PsA, Reactive

arthritis (ReA). Criteria needed to Dx undiferentiated SpA.

Spondyloarthropathy: several criteria have been proposed

Key Features: Inflammatory axial arthritis (sacroiliitis and spondylitis) Peripheral arthritis (often asymmetric and oligoarticular) Enthesitis (inflammation at tendinous/ligamentous

insertions) HLA-B27 positivity XRay evidence of erosions + hyperostosis (reactive bone) Extra-axial, Extra-articular Features

Spondyloarthopathies (SpA)

Periarticular: Enthesitis, tendinitis, dactylitis (sausage-digit)

Ocular: Uveitis, Conjunctivitis

Gastrointestinal: Painless oral ulcerations, asymptomatic

gut inflammation,

symptomatic colitis

Genitourinary: urethritis, vaginitis, balanitis

Cardiac: Aortitis, valvular insufficiency, heart block

Cutaneous: keratoderma blennorrhagicum, psoriasis or nail

lesions (onycholysis, dystrophy, pitting).

SpA: Associated Extraarticular Features

Alternate buttock pain

Sacroiliitis

Positive family history

Psoriasis

Inflammatory bowel disease

Urethritis or cervicitis or acute diarrhea occurring within 1

month before the onset of arthritis

SpondyloarthopathiesESSG Criteria*

Inflammatory Spinal Pain

Synovitis(Asymmetrical or

Predominantly lower limbs)

OR

PLUS (One or more of the following:)

* European Spondyloarthropathy Study Group Criteria for Spondyloarthropathy, 1991

Dougados M, et al. Arthritis Rheum. 1991 Oct;34(10):1218-1227. Sensitivity 78-88%; Specificity 92-95%

HLA-B27

Class I MHC, important in antigen presenation CD8 T cells

Associated with the spondyloarthropathies: Ankylosing spondylitis, Reiter's syndrome, Psoriatic arthritis, and enteropathic arthritis.

HLA-B27 is a normal gene found in 8% of Caucasians 3-4% of African-Americans, 1% of Orientals.

But not in American Orientals or Koreans

Actual risk of developing AS in ANY HLA-B27(+) person is only 1-2%.

Over 95% of patients with ankylosing spondylitis are B27+

there is 20-30% risk to 1st degree relatives of AS patients

SpA Prevalence by Geographic Region

SpA HLA-B27

Japan (total population) 0.0095% <1.0%

Thailand 0.12% Not available

United States (caucasians) 1-2% 8%

Germany (adults) 1.9% 9.3%

Russia and Alaska 2.0% to 3.4% Not available

Eskimo (adults) 2.5% >20.0%

Hukuda S, et al. Hukuda S, et al. J Rheumatol.J Rheumatol. 2001;28:554-559. 2001;28:554-559.Khan MA. Khan MA. Curr Opin Rheumatol.Curr Opin Rheumatol. 1995;7:263-269. 1995;7:263-269.Khan MA. Khan MA. Ann Intern Med.Ann Intern Med. 2002;136:896-907. 2002;136:896-907.

Spontaneous inflammatory disease in transgenic rats expressing HLA‑B27 and human b2m:An animal model of HLA‑B27‑associated human disorders. Hammer RE, Tauog JD, et al. Cell 63:1099, 1990.

• Lewis rats transfected with human HLA-B27 & B2microglobulin

• Developed diarrhea, colitis, peripheral arthritis, spondylitis, orchitis, nail dz

• B27 manifestations not seen in a sterile environment

Clinical Associations with HLA-B27

Khan MA. Ann Int Med 2002Disorder HLA-B27 (%)

Ankylosing Spondylitis > 90%

Reiter’s syndrome 80%

Juvenile Spondyloarthritis 70%

Inflammatory bowel dz 50%

Psoriatic arthritis With Spondylitis With Peripheral arthritis

50% 15%

Acute Anterior Uveitis 50%

Aortic insuff. w/ heart block 80%

SAPHO 20-30%

Seronegative Spondyloarthropathies - HLA-B27

HLA-B27 may influence disease expression

B27-positive individuals are more likely to have an earlier onset, sacroiliitis, spondylitis, acute anterior uveitis, and a more severe clinical course.

B27-negative patients are more likely to develop peripheral arthropathritis, skin and nail disease, or inflammatory bowel disease.

Thus = Increased risk of spondylitis and uveitis.

HLA-B27 Diagnostic Testing not necessary to diagnose most patients with spondyloarthropathy

(eg Reitier’s, AS). may be useful in diagnosing patients with an incomplete or

undifferentiated spondyloarthropathy. not useful as a screening test for arthritis.

Factors other than HLA-B27

Male dominance: sex hormone dependant?

Age: disease onset in young adults

Monozygotic HLA-B27 (+) twins show Dz penetrance <50%

Navajo and Eskimo Indians have high frequency of HLA-

B27(+) and also ankylosing spondylitis and Reactive arthritis

Haida and Pima Indians have high frequency of HLA-B27(+)

and ankylosing spondylitis, BUT NOT reactive arthritis

Other genes?

Ankylosing Spondylitis in USA

P C P R x1 2 5 ,0 0 0

R h eu m R x1 2 5 ,0 0 0

U n D x - U n R x1 0 0 ,0 0 0

A S3 5 0 ,0 0 0

M ild D z1 7 3 ,0 0 0

M od era te D z3 7 ,0 0 0

S evere D z2 2 ,0 0 0

F u sed1 8 ,0 0 0

Modified New York Criteria for AS

Clinical criteria

Low back pain and stiffness for >3 mo, which improves

with exercise, but is not relieved by rest

Limited lumbar spine motion: in sagittal and frontal planes

Limitations of chest expansion (age/sex standardized)

Radiographic criteria: Requires EITHER Bilateral

sacroiliitis Grade 2 or Unilateral sacroiliitis Gr 3

Definite AS = 1 clinical plus 1 radiographic criteria

Probable AS = 3 clinical criteria and no radiologic criteria or

1 radiologic criterion and no clinical criteria

van der Linden S, et al. van der Linden S, et al. Arthritis Rheum.Arthritis Rheum. 1984;27:361-368. 1984;27:361-368.

ANKYLOSING SPONDYLITIS

Inflammatory arthritis affects the axial spine: starts in SI & ascends upwards to Cervical Spine

HLA-B27+ > 90% Whites. AS occurs in 1-2% of HLA-B27+ persons (20% risk to 1st degree relatives of AS patients)

More common in Caucasians than African-Americans

Male Predominant disease 5:1 to 10:1 Females:less severe or have asymptomatic Sacroliliitis

Insidious disease onset between 16-30 yrs. Rare after 45 yrs. (Juvenile spondylitis: males >9yrs old)

Triad: Inflammatory back pain, immobility, AM Stiffness

AS: Inflammatory Back Pain

Onset

Before Age 30 yrs.

Insidious onset

AM Stiffness > 60 minutes

Chronicity : Sxs > 3 mos.

Decreases with exercise/activity

Ankylosing SpondylitisDifferentiating Inflammatory vs Mechanical Back Pain

Inflammatory Back Pain Features Mechanical Back Pain

Prolonged > 60min. AM Stiffness Minor < 45 min.

Early AM Max. Pain/Stiffness Late in day

Improves Symptoms Exercise/activity Worsens Symptoms

Chronic Duration Acute or Chronic

9-40 yrs. Age at Onset 20-65 yrs.

Sacroiliitis, Vertebral

ankylosis,

syndesmophytes

Radiographs Osteophytes,

malalignment

Diagnosis is usually delayed 5-7 years.

Mean 7.5 years from onset of LBP to XRay sacroiliitis

Incidental diagnosis often made on XRAYs (pelvis, LS or

thoracic spine, CXR). Will AP radiographs suffice?

Dx made earlier with MRI

Diagnosis suggested by extraspinal manifestations:

enthesitis, uveitis (30-40%), peripheral oligoarthritis

Rarely Late diagnosis with Complications: Spinal fusion,

fracture, cauda equina syndrome, restrictive lung disease,

aortic insufficiency

DX of ANKYLOSING SPONDYLITIS

Spectrum of ASEarlyLBPStiffnessFatigue

Spinal LimitationFunctional limitsNight Pain

SpinalImmobility

Symptoms

Extra-articular Manifestations

OcularSkin/nailEnthesitis

Chronic UveitisIBD

AortitisRestrictive lung Heart block

Severe

Morbidity Mortality

PainFunctional limitation

AS complicationsDrug toxicityComorbidities

FractureDeath

Disease Progression

SacroiliitisHip DzSpondylitisPeripheral Dz

Cervical DzBamboo Spine

ModerateOnset

Ankylosing Spondylitis: X-rays

Sacroiliitis: Scoring System

Grade 0 : Normal

Grade 1: Suspicious changes

Grade 2: Minimal Change. Localized

erosions or sclerosis not altering joint

width

Grade 3: Definite moderate to severe

change, with one or more of the

following: Erosions; Sclerosis; Joint Space

Widening; Joint Space Narrowing;

Partial ankylosis

Grade 4: Severe. Total Ankylosis

SpA Characteristic XRAY

change

Erosions

Osteitis (Sclerosis)

Bridging Syndesmophytes

Ankylosis of joints

Sacroiliitis grade 3 –4 Sacroiliitis grade 3 –4 bilaterallybilaterally

Sacroiliitis grade II Sacroiliitis grade II bilat.bilat.

SclerosisSclerosisErosionsErosions

Enthesopathy

Periosteal

new bone

formation

Bone

McGonagle D. McGonagle D. Arthritis Rheum.Arthritis Rheum. 1999;42:1080-1086. 1999;42:1080-1086.

Subchondral

bone

inflammation

and

resorption

Tendon

©ACR©ACR

Inflammatory Rheumatoid arthritis Ankylosing spondylitis Reiter's syndrome Psoriatic arthritis Inflammatory bowel disease Lyme disease Late‑onset Pauciarticular JRA LeprosyMechanical/Degenerative Trauma OsteoarthritisMetabolic/Endocrine DISH Acromegaly Fluorosis Retinoid therapy Hypoparathyroidism Hyperparathyroidism POEMS syndrome X‑linked hypophosphatemia

Severe Complications of AS

Spinal stiffness/ankylosis in kyphotic position

Osteoporosis/spinal fractures

Severe uveitis (25-40%)

Neurologic complications

Other organ involvement

heart

lung

kidney

Mortality

Fractures in Ankylosing Spondylitis

Cumulative prevalence 10-20% in AS Mainly thoracic spine involved Peripheral bony fractures not increased Contributing factors:

Inflammation, low bone density, reduced mobility Reported fracture prevalence in AS patients:

mean age prevalence34 yr: 9.5% vs. 3.4% (Cooper 1994)38 yr: 16.7% vs. 2.6% (Mitra 2000)41 yr: 18% (Ralston 1990)

Relative risk for vertebral fractures 6-8 fold increased

Myocardial Involvement in AS: Diastolic Left Ventricular Function Disturbances

Brewerton, Lancet 1987 73 male AS patients without cardiopulmonary symptoms 16/30 (53%) diastolic function disturbancy (TTE) 28 autopsies: minor increase of interstitial myocardial

connective tissue no inflammation, no amyloidosis

Crowley, Crowley, Am J CardiolAm J Cardiol 1993 1993 59 AS patients, without cardiopulmonary symptoms TTE: 20% diastolic LV dysfunction

; ;

Ankylosing Spondylitis - Mortality 1.5 – 4 fold increased

amyloidosis

spinal fractures

cardiovascular disease

gastrointestinal bleeding

nephritis

pulmonary diseases

colon cancer

violence, alcohol

Myllykangas-Luosujarvi R et al. Myllykangas-Luosujarvi R et al. Br J RheumatolBr J Rheumatol 1998; 37:688 1998; 37:688 (N = 71)(N = 71)Lehtinen K. Lehtinen K. Ann Rheum DisAnn Rheum Dis 1993; 52:174 1993; 52:174 (N = 398)(N = 398)Khan MA et al. Khan MA et al. J RheumatolJ Rheumatol 1981; 8:86 1981; 8:86 (N = 56)(N = 56)Radford EP et al. Radford EP et al. NEJMNEJM 1977; 15:297 1977; 15:297 (N = 836)(N = 836)

Mortality and Causes of Death in

AS Patients Admitted to Hospital 398 patients (47 women, 351 males) with definite AS

Mean age at first admission 36.5 years

After a mean follow up of 25.7 years 152 patients (12 women, 140 males) had died

The expected mortality of the general population of the same sex and age was 103 (9 w, 94 m)

The overall mortality of AS patients: 1.5 times that expected

Risk factors: age, high ESR, peripheral joint involvement

Lehtinen K. Lehtinen K. Ann Rheum DisAnn Rheum Dis 1993 Mar; 52(3):174-6 1993 Mar; 52(3):174-6

Rheumatology: a Pain in the Butt!

17 yr. old Latin girl with a 4 month hx of Left “Hip Pain”.

Pain is L posterior gluteal, nonradiating.

Hurts to walk. Not improved by exercise. No other joint

pain or swelling

C/O fevers + chills, malaise, NO AM Stiffness

Denies sexual activity, IVDA, EtOH, and foreign travel.

She has never been to Mexico, but likes the Chalupas!

Exam: T=38oC, mild hepatomegaly, 3+ tender over the

Left SI joint - No warmth or erythema

WBC = 3.8 (L shift); Hct = 41%; ESR = 87 mm/hr

Left SI “blurred” on XRAY. Bone scan positive @ L SI

Rheumatic Pain in the Butt

Causes of Sacroiliitis (Unilateral)

SpA, Reiters, Psoriatic arthritis, AS, IBD

Septic - Staph Aureus in IVDA

Septic - Pneumococcus, Klebsiella, Proteus,

Pseudomonas, Brucella, mycobacterial, fungal

Increased SI Sclerosis

Hyperparathyroidism

DJD

Osteitis Condensans Ilii - radiographic s of ilieal

sclerosis common during/after pregnancy (No Sxs)

Diagnostic test/procedure?

Brucella Sacroiliits

Source: Goat (B. Mellitensis), Cow (B. Abortus), Hogs (B.

Suis) and Dog (B. canis)

Human infx thru skin or ingestion of animal tissue or milk.

At Risk: Slaughterhouse, Veterinarians, those who ingest

unpasteurized milk or cheese (ie from Mexico)

Features: Constitutional, arthralgias, myalgias,

HepatoSplenomegaly, peripheral arthritits, sacroiliitis, and

spondylitis

Dx: culture or serologic tests

Rx: tetracycline (+ rifampin) > 4 weeks

REACTIVE ARTHRITIS Acute inflammatory arthritis occuring 1-3 weeks after

infectious event (GU, GI, idiopathic)

TRIAD: arthritis + urethritis (vaginitis) + conjunctivitis (classic triad found in < one-third of pts)

Usually asymmetric oligoarticular + extraarticular Sxs Arthritis recurrent in 15-30%, more in chlamydial arthritis pts.

HLA-B27+ in 75-80% Caucasians

Post-venereal onset: more common Sex 5:1 M:F

Post-dysenteric: less, equal M=F

Course: self limiting (< 6 mos), chronic, intermittent

Complications: Acute anterior uveitis 5%, carditis, fasciitis

Decreasing incidence in the HIV era (condom use)

COMMON PATHOGENS

Enteric Infections

Shigella flexneri, serotype 2a, 1b

Salmonella typhimurium, S. enteritidis

Yersinia enterocololitica (serotypes 0:3, 0:8, 0:9;

SCANDINAVIA)

Campylobacter jejuni

Urogenital Infections

Chlamydia trachomatis, C.Pneumoniae

Ureaplasma Urealyticum

Infectious Triggers for Reactive Arthritis

Bacterial: S. paratyphi, S heidelberg, S. abony, S. blocley, S. schwarzengrund, S. haifa, S. manila, S. newport, S. bovismorbificans Y. pseudotuberculosis (outside of Scandinavia) C. fetus Vibrio parahemolyticus C. psittaci Streptococcal (Group A,G G) Clostridium difficile Propionibacterium Corynebacterium Acne Staphylococcus aureus (Toxic shock arthritis)

Spirochetal: Borrelia burgdorferi

Mycobacterium tuberculosis and avium intracellulare (Poncet's disease)

Parasitic: Giardia lamblia, Strongyloides stercoralis , Cryptosporidium, Ascaris lumbricoides, Taenia saginata, Filaria

Immunotherapy/Immunization Related Bacillus Calmette-Guerin : intravesical injection Hepatitis A vaccine

UNCOMMON Infectious Triggers

Chlamydial Arthritis

More than 50% of Reiter’s patients have Abs to Chlamydia

Chlamydial Ags by RNA or DNA probes found in joints

May account for up to 10% of all EARLY Arthritis patients

C. Trachomatis > C. psittaci or C. Pneumoniae (erythema nodosum, pneumonia, myocarditis)

Manifestations similar to Reiters, < 50% B27+; and ~15% have no urogenital sxs.

Dx: Sxs + serology or PCR probe

Rx: doxycycline or lymecycline > 3 mos. to eradicate infx and decrease sequellae

Post-Dysenteric Outbreaks of Reiters Epidemics of known arthritogenic bacteria

< 20% of HLA-B27(+) persons develop incomplete Reiters

Fewer develop Complete Reiters syndrome

Pts w arthritis more likely to be HLA-B27 negative in some

studies

Shigellosis: 0.2-2% of patients develop reactive arthritis

often diarrhea resolves before arthritis appears

Salmonella: 1-3% develop reactive arthritis (6-12% seen?)

Like Shigella, arthritis more likely in HLA-B27 or HLA-B7 (+)

Other cross reactive Ags: Bw22, B40, B42, or B60

HIV and Reactive Arthritis

1st described 1987, after immunosuppression HIV AIDS

B27+ HIV+ patients may manifest a severe form of: Reactive arthritis; Psoriatic arthritis; Spondyloarthropathy

Common: asymmetric poly- or oligoarthritis, lower extremitiy arthritis,

dactylitis, enthesitis, fasciitis, conjunctivitis, urethritis

Anti-Viral Therapy as resulted in these being less common in

the USA and more common in sub-Saharan Africa

DOES NOT OCCUR anklylosing spondylitis OR uveitis

Epidemiologic studies DID NOT show increased incidence of

Reiters in HIV+ populations

Notes on Rx: poor NSAID response; progression of AIDS w/

immunosuppressive Rx

GU involvement• Urethritis• Prostatitis• Orchitis• Balanitis• Vaginitis• Cervicitis

Sausage Digits= periostitis + enthesitis + synovitis. Seen in SpA, JRA, MCTD

GC arthritis vs Reiter’s Syndrome

GC Arthritis Reiter’s

Sex F > M M >>>F

Race B>W>L W>B>L

Duration Days Days-Mos

Sore throat 25% 15%

Eye 1% 60%

Genital lesions <5% 33%

Jt. Distribution Mono/Oligo Oligo/Poly

Tenosynovitis 50% 20%

Syn fluid WBC >40K ~20K

+ C/S <20% 0

Psoriasis 2-3 million in USA

Psoriatic Arthritis400,000

PsA Dx320,000

PsA Rx288,000

PSORIATIC ARTHRITIS (PsA)

Chronic inflammatory arthropathy in setting of psoriasis

Etiology and genotype unclear

1-5% of US population has Psoriasis: 5-42% of these will

develop psoriatic arthritis (skin usually precedes joints) Frequency of PsA increases with disease severity and duration

Nail changes: pitting, dystrophy, onycholysis

Course: chronic, destructive arthritis in 30-50%

Classification of Psoriatic Arthritis

Type Key Clinical Features Incidence

Asymmetric polyarthritis

or oligoarthritis

Morning stiffness, DIP and PIP

involvement, nail disease, 4 joints

involved

40%

Symmetric polyarthritisSymmetric polyarthritis, RA-like

distribution, but RF negative25%

Ankylosing spondylitisInflammatory low back pain, sacroilitis,

axial involvement, 50% HLA-B27+20%

Distal interphalangeal

joint disease

Nail changes, often bilateral joint

involvement15%

Arthritis mutilans

Destructive form of arthritis,

telescoping digits, joint lysis, typically

in phalanges and metacarpals

<5%

SAPHO Syndrome Synovitis, Acne, Pustolosis, Hyperostosis, Osteitis

(Pustular Skin Disease + Osteitis or Arthritis

Rare form of reactive

Most reports from Japan > Scandinavia > France > USA

Arthritis of Amphiarthroses (Saddle joints): AC, SC, Manubriosternal

Imaging: erosions, osteitis, ~30% sacroiliitis, +Bone Scan

Therapy: Rx of pustular skin dz +/- response to Abx, NSAIDs, Steroids, SSZ, colchicine,

pamidronate Good response to TNF inhibitors

ENTEROPATHIC ARTHRITIS 5-20% of IBD patients (Crohns disease or Ulcerative colitis) will

develop inflammatory arthritis

Risk increases with extent of colonic dz and presence of

other extraintestinal manifestations: abscesses, E. Nodosum,

uveitis, pyoderma gangrenosum

Gut disease may be asymptomatic for years Subsets:

Asymmetric oligoarthritis (intermittent or chronic)

Seronegative RA-like polyarthritis 20% of IBD pts

Spondylitis 10-15% (may be misdiagnosed as AS)

Peripheral arthritis parallels the gut! NOT THE SPINE!

Uveitis: Definitions

Anterior Uveitis defined as the presence of anterior chamber inflammatory flare or cells associated with keratic precipitates and/or iris lesions, such as synechiae

Intermediate uveitis defined as the presence of cells in the vitreous with/without the presence of inflammatory cell condensations (snowballs) in the anterior vitreous or the peripheral retina.

Posterior uveitis was defined as the presence of inflammatory signs involving the retina, choroid, retinal vessels, and/or posterior vitreous humor.

Panuveitis was defined as a combination of inflammation involving the 3 previously described sites.

UVEITIS: CLINICAL ASSOCIATIONS

20-40% associated with systemic Dz

Anterior Uveitis:Eye pain, photphobia,

↓vision, unilateral > B/L, acute > chronic,

may be recurrent, No correlation with

articular disease Iritis, iridocyclitis, uveitis

Iriis, Ciliary Body

HLA-B27 SpA (AS, RS)

(less common in B27-)

25-40% of AS pts

JRA, Sarcoid, Behcets

Infx: herpes, Tbc Khan MA. Khan MA. AR.AR.;20: 909, 1977;20: 909, 1977Maksymowych WP. Maksymowych WP. ARD ARD 54:128, 199554:128, 1995

Nonpharmacologic measures Patient education, joint protection, maintenance of function and

posture (Ankylosing Spondylitis Association, Arthritis Foundation)

Exercise, rest, physical therapy, diet, vocational counseling

Pharmacologic therapies Analgesic agents

Use to control noninflammatory symptoms or “burnt out”

spondyloarthropathy

Maybe useful as adjunctive therapy during active inflammatory Dz

NSAIDs - Mainstays for Sx therapy; Does not change course of SpA

Corticosteroids - rarely used; rarely effective (occ intralesional use)

DMARD: SSZ, MTX only effective with peripheral arthritis – not spine

anti-TNF therapies: highly effective with inflammatory spondylitis

SpA: Therapeutic Options

May be useful in the control of: inflammatory back pain,

spinal stiffness, peripheral arthritis, enthesopathy No evidence that NSAIDs inhibit disease progression

FDA-approved NSAIDs for AS: phenylbutazone

Indomethacin, indomethacin-SR, enteric coated

acetylsalicylic acid, naproxen, sulindac, diclofenac.

Few controlled and antecdotal reports suggest that certain

NSAIDs may be more effective:

phenylbutazone: no longer available due to risk of

agranulocytosis

indomethacin: especially in long acting form. CNS Sx?

diclofenac: as effective as Indocin, less toxic? LFTs!

NSAIDs

Systemic corticosteroids are seldom used in the

Spondyloarthropathies.

No evidence to support the use of systemic low dose

OR high (“pulse”) dose therapy

Most useful as local therapy:

ophthalmic preparations: for ocular inflammation

intralesional injections: for enthesitis or tendinitis

intra-articular injection: for uncontrolled monarthritis

intra-articular injection of sacroiliac joint: uncontrolled

trials suggest efficacy

Spondyloarthropathies: Corticosteroids

Consider DMARDs when: Antiinflammatory therapy is insufficient

Progressive inflammatory axial disease

Active persisent polyarthritis

Uncontrolled extra-spinal/articular disease

But Which DMARD? None shown to be effective at Axial disease

None FDA approved for AS, SpA

MTX indicated in psoriasis – not psoriatic arthritis– Hepatotoxicity Issues

Reliance on antecdotes and experience in RA

NSAID Resistant AS/SpA

Gold - no proven benefit! Intramuscular (aurothioglucose, aurothiomalate)

Dosing similar to that used in rheumatoid arthritis

Primarily studied in psoriatic arthritis

Hydroxychloroquine Controlled and uncontrolled trials in psoriatic arthritis, suggesting

some efficacy.

Dermatology literature suggests it may exacerbate Psoriasis?

Dose: 200-400 mg per day

Azathioprine Uncontrolled and controlled trials in Reiters and psoriatic arthritis

Dose: 1-2.5 mg/kg/day

Ineffective DMARDs

Methotrexate

Controlled & uncontrolled trials in psoriatic arthritis and AS

Dose: 7.5 - 20 mg per week

AS: of no proven benefit

Psoriatic Arthritis: effective against skin and joint disease

High incidence of hepatotoxicity

Guidelines require regular LFTs, avoid EtOH, Liver Bx q 1500 mg

Sulfasalazine

Well studied in AS, PsA, Reiters

Effective against peripheral arthritis, NOT with axial disease

May work via Tx of asymptomatic ileitis often present

Dose: 2000-4000 mg qd

DMARDs

Rationale for TNF Therapy in Spondyloarthropathies

SpA Primary Pathology = Enthesitis McGonagle D, etal. Curr Opin Rheum 11:244, 1999

Transgenic mice overexpressing TNF develop enthesitis and arthritis resembling AS w/ axial skeletal kyphosis & ankylosis with inflammatory & fibrotic change @ end plates, entheses Crew MD, et al. J Interferon Cytokine Res. 18:219, 1998

Localization of TNF in Sacroiliac joints Stone M, et al. Arthritis Rheum 2000 [abstract]

Osteoclasts and Synoviocytes in PsA express RANKL- Ritchlin C, et al. ACR 2001

Therapeutic benefit of TNF inhibition in AS & PsA

Study Scheme Etanercept in AS, Etanercept in AS, Phase 3 DataPhase 3 Data

Screening Randomization284 Patients

Placebo139 Patients

Etanercept138 Patients

24 Wks

330 Patients

Primary ASAS 20 response criteria at 12 wks

Conditional

primary

ASAS 20 response criteria at 24 wks

Secondary ASAS 50, ASAS 70 response criteria at 12 and 24

wks; percent and time to reach ASAS partial

remission; safety data

Other Spinal mobility measures; peripheral joint count;

ESR; CRP

Endpoints Etanercept in AS, Phase 3 DataEtanercept in AS, Phase 3 Data

ASAS = Ankylosing Spondylitis Assessment Study Group response criteria.ASAS = Ankylosing Spondylitis Assessment Study Group response criteria.

Partial Remission Defined in Protocol Etanercept in AS, Phase 3 Etanercept in AS, Phase 3 DataData

Value of <20 in each of the following 4 domains:

Patient global assessment by VAS

Pain score by VAS

BASFI

BASDAI (two morning stiffness-related scores)

Data on file, Amgen, Thousand Oaks, Calif. Data on file, Amgen, Thousand Oaks, Calif.

Inclusion and Exclusion Criteria

Inclusion criteria Meet modified NY criteria for AS Have active disease as determined by stiffness,

global, pain scores, functional indexExclusion criteria Total spinal ankylosis Prior treatment with TNF inhibitorAllowances Stable doses of NSAIDs, prednisone 10 mg/day,

SSZ, HCQ, MTX

Placebo

(n=139)

Etanercept

(n=138)

Mean age (yrs) 41.9 42.1

Male (%) 76 76

Caucasian (%) 91 94

Mean disease

duration (yrs)

10.5 10.1

HLA-B27+ (%) 84 84

Demographics Etanercept in AS, Etanercept in AS, Phase 3 DataPhase 3 Data

Data on file, Amgen, Thousand Oaks, Calif. Data on file, Amgen, Thousand Oaks, Calif. Manuscript in preparationManuscript in preparation..

ASAS 20 Response at Weeks 12 and 24 Etanercept in AS, Phase 3 Etanercept in AS, Phase 3 DataData

27272323

6060 5858

00

1010

2020

3030

4040

5050

6060

7070

Week 12Week 12 Week 24Week 24

PLBPLB EtanerceptEtanercept

% of Patients% of Patients

**PP<0.0001<0.0001

** *



ASAS 20 Rapid Response Etanercept in AS, Phase 3 DataEtanercept in AS, Phase 3 Data

WeeksWeeks

00

1010

2020

3030

4040

5050

6060

7070

00 44 88 1212 1616 2020 2424

PlaceboPlacebo

EtanerceptEtanercept

* ** * *

% of Patients% of Patients

**PP<0.0001<0.0001


ASAS 50 and ASAS 70 Responses Etanercept in AS, Phase 3 DataEtanercept in AS, Phase 3 Data

00

1010

2020

3030

4040

5050

ASAS 50ASAS 50

1212 2424

PlaceboPlacebo

EtanerceptEtanercept* *

* *

**PP<0.0001<0.0001

ASAS 70ASAS 70

1212 2424

% % PatientsPatients

WeekWeek WeekWeek

1313

45454242

101077

2929 2828

55


00

55

1010

1515

2020

2525

00 44 88 1212 1616 2020 2424

PlaceboPlacebo

EtanerceptEtanercept

**PP<0.01; **<0.01; **PP<0.001<0.001 WeeksWeeks

% Patients

*

** ***

**

Partial RemissionEtanercept in AS, Phase 3 DataEtanercept in AS, Phase 3 Data


00

55

1010

1515

2020

2525

3030


16.716.7

0000

55

1010

1515

2020

2525

3030


9.79.7

0000

55

1010

1515

2020

2525

3030


2525

00

Spinal Mobility Measures at 24 WeeksMedian Percent Improvement From Baseline

Occiput-to-WallOcciput-to-WallMeasurementMeasurement

Modified Schober’sModified Schober’sChest ExpansionChest Expansion

**PP values values by van Elteren’s test, which is a non-parametric rank test based on distribution of by van Elteren’s test, which is a non-parametric rank test based on distribution of values and not on mean or medianvalues and not on mean or median. .

Data on file, Amgen, Thousand Oaks, Calif. Data on file, Amgen, Thousand Oaks, Calif. Manuscript inManuscript in preparation.preparation.

**

**

**

*P*P<0.0001<0.0001 *P*P<0.0001<0.0001*P*P=0.0014=0.0014

Etanercept in AS, Phase 3 DataEtanercept in AS, Phase 3 Data

Acute Phase ReactantsChange From Baseline

00 00

-5.4

0

60 6069 73

-20-20

00

2020

4040

6060

8080

PlaceboPlacebo

EtanerceptEtanercept** **

** **

**PP<0.0001<0.0001

Mean % ImprovementMean % Improvement

Week 12Week 12

ESR CRP

Week 24Week 24 Week 12Week 12 Week 24Week 24

Data on file, Amgen, Thousand Oaks, Calif. Data on file, Amgen, Thousand Oaks, Calif. Manuscript inManuscript in preparation.preparation.

Etanercept in AS, Phase 3 DataEtanercept in AS, Phase 3 Data

Adverse Events With Frequency 5%Etanercept in AS, Phase 3 DataEtanercept in AS, Phase 3 Data

Placebo (%)

(n=139)

Etanercept (%)

(n=138)

ISR 9 30

Hematoma/bruising injection

site

17 21

URI 12 20

Headache 12 14

Accidental injury 4 12

Diarrhea 9 8

Rash 7 8

Rhinitis 7 6

Nausea 5 5

Abdominal pain 5 5Data on file, Amgen, Thousand Oaks, Calif. Data on file, Amgen, Thousand Oaks, Calif. Manuscript in preparationManuscript in preparation..

Placebo (n=5) Etanercept (n=9)

2 injury accidents 3 fractures

1 viral infection 1 fever/rash

1 chest pain 1 cellulitis

1 suicide attempt 1 ulcerative colitis

1 lymphadenopathy

1 wound infection (cat

bite)

1 intestinal obstruction

Serious Adverse EventsEtanercept in AS, Phase 3 DataEtanercept in AS, Phase 3 Data


Infliximab in AS Study design:Study design: Randomized, double-blind, placebo-Randomized, double-blind, placebo-

controlled, national multicenter studycontrolled, national multicenter studywith open follow-up phase with open follow-up phase

Number of patients:Number of patients: N=70N=70

Duration of treatment:Duration of treatment: 1 year1 year

Study protocol:Study protocol: 3 months: 35 patients placebo/ 3 months: 35 patients placebo/ 35 patients infliximab35 patients infliximab

9 months: 66 patients open infliximab9 months: 66 patients open infliximab

Medication:Medication: 5 mg/kg infliximab 5 mg/kg infliximab

at week 0, 2, 6 at week 0, 2, 6 every 6 weeks every 6 weeks

Braun J, et al. Braun J, et al. Lancet.Lancet. 2002; 2002;359:1187-1193359:1187-1193..Brandt J, et al. Brandt J, et al. Ann Rheum Dis.Ann Rheum Dis. 2002;61(suppl 1). Abstract SAT0138. 2002;61(suppl 1). Abstract SAT0138.

0

20

40

60

80

0 2 4 6 8 10 12

Weeks

Pati

ents

Resp

on

din

g (

%)

Placebo

Infliximab

Braun J, et al. Braun J, et al. Lancet.Lancet. 2002; 2002;359:1187-1193359:1187-1193..

** *

*P<0.01

Infusions at 0, 2, and 6 weeks

Infliximab in AS BASDAI 20

Infliximab in AS

Patients With BASDAI 50 Over 48 Weeks

Braun J, et al. Braun J, et al. Lancet.Lancet. 2002; 2002;359:1187-1193359:1187-1193..Brandt J, et al. Brandt J, et al. Ann Rheum Dis.Ann Rheum Dis. 2002;61(suppl 1). Abstract SAT0138. 2002;61(suppl 1). Abstract SAT0138.

Weeks

Infliximab 5 mg/kg (0, 2, 6 weeks and every 6 weeks)Placebo/Infliximab (5 mg/kg) at week 12

0

20

40

60

80

0 2 6 12 18 24 30 36 42 48

Pat

ien

ts R

esp

on

din

g %

Open-label phase

Double-blind phase

0

10

20

30

40

50

0 2 4 6 8 10 12

Weeks

Pat

ien

ts i

n P

arti

al R

emis

sio

n

(%)

Placebo

Infliximab*

*P =0.005

Infliximab in AS

Patients With Partial Remission

Braun J, et al. Braun J, et al. Lancet.Lancet. 2002; 2002;359:1187-1193359:1187-1193..

Infusions at 0, 2, and 6 weeks

Study ParametersStudy design • 6 mo duration

• Multicentered •

Randomized •

Double-blind, PLB-controlled

Dosage • Etanercept 25 mg, 2x/wk or PLB

Inclusion criteria

Exclusion criteria

Allowances

Etanercept in Psoriatic Arthritis, Phase 3 Study, Radiographic DataEtanercept in Psoriatic Arthritis, Phase 3 Study, Radiographic Data

Active psoriatic arthritis with 3 swollen and tender joints

Psoriasis

Prednisone 10 mg/day MTX 25 mg/week

Mease PJ, et al. Mease PJ, et al. Arthritis Rheum.Arthritis Rheum. 2001;44(suppl):S90. Abstract 226. 2001;44(suppl):S90. Abstract 226.

Significant concurrent medical disease

Study ParametersEtanercept in Psoriatic Arthritis, Phase 3 Study, Etanercept in Psoriatic Arthritis, Phase 3 Study, Radiographic DataRadiographic Data

Demographics • PLB n=104, etanercept n=101 • M

> F •

Mean duration disease 6.4–7.1 yrs

• Mean prior DMARDs 1.6–1.7

Primary

Endpoints

• ACR20 at 3 mo

Secondary

Endpoints

ACR20 at 24 weeks ACR50 and 70 at 12 and 24 weeks Psoriatic Arthritis Response Criteria (PsARC) at 12

and 24 weeks Percent improvement in individual parameter of

disease activity at 12 and 24 weeks

24 Weeks24 Weeks Placebo Placebo Etanercept Etanercept

n=104n=104 n=101n=101

12 Weeks*12 Weeks* Placebo Placebo Etanercept Etanercept

n=104n=104 n=101n=101

Patient Status

Completed (%) 95 99 6992

Discontinued (%)Lack of efficacy 2 0 225Other 3 1 93

*Primary endpoint*Primary endpoint

Data on file, Amgen, Thousand Oaks, Calif.Data on file, Amgen, Thousand Oaks, Calif.

ACR Response at 12 Weeks

**PP0.0010.001ACR 20ACR 20 ACR 50ACR 50 ACR 70ACR 70

44 00

38 *38 *

11 *11 *15

59 *

00

2020

4040

6060

8080


PlaceboPlaceboEtanerceptEtanerceptPrimary

Endpoint

100100Etanercept in Psoriatic Arthritis, Phase 3 Study, Radiographic DataEtanercept in Psoriatic Arthritis, Phase 3 Study, Radiographic Data


ACR Response at 24 Weeks

ACR20 ACR20 ACR50ACR50 ACR70ACR70

11441313

50 50 **

37 37 **

9 9 ****

00

2020

4040

6060

8080


**PP0.0010.001****PP0.0090.009

100100Etanercept in Psoriatic Arthritis, Phase 3 Study, Radiographic DataEtanercept in Psoriatic Arthritis, Phase 3 Study, Radiographic Data

PlaceboPlaceboEtanerceptEtanercept


ACR 20 Response at 12 Weeks by MTX Use

EtanerceptEtanerceptPLBPLB EtanerceptEtanercept PLBPLB

With MTXWith MTX

1919

6262**

1313

5858**

00

2020

4040

6060

8080

Without MTXWithout MTX

**PP0.0010.001

100100




Improvement in PASI Score at 6 Months

Median percent improvement in PASI

score 0 47 <0.0001

Percent of patients who improved PASI by:

50% 18 47 <0.0005

75% 3 23 0.0013

PlaceboPlacebon=62n=62

EtanerceptEtanerceptn=66n=66ParameterParameter

PP value value



Psoriatic Arthritis: Improved Skin Lesions

12 Weeks12 WeeksBaselineBaseline

Elbow of patient 577; 50% improvement in target lesion.Elbow of patient 577; 50% improvement in target lesion.

Etanercept Phase III Adverse Events in 5% of Patients

PlaceboPlacebo EnbrelEnbreln=104n=104 n=101n=101

Event Event (%)(%) (%)(%)

Any non-infectious eventAny non-infectious event 6666 6464Any infectious eventAny infectious event 4343 4040

Injection site reactionInjection site reaction 99 36*36*Upper respiratory infectionUpper respiratory infection 2323 2121Injection site ecchymosisInjection site ecchymosis 1111 1212Accidental injuryAccidental injury 55 88HeadacheHeadache 55 88SinusitisSinusitis 88 66Urinary tract infectionUrinary tract infection 66 66RashRash 77 55

**PP<.001<.001

Study DesignR

and

om

ized

Ran

do

miz

ed

X-rayX-ray

6

Etanercept (n=101)

X-rayX-ray

Double-Blind TrialDouble-Blind Trial Open-Label ExtensionOpen-Label Extension

12

Etanercept

0

X-rayX-ray

MonthsMonths

Placebo (n=104)* Etanercept

*81 of the placebo patients entered the open-label extension prior to obtaining the 12-

month x-ray, with a mean 28-day exposure to etanercept

Ory P, et al. Ory P, et al. Arthritis RheumArthritis Rheum. 2002;46(suppl 9):S196. Oral presentation 442. 2002;46(suppl 9):S196. Oral presentation 442..


Baseline Radiographic Features Were Different

PlaceboPlacebo(n=104)(n=104)

EtanerceptEtanercept(n=101)(n=101) P P value*value*

Total Sharp scoreTotal Sharp score 18.3 (7.5)18.3 (7.5) 25.9 (11.5)25.9 (11.5) 0.060.06

Erosion scoreErosion score 8.6 (3.3)8.6 (3.3) 12.9 (5.5)12.9 (5.5) 0.020.02

Joint space Joint space narrowing scorenarrowing score

9.7 (4.3)9.7 (4.3) 13.0 (6.0)13.0 (6.0) 0.150.15

*Wilcoxon Rank Sum*Wilcoxon Rank Sum

Mean (median)Mean (median)


Ory P, et al. Ory P, et al. Arthritis RheumArthritis Rheum. 2002;46(suppl 9):S196. Oral presentation 442. 2002;46(suppl 9):S196. Oral presentation 442..

Placebo (n=104)Placebo (n=104)

Etanercept (n=101)Etanercept (n=101)

Annualized Rates of Progression DifferedAnnualized Rates of Progression Differed

-0.2-0.2

00

0.20.2

0.40.4

0.60.6

0.80.8

11

1.21.2

PP=0.0006=0.0006

PP=0.0002=0.0002

PP=0.2033=0.2033

PP=0.0001=0.0001

PP<0.0001<0.0001

PP=0.438=0.438

TSSTSS EROERO JSNJSN TSSTSS EROERO JSNJSN

6 months6 months 12 months12 months



References Dougados M, van der Linden SM, Juhlin R, et al: The European Spondyloarthropathy

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Amor B, Dougados M, Mijiyama M, et al: Criteres de classification des spondyloarthropathies. Rev Rhum 57:85-89, 1990

Amor B, Dougados M, Khan MA. Management of refractory ankylosing spondylitis and related spondyloarthropathies. Rheum Dis Clin N Amer 21: 117-128, 1995

Wasner C, Britton MC, Kraines G, et al. Nonsteroidal anti-inflammatory agents in rheumatoid arthritis and ankylosing spondylitis. JAMA 246:2168-2172, 1981

Cush JJ, Lipsky PE. Reiter’s syndrome and reactive arthritis. In, Arthritis and Allied Conditions - A Textbook of Rheumatology. W.J. Koopman (ed)., 13th edition, Philadelphia, Williams & Wilkins, 1996, pp 1209-1227

Cush JJ, Lipsky PE. The Spondyloarthropathies. In, Cecil Textbook of Internal Medicine. J.C. Bennett, et al (eds). 20th ed., W.B. Saunders, 1996

Taurog JD, Richardson JA, Croft JT. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med 1994 Dec 1;180(6):2359-64

Bodaghi B, et al. Chronic Severe Uveitis: Etiology and Visual Outcome in 927 Patients from a Single Center. Medicine 80 (4): 263-70, 2001

Granfors K, et al. The cutting edge of spondylarthropathy research in the millennium. Arthritis Rheum 46(3):606-13, 2002

Gorman JD, Sack KE, Davis JC. Treatment of ankylosing spondylitis by inhibition of

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of psoriatic arthritis and psoriasis: a randomised trial. Lancet 356:385-90, 2000

Van den Bosch F, Kruithof E, Baeten D, et al. Randomized double-blind

comparison of chimeric monoclonal antibody to tumor necrosis factor (infliximab)

versus placebo in active spondyloarthropathy. Arthritis Rheum 46: 755-65, 2002

Braun J, Brandt J, Listing J, et al. Treatment of active ankylosing spondylitis with

infliximab: a randomized controlled multicentre trial. Lancet 359:1187-93, 2002

Wagner AD. Andresen J. Jendro MC. Hulsemann JL. Zeidler H. Sustained

response to tumor necrosis factor alpha-blocking agents in two patients with SAPHO

syndrome. Arthritis Rheum 46(7):1965-8, 2002

Winchester R. Psoriatic arthritis and the spectrum of syndroms related to the

SAPHO syndrome. Curr Opin Rheumatol 11:251-56, 1999

Khan MA. Update on spondyloarthropathies. Ann Int Med 136 (12): 896-907,

2002

Van der Linden SJ, van der Heijde D. Ankylosing spondyltis. Rheum Dis Clin North

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oligoarthritis in young male 17 yowm 3 mos. of b/l knee swelling and pain pain/swelling began...

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