BioPharma

The Spondyloarthropat

hies

Kathryn Dao, MD

Arthritis Center

September 15, 2005

Objectives

Identify the different spondyloarthropathies

Beware of misconceptions

Know the clinical features

Be familiar with treatment options

What does the term “seronegative” mean

when applied to the term seronegative

spondyloarthropathy?

a) Patients do not form antibodies

b) Patients are negative for HLA-B27

c) Patients are negative for RF

d) Patients are negative for ANA

Spondyloarthropathies

Seronegative Spondyloarthropathy: a misnomer !!thought to be variant of RA, hence “seronegative”

Definition: A group of inflammatory arthropathies

that share distinctive clinical, radiographic and

genetic features. These diagnoses include:Ankylosing spondylitis Reactive arthritis (Reiter's syndrome)Psoriatic arthritis Enteropathic arthritis (Crohns, Ulcerative colitis)

Family of Spondyloarthropathies

AS Undifferentiated

Spondylo-arthropathy

JuvenileSpondylitis

IBD Associated

Arthritis

PsoriaticArthritis

ReactiveArthritis

SAPHOAcute Ant.

Uveitis

Evolution of Undifferentiated SpA to AS

0102030405060708090

100%

0 5 years 10 years

uSpA

AS

othersn = 88 initiallyn = 88 initially

n = 54 after 10 n = 54 after 10 yrsyrs

Mau et al. J Rheumatol 1988;15:1109

Definite radiological sacroiliitis: Definite radiological sacroiliitis:

after after 9-14 yrs9-14 yrs

Spondyloarthropathy: several criteria have been

proposed

Key Features: Inflammatory axial arthritis (sacroiliitis and spondylitis)Peripheral arthritis (often asymmetric and

oligoarticular)EnthesitisHLA-B27 positivityXRay 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%

What is HLA-B27?

a) It is an antibody

b) It is an MHC I molecule

c) It is an MHC II molecule

d) It is an antigen

HLA-B27

Class I MHC, important in antigen presentation CD8 T cells

Associated with the spondyloarthropathies

HLA-B27 is a normal gene found in 8% of Caucasians

3-4% of African-Americans, 1% of Orientals.

Risk 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

B27 increases risk of SPONDYLITIS and UVEITIS

BONUS: What evolutionary advantage does HLA-B27 confer?

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

• Lewis rats transfected with human HLA-B27 & B2microglobulin

• Sx’s: diarrhea, colitis, peripheral arthritis, 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%

Ankylosing Spondylitis

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

Unlike children, adults who are

diagnosed with AS have SI joint

involvement early in the

disease (True/False)?

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 B27+

persons (20% risk to 1st degree relatives of AS pts)

More common in Caucasians than African-Americans

Male Predominant disease 5:1 to 10:1

Females have less severe

Insidious disease onset between 16-30 yrs. Rare after

45 yrs.

Juvenile spondylitis: males >9yrs old

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

Early Diagnosis of Spondyloarthritis

Obstacles causing delay in Dx: Pt behavior, LBP common, MD education, XRay reliance, non- or misuse of HLA-B27

Inflammatory LBP: Chronic; AM Stiff >30 min;improved with exercise; Age<45yrs; waking from night pain; alternating buttock pains

*SpA features: enthesitis, heel pain, dactylitis, alternating butock pain, uveitis, +FHx, Crohns, Psoriasis, buttock pain, asymmetric arthitis, elevated ESR or CRP.

Rudawaleit M, et al. Ann Rheum Dis 63:535, 2004; Kahn M. RHEUMATOLOGY, 2003; Undewood, Dawson. Br J Rheum 35:1074, 1995

Findings Probability of

SpA (%)

Low back pain 5%

Inflammatory

LBP

14%

SpA Features* 1-2

>3

30-70%

>90%

XRay Evidence >90%

(AxialDz)

HLA-B27 >90%

(Axial+Periph)

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 involvmentSpondylitis

Periph.arthritisBamboo Spine

ModerateOnset

Ankylosing Spondylitis: X-rays

Lumbar Flexion (Schober)

A mark is placed between the anterior and posterior iliac spines,a further mark 10 cm above, the patient bends forward as far as possible,

the difference is recorded

Result: 0.5 cm (normal > 4 cm)

J Brandt, J Sieper

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

Spinal fractures (10-20%) axial/T spine; incr 6-8 fold

Severe uveitis (25-40%)

Other organ involvement

Heart: AI, Heart Block

Lung: ILD, apical Fibrosis

kidney: amyloidosis, nephritis

Mortality: 1.5-4 fold increase Amyloidosis, spinal

fractures, cardiovascular, gastrointestinal bleeding,

pulmonary diseases, colon cancer, violence, alcohol

Reactive arthritis have been associated

with all the following except:

a) Chlamydia

b) Ureaplasma

c) Campylobacter

d) Gonorrhea

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

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

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

KB: keratodermablenorrhagicum

Reactive Arthritis: Treatment

Yli-Kertula, et al. ARD 62:880, 2003

71 ReA pts: RCT of Cipro 4-7 yr earlier

53 reassessed(26 cipro, 27Placb

HLAB27(+): 20 cipro, 25 placebo

Chronic Dz: 8%Cipro, 41%Placb

New Ank Sondy: 0 Cipro, 2 Plac

New Uveitis: 0 Cipro, 3 Placb

Conclude: 3 mos of Abx indicated in ReA

Laasila K, et al. ARD 62:655, 2003

1988 3 mos DBRCT showed 3 mos lymecycline improved ReA outcome: decrease duration of Chlamyda ReA

2003 F/U Study: 17/23 participated

@ FU:16 LBP, 10 peripheral arthritis

Sacroiliitis: 1 unilateral Grade I 2 bilateral Grade II 1 Grade IV

One AS, one chronic SpA

Chr. Abx doesn ‘t change outcome

• Antibotic TX (doxycycline, ciprofloxacin) x3 mos indicated with proven ReA • Abx do not affect outcome of Shigella, Salmonella infection

What is the diagnosis?a)Bad manicureb)Rheumatoid arthritisc)Psoriatic arthritisd)Erosive OA

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

develop psoriatic arthritis (skin usually precedes joints)

Frequency of PsA increases with disease severity

and duration

Estimated 350-400,000 patients in USA

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%

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%

Pencil and Cup Deformity

In patients with inflammatory bowel

disease and joint pains, the activity of

the gut will parallel the activity of the…

a) Peripheral joints

b) Spine

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: CLINICAL ASSOCIATIONS

20-40% associated with systemic Dz

Anterior Uveitis:Eye pain, photophobia,

↓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, TbcKhan MA. Khan MA. AR.AR.;20: 909, 1977 Maksymowych WP. ;20: 909, 1977 Maksymowych WP. ARD ARD 54:128, 199554:128, 1995

In a patient you suspect having a

spondyloarthropathy (dactylitis, inflammatory back

pain symptoms, and heel pain), what do you give

to help them until they can see a rheumatologist?

a) steroids

b) methotrexate

c) sulfasalazine

d) NSAIDs

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: the Big Hurt Analgesic agents: too little too late NSAIDs - Mainstays of therapy (when disco was happening) Corticosteroids - rarely used; rarely effective DMARDs: (SSZ, MTX) who were we fooling? Biologics: (anti-TNF therapies) are they for real?

SpA: Therapeutic Options

Effective: inflammatory back pain, spinal stiffness, peripheral

arthritis, enthesopathy No evidence that NSAIDs inhibit disease progression

ACR2003 Wanders, vander Heijde: celecoxib Rx pts less progression

FDA-approved NSAIDs for AS: phenylbutazone

Indomethacin, indomethacin-SR, enteric coated

acetylsalicylic acid, naproxen, sulindac, diclofenac.

Anecdotal reports & few studies suggest that specific NSAIDs

may be more effective:

phenylbutazone: limited availability:risk of agranulocytosis

indomethacin: especially in long acting form. CNS Sx?

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

NSAIDs

Consider DMARDs when: Antiinflammatory therapy is insufficient to control Sxs

Progression of inflammatory axial disease

Active persisent polyarthritis

Uncontrolled extra-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 anecdotes and RA experience

NSAID Resistant AS/SpA

Gold - no proven benefit! Intramuscular (aurothioglucose, aurothiomalate)Auranofin 238 AS pts:no effect on Axial dz; but

+effect on MD global, functionPrimarily studied in psoriatic arthritis > AS > Reactive

HydroxychloroquineControlled and uncontrolled trials in psoriatic arthritis,

suggesting some efficacy. Azathioprine: Uncontrolled and controlled trials in ReA

and psoriatic arthritis MTX: no benefit in AS

Beneficial in psoriasis and psoriatic arthritis

Ineffective DMARDs

Conclusion

SpondyloarthropathiesInflammatory arthropathies

Share genetic, clinical and radiologic

features

Ag driven immune response causing

symptoms

New therapies allow for more effective

management of these diseases

Sulfasalazine in SpAs: AS, PsA, and ReA

619 patients

Axial disease (n=187)

Peripheral articular (n=432)

SSZ 2 gr/day vs Placebo

36 weeks

Results: Axial – no SSZ response

Peripheral – favor SSZ (P=0.0007)

SSZ effective for peripheral arthritis of SpAs

Clegg DO, et al. Clegg DO, et al. Arthritis Rheum.Arthritis Rheum. 1999;42:2325-2329. 1999;42:2325-2329.

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

Pre-infusion Post-infusion

Stone M et al. Stone M et al. Arthritis RheumArthritis Rheum 2000 (abstract). 2000 (abstract).

2 Days

Use of Infliximab in Spondyloarthropathy: Efficacy

BASDAI

The Bath Ankylosing Spondylitis Disease Activity Index

(BASDAI) measures disease activity based on 6 self-

administered questions relating to:

Fatigue

Spinal pain

Peripheral arthritis

Enthesitis

Morning stiffness : 2 questions (meaned)

Average 1- 5/6; range 0-10

Garrett S, et al. Garrett S, et al. J Rheumatol.J Rheumatol. 1994;21:2286-2291. 1994;21:2286-2291.

ASAS 20Preliminary Response Criteria AS

Patient global VASPatient global VAS

Patient Pain VASPatient Pain VAS

Function (BASFI)Function (BASFI)

Stiffness (BASDAI)Stiffness (BASDAI)

Improvement of 20% AND 10 units in at least 3 domainsImprovement of 20% AND 10 units in at least 3 domains

No worsening in remaining domainNo worsening in remaining domain

Anderson et al Arthritis Rheum 2001:44:1876-886

ASAS Partial Remission: < 20 in all 4 domains