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 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
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
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
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%
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
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