Why do we struggle with the diagnosis?

Seronegative Spondyloarthritis
Why Do We Struggle with the
Diagnosis?
Ewa Olech, MD
University of Nevada School of Medicine
Division of Rheumatology
Disclosures
• Grant/ Research support:
– Abbvie, Amgen, Pfizer
• Consulting:
– Abbvie, Amgen, Celgene, Pfizer
• Speaking:
– Abbvie, Amgen, BMS, Pfizer
Objectives
• Review epidemiology and genetic risks
of Seronegative Spondyloarthritis
• Examine pathophysiology and the
underlying disease process
• Review clinical features, manifestations
and comorbidities of SpA
• Discuss treatment options and
management strategies
SpA - Continually Evolving Concept
• First established in 1974
• No single shared distinguishing feature
• Highly heterogeneous clinical
presentation
• Diagnosis based on often-changing and
unpredictable signs and symptoms
• Misdiagnosis or delayed diagnosis
More People Are Afflicted
with SpA than RA
Helmick CG et al, Arthritis Rheum. 2008
Reveille JD et al, Arthritis Care Res. 2012
SpA – Spectrum of Interrelated
Diseases
Characteristics of the
Spondyloarthritis
•
•
•
•
•
•
•
Inflammatory arthritis of the SI joints and spine
Peripheral arthritis
Enthesopathy
Negative RF
Familial clustering
Association with HLA-B27
Common spectrum of
extra-articular features
• Potential infectious trigger
HLA-B27
HLA-B27 and the Seronegative
Spondyloarthritides
Disorder
Ankylosing Spondylitis
Reactive Arthritis
Psoriatic Arthritis
Psoriatic Spondylitis
Enteropathic Arthritis
Enteropathic Spondylitis
Juvenile Spondyloarthropathy
Undifferentiated Spondyloarthropathy
Acute Anterior Uveitis
HLA-B27
frequency (%)
95%
70%
25%
60%
7%
70%
70%
70%
50%
Jerry
• 42 y/o Caucasian male, construction worker,
c/o bilateral ankle pain and swelling for 4-5
months, worse in AM, started with right
Achilles tendon
• Difficulties with work and ADLs
• Minimal response to NSAIDs
Jerry cont.
• PCP susp. gout - started allopurinol,
colchicine & Medrol Dosepak
• Responded initially, but subsequently
the pain returned
• Orthopedic surgeon injected the right
ankle with Kenalog - minimal temporary
response
Jerry’s Physical Exam:
Jerry’s Labs and X-rays:
•
•
•
•
•
•
•
•
CBC, CMP – normal
Hepatitis panel – negative
Uric Acid – 7.4 mg/dL
RF, anti-CCP – negative
HLA-B27 – not present
ESR – 15 mm/hour
CRP – 2.0 mg/dL (normal < 0.8 mg/dL)
Radiographs bilat. ankle - normal
Jerri’s MRI of the Right Ankle
• Diffuse bone
marrow edema of
the calcaneous
• Swelling of the
Achilles Tendon
• Fluid collection in
retrocalcaneous
bursa
Jerry’ ROS and Detailed PE:
• Scaly rash on the scalp and ears
• Nail changes
• Chronic diarrhea for the past several months
PSORIATIC ARTHRITIS
PsA - Epidemiology
• Prevalence of Ps: 1 – 2%
– 20 – 40 % develop arthritis
• Prevalence of PsA: 0.04-1.2%
• Peak age of onset between 30-55 years
• Highest incidence in patients with
extensive skin involvement
• Males and females are equally affected
1Taylor
WJ. Curr Opin Rheumatol. 2002;14:98–103.
P. Curr Opin Rheumatol. 2004;16:366–370.
3Brockbank J, et al. Exp Opin Invest Drugs. 2000;9:1511–1522.
4Kane D, et al. Rheumatology. 2003;42:1460–1468.
2Mease
Pathogenesis of Ps and PsA
Nograles
KE, et al. Clin Pract Rheumatol 2009,5:83-91
Main Features of PsA
*Low levels of RF and ACPA can be found in 5-16% of patients; **To a lesser degree than in RA
***Spinal disease occurs in 40-70% of PsA patients
Helliwell PS & Taylor WJ. Ann Rheum Dis 2005;64(2:ii)3-8
Fitzgerald “Psoriatic Arthritis” in Kelley’s Textbook of Rheumatology, 2009
Classical Description of PsA Using the
Diagnostic Criteria of Moll and Wright
Includes 5 clinical patterns:

Asymmetric mono-/oligoarthritis (~30%)

Symmetric polyarthritis (~45%)

Distal interphalangeal (DIP) joint involvement (~5%)

Axial (spondylitis and sacroiliitis) (HLA-B27) (~5%)

Arthritis Mutilans (<5%)
• However patterns may change over time and are therefore
not useful for classification 5
HLA: Human leucocytes antigen
1. Moll JMH, Wright V. Semin Arthritis Rheum 1973;3:55-78
Psoriatic arthritis: asymmetric synovitis
Psoriatic arthritis: nail changes, rash, and
arthritis
Psoriatic arthritis: nail dystrophy and arthritis
Psoriatic arthritis: nail changes, rash, and
arthritis
Arthritis Mutilans
Dactylitis
• Diffuse swelling of a digit (acute or chronic)1
• Referred to as “sausage digit”1
• Up to 40% of PsA patients1,2
• Feet most commonly
affected1
• Dactylitis involved
digits show more
radiographic damage1
ACR Slide Collection on the Rheumatic Diseases; 3rd edition. 1994.
1Brockbank J, et al. Ann Rheum Dis. 2005;64:188–190.
2Veale D, et al. Br J Rheumatol. 1994;33:133–38.
Dactylitis/ Sausage Digit
Enthesitis
• Entheses - regions of
tendon, ligament, or
joint capsule
attachment to bone1
• Enthesitis inflammation at the
enthuses (most
common – Achilles
and plantar fascia)1,2
• Isolated enthesitis
may be the only
rheumatologic sign of
McGonagle D. Ann Rheum Dis. 2005;64(Suppl II):ii58–ii60.
PsA3
1
2Anandarajah
AP, et al. Curr Opin Rheumatol. 2004;16:338–343.
3Salvarani C. J Rheumatol. 1997;24:1106–1140.
Comorbidities in PsA Patients
Ocular inflammation1
(Iritis/Uveitis/ Episcleritis)
IBD2
PsA patients6-8
• Psychosocial burden
• Reactive depression
• Higher suicidal ideation
• Alcoholism

Metabolic Syndrome3-5
• Hyperlipidemia
• Hypertension
• Insulin resistent
• Diabetes
• Obesity
 Higher risk of
Cardiovascular disease (CVD)
1Qieiro
et al. Semin Arth Rheum 2002;31:264; 2Scarpa et al. J Rheum 2000;27:1241; 3Mallbris et al. Curr Rheum Rep 2006;8:355;
et al. J Am Acad Derm 2006;55:829; 5Tam et al. 2008;47:718; 6Kimball et al. Am J Clin Dermatol 2005;6:383-392;
7Naldi et al. Br J Dermatol 1992;127:212-217; 8Mrowietz U et al. Arch Dermatol Res 2006;298(7):309-319
4Neimann
Radiologic Damage Can Occur
Early in PsA
Kane D et al. Rheumatology (Oxford) 2003
PsA: Progressive Joint Changes
Arthritis
Mutilans
Pencil-in-cup Osteolysis
Gross Osteolysis
Psoriatic
Arthritis:
Hand
Juxta-articular Periostitis and
Ankylosis
PsA Treatment Goals
Improve signs and symptoms
Prevent progression of joint damage
Improve physical function
Pharmacologic Treatment for PsA
NSAIDs & steroids
Conventional DMARDs
Methotrexate, Sulfasalazine, Leflunomide,
Cyclosporine, Azathioprine, Hydroxychloroquine
Biologic DMARDs
Anti-TNF Inhibitors: Infliximab, Etanercept,
Adalimumab, Golimumab, Certolizumab Pegol
Anti-IL-12 & IL-23 Inhibitor: Ustekinumab
Small Molecules
Phosphodiesterase 4 Inhibitor: Apremilast
Conventional RA DMARDs
Therapeutic Agent
Usual
Maintenance
Dose
Route
Methotrexate
7.5–20 mg/wk
Oral, SQ
Hydroxychloroquine
200 mg BID
Oral
Sulfasalazine
1,000 mg 2–3 x a
day
Oral
Leflunomide
10 - 20 mg/day
Oral
Azathioprine
50–150 mg/day
Oral
Cyclosporine
2.5–4 mg/kg/day
Oral
Approved anti-TNF agents for
Psoriatic Arthritis
Therapeutic
Trade
Usual Maintenance Route
Agent
Name
Dose
Infliximab
Remicade 5–10 mg q 4 - 8 wks
IV
Etanercept
Enbrel
50 mg weekly
SQ
Adalimumab
Humira
40 mg q 2 wks
SQ
Golimumab
Simponi
50 mg q 4 wks
SQ
Certolizumab
Pegol
Cimzia
200 mg q 2 wks or
400 mg q 4 wks
SQ
39
Structures of TNF Inhibitors
Etanercept
(Enbrel®)1
Adalimumab (Humira®),
Golimumab (Simponi®)
Infliximab
(Remicade®)2
Fab′
Receptor
IgG1
Fc
IgG1
Fc
Recombinant
receptor/Fc fusion
protein
Recombinant
human/mouse
chimeric IgG1
Fcfree
Recombinant
human IgG1
Monoclonal
antibody
Certolizumab pegol
(CIMZIA®)5
1 Fab′
PEG
Recombinant
humanized PEGylated
IgG1 Fab’ fragment
Safety Considerations with
anti-TNFα Inhibitors
• Serious infections
• Opportunistic infections
– TB, histoplasmosis,
listeriosis, cocci,
aspergillosis, PCP
• Hepatitis B reactivation
• Malignancies
• Demyelination
•
•
•
•
•
Hematologic abnormalities
Administration reactions
CHF
Autoantibodies & lupus
Combination of biologics
not to be used
Hochberg, et al. Semin Arthritis Rheum. 2005;34:819
Keystone et al. J Rheumatol Suppl. 2005;74:8
Schiff et al. Ann Rheum Dis. 2006;65:889
Scott and Kingsley. N Engl J Med. 2006;355:704.
Ustekinumab
Selectively Targets IL-12 & IL-23
Human IgG1 monoclonal antibody/
binds with specificity to p40 protein subunit
Ustekinumab Dosing
• Patients <220 lbs:
– 45mg at 0 & 4 wks, then q 12 wks
• Patients >220 lbs
– 90mg at 0 & 4 wks, then q 12 wks
Ustekinumab Important
Safety Information
•
•
•
•
•
Infections
Pre-Treatment Evaluation of Tuberculosis (TB)
Malignancies
Hypersensitivity Reactions
Reversible Posterior Leukoencephalopathy
Syndrome (RPLS)
• Immunizations
• Most Common AEs: nasopharyngitis, URI, headache,
fatigue
Apremilast - Oral Non-biologic
Phosphodiesterase 4 (PDE4) Inhibitor
• Cyclic adenosine
monophosphate
(cAMP) - a second
messenger for a variety
of inflammatory
mediators
• PDE4 - degrades
cAMP to AMP in
inflammatory cells
Apremilast (Otezla)
Inhibits PDE4 Intracellularly
• By elevating cAMP
levels, apremilast
indirectly modulates
production of
inflammatory
mediators
Apremilast - Dosing
• Initial 5-day titration period
• Maintenance dose: 30 mg twice
• Should be reduced in patients with severe
renal impairment
– creat. clearance < 30 mL/min
Apremilast
Important Safety Information
• Contraindications:
– Known hypersensitivity
• Warnings and Precautions:
– Depression
– Weight decrease
– Drug interactions: CYP450 enzyme inducers (rifampin,
phenobarbital, carbamazepine, phenytoin)
• Adverse Reactions:
– Diarrhea, nausea, headache, URI, vomiting,
nasopharyngitis, upper abdominal pain
Group for Research and Assessment of
Psoriasis and Psoriatic Arthritis
PsA Treatment Guidelines
Jason
• 36-years old Caucasian male, EMT
• PMHx: OA bilateral knee, S/P bilateral
knee arthroscopy
• Cc: bilateral knee pain & swelling;
recently bilateral heel pain
• ROS:
– back/ buttock pain for 5 years
– recently constitutional symptoms
• Previously evaluated by podiatrist,
ortho, chiropractor, rheumatologist
Jason Cont:
• PE:
– normal, except swelling and tenderness of
bilat knee & tenderness of the bilat plantar
foot and lumbar-sacral area
• Labs:
– CBC, CMP – normal
– Hepatitis panel – negative
– RF, anti-CCP – negative
– ESR – 10 mm/hour
– CRP – 1.5 mg/dL (normal < 0.8 mg/dL)
– HLA-B27 – present
Enthesitis (Heel)
Radiograph of SI Joints
Ankylosing Spondylitis
Epidemiology of AS
• The incidence of AS underestimated1
– Between 350,000 - 1 million Americans2,3
– 0.1% to 0.9% of the population worldwide4,5
• Age of onset typically between 15 - 35 years1,2,3
• 2-3 times more frequent in men than in women6
1The
Spondylitis Association of America. Available at: www.spondylitis.org. Accessed December 2,2004.
2Davis J. Semin Arthritis Rheum. 2004;34:668–677.
3Newman PA, et al. Rheum Dis Clin Am. 2003;29(3):561–571.
4Lawrence RC, et al. Arthritis Rheum. 1998;41(5):778–99.
5Sieper J, et al. Ann Rheum Dis. 2002;61(suppl 3);iii8–18.
6Khan MA. Ann Intern Med. 2002;136:896–907.
Age at First Symptoms and
First Diagnosis in AS Patients
Feldtkeller et al. Curr Opin Rheumatol 2000; 12:239-247
Clinical Features of AS
•
Chronic inflammatory low back/ buttock pain &
stiffness1
–
–
–
•
Insidious onset
‘Gel phenomenon‘; patients may wake-up at night
Improvement with exercise/ hot shower
Peripheral joint involvement2
–
Synovitis, dactylitis, enthesitis
•
Constitutional symptoms
•
Extraarticular manifestations
•
Limitation of spinal mobility & chest expansion
•
Characteristic radiographic findings late in disease
1Khan
MA In: Hochberg M, et al., eds. Rheumatology 3rd ed. Edinburgh, Scotland: Mosby;2003:1161–1170.
2Keat A. In: Klippel JH, ed. Primer On The Rheumatic Diseases.
Inflammatory Enthesitis
Hallmark of AS
• Subchondral
bone
inflammation
and
resorption
• Periosteal
new bone
formation
McGonagle D. Arthritis Rheum. 1999. 42:1080-1086.
Enthesitis and Disease Progression
• Enthesitis of the
Spine
– At capsular and
ligamentous
attachments
– Involvement of bony
attachment of Anterior
Longitudinal Ligament
AS: thoracic and lumbar vertebrae "squaring,"
osteopenia, and ossification
Ankylosing
Spondylitis:
lumbar
vertebrae,
bamboo spine
Normal SI Joints
Sacroiliitis
AS: Advanced Sacroiliitis
Ankylosing spondylitis:
advanced sacroiliitis
(radiograph)
Ankylosing
Spondylitis:
Postural
Changes
Ankylosing
Spondylitis:
Ankylosis of
Lumbar Spine
Chest Expansion
Progression of Deformities
AS: Modified New York Criteria
1. Low back pain >3 months
• Improved with exercise
Definite AS equals:
at least 1 criteria
• Not relieved by rest
2. Limited lumbar motion
3. Reduced chest expansion
4. Bilateral grade ≥2 sacroiliitis
on x-ray
PLUS
Either 4 or 5
5. Unilateral grade 3 to 4 on
sacroiliitis on x-ray
van
der Linden S, et al. Arthritis Rheum. 1984;27:361–368.
Stages of Axial SpA
Rudwaleit M et al. Arthritis Rheum 2005; 52:1000-8
MRI of the SI Joints
Subchondral
marrow
inflammation
shown by
increased
MRI signal
c/w sacroiliitis
AS Treatment
• Exercise
• NSAIDS
• Traditional DMARDs – peripheral arthritis
• Biologics
• Surgery
Treatment Goals:
– Improve Symptoms
– Avoid unnecessary diagnostic procedures and
inappropriate treatment
Summary
• The manifestations of SpA are
unpredictable and can present in multiple
areas of the body
 The complex nature of SpA make the
diagnosis difficult
 Timely diagnosis &
treatment may help
improve symptoms
of SpA, and
prevent joint
damage in PsA
THANK YOU