Ankylosing

Ewa Olech, MD University of Nevada School of Medicine Division of Objectives

 Review epidemiology and genetic risks of SpA  Examine pathophysiology and the underlying disease process  Review clinical features, manifestations and comorbidities of SpA  Discuss treatment options and management strategies The Spectrum of Spondyloarthritis Characteristics of the Spondyloarthritis

 Sacroiliac & spinal joint involvement  Peripheral  Common spectrum of extra-articular features (especially mucocutaneous, ocular)  Negative  Familial clustering  Association with HLA-B27  Potential infectious trigger HLA-B27 and the Seronegative Spondyloarthritides HLA-B27 Disorder frequency (%) 95% 70% 25% Psoriatic spondylitis 60% Enteropathic arthritis 7% Enteropathic Spondylitis 70% Juvenile 70% Undifferentiated Spondyloarthropathy 70% Acute Anterior 50% Most Common Seronegative

1. Ankylosing Spondylitis (AS) 2. Reactive Arthritis (ReA) 3. Enteropathic Arthritis (associated with IBD) 4. Psoriatic Arthritis (PsA) Pattern of Peripheral Synovitis in the Spondyloarthropathies Condition Pattern of Involvement Ankylosing • Asymmetric large-joint , primarily lower Spondylitis extremities Reactive • Asymmetric large-joint oligoarthritis, primarily lower Arthritis extremities Enteropathic • Asymmetric large-joint oligoarthritis, primarily lower Arthritis extremities Psoriatic • Oligoarticular disease: Asymmetric large-joint Arthritis oligoarthritis, primarily lower extremities • Polyarticular disease: Symmetric involving large and small joints resembling RA • DIP joint disease: Associated with nail involvement • : Severely destructive arthritis involving the hands with shortening of the digits 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  The mean delay in the diagnosis: 5-11 years

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. is the Hallmark of AS

 Enthesitis may affect:  Capsules and intracapsular ligaments of large synovial (diarthrodial) joints and apophyseal joints  Ligamentous structures of cartilaginous joints  intervertebral discs  manubriosternal joints  symphysis pubis  Ligamentous attachments  spinous processes of the vertebrae  illiac crests  trochanters  patellae  calcanei  clavicle

Vernon -Roberts B. Spondyloarthropathies: AS -pathology. In: Hochberg M, et al., eds. Rheumatology 3rd ed. Edinburgh, Scotland: Mosby;2003:1205. Available at: www.rheumtext.com. Accessed December 6,2004. Enthesitis in Spondyloarthritis Enthesitis (Heel) MRI of

 Diffuse bone marrow edema of the calcaneous  Swelling of the  Fluid collection in retrocalcaneous bursa Inflammatory Enthesitis

 Subchondral bone and resorption  Periosteal new bone formation

McGonagle D. Arthritis Rheum. 1999. 42:1080-1086. Enthesitis  Enthesitis of the Spine  Occurs at capsular and ligamentous attachments  Involvement of bony attachment of Anterior Longitudinal Ligament Ankylosing spondylitis: thoracic and lumbar vertebrae "squaring," osteopenia, and ossification Ankylosing spondylitis: lumbar vertebrae, bamboo spine Cervical Spine Normal Ankylosing spondylitis: advanced sacroiliitis

Ankylosing spondylitis: advanced sacroiliitis (radiograph) AS: Sacroiliitis by MRI

Thick Arrows: Subchondral marrow Thin Arrow: inflammation shown by Joint cavity increased MRI signal

 Maksymowych WP. Can Fam Physician. 2004;50:257 –262. Available at: http://www.cfpc.ca/cfp/2004/Feb/vol50 -feb- cme -3.asp. Accessed November 3,2004. Inflammatory versus Mechanical Low Inflammatory pain Mechanical pain Age at onset <40 yr Any age (usually later) Type of onset Insidious Acute Symptom duration >3 mo <4 wk Morning stiffness >30 min <30 min Nocturnal pain Common Absent Effect of exercise Improvement Exacerbation Sacroiliac joint Frequent Absent tenderness Back mobility Loss in all planes Abnormal flexion Chest expansion Often decreased Normal Neurologic deficits Unusual Possible Clinical Features

• Chronic inflammatory and stiffness1 – Buttock pain – Symptoms worsen after prolonged periods of inactivity ('gel phenomenon') – Symptoms improved with exercise / hot shower – Some patients may wake-up at night to exercise or move about for a few minutes before returning to bed • Peripheral joint involvement2 – Synovitis – – Enthesitis

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. Clinical Features

• Limitation of spinal mobility and chest expansion • Characteristic radiographic findings late in disease • Constitutional symptoms may occur in early stages – anorexia – malaise – weight loss – low-grade fever – • Extraarticular manifestations

Khan MA. Spondyloarthropathies: clinical features of AS. In: Hochberg M, et al., eds. Rheumatology 3rd ed.. Extraarticular Manifestations of AS

Eyes (Acute Anterior Uveitis) Lungs (Restrictive Lung Disease, Apical Fibrocystic Disease) Heart (Aortic Insufficiency, Heart Block) Kidneys (Amyloidosis) Gut Skin (Inflammatory Bowel Disease, (Psoriasis & Nail Changes) Microscopic Inflammatory Lesion) Osteoporosis  Dactylitis Khan MA. Ann Intern Med. 2002;136:896 –907. Acute Anterior Uveitis

 Most common extraarticular complication (approximately 1/3 of patients with AS)  Unilateral, asynchronous with arthritis flares  Pain, redness, lacrimation, photophobia, blurred vision  Untreated can lead to vision loss Anterior Uveitis

 Pt with AS, red, sore, gritty eyes, blurred vision should get an urgent ophthalmologic examination Patient Case

 26 yrs old Caucasian male  C/o inflammatory back pain since 20 y/o  Recently bilateral heel pain  Constitutional sx: fatigue, low grade fever, weight loss  Labs:  HLA B27 – positive  Elevated CRP Sacroiliitis – bilateral grade 3 changes AS: Modified New York Criteria

1. Low back pain >3 months

• Improved with exercise Definite AS equals: • Not relieved by rest at least 1 criteria 2. Limited lumbar motion

3. Reduced chest expansion PLUS 4. Bilateral grade ≥2 sacroiliitis on x-ray 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.

Ankylosing spondylitis: postural changes Ankylosing spondylitis: , lumbar spine Schoeber’s Wall to Occiput Chest Expansion Progression of Deformities TREATMENT OF ANKYLOSING SPONDYLITIS Treatment

 Exercise  NSAIDS  Traditional DMARDs – peripheral arthritis  Biologics  Surgery

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Structures of TNF Inhibitors

Etanercept Infliximab Adalimumab (Humira®), Certolizumab pegol (Enbrel®)1 (Remicade®)2 Golimumab (Simponi®) (CIMZIA®)5 1 Fab′ Receptor Fab′

IgG1 IgG1 Fc Fc Fc- PEG free Recombinant Recombinant Recombinant Recombinant receptor/Fc fusion human/mouse human IgG1 humanized PEGylated protein chimeric IgG1 IgG1 Fab’ fragment

Monoclonal antibody

42 Approved anti-TNF agents for Ankylosing Spondylitis Therapeutic Trade Mechanism of Usual Maintenance Route Agent Name Action Dose

Infliximab Remicade TNF-α 5–10 mg q 4 - 8 wks IV inhibitor Enbrel TNF-α 50 mg weekly SQ inhibitor Adalimumab Humira TNF-α 40 mg q 2 wks SQ inhibitor Golimumab Simponi TNF-α 50 mg q 4 wks SQ inhibitor Certolizumab Cimzia TNF-α 200 mg q 2 wks or SQ Pegol inhibitor 400 mg q 4 wks THANK YOU