Ankylosing Spondylitis Late Complications Atul Deodhar MD Associate Professor of Medicine Medical Director, Rheumatology Clinics Oregon Health & Science University Portland, OR Spondylitis Association of America Webinar March 21st, 2009

General Comments on AS Major part of the disease progression occurs in the first 10 years of the disease1 ‘Bamboo spine’ occurs in 20% after 20 years3 Women have more involvement of cervical spine & peripheral joints than men2 AS has no adverse effect on fertility, pregnancy or fetus Unlike in RA, pregnancy has no consistent effect on AS disease activity Men have worse radiographic progression than women, but ‘self-reported’ functional limitations are worse in women4 Need references 1Carette S. et al. Arthritis Rheum 1983;26:186-90 2Lee W et al. Arthritis Rheum 2008;59:449-54 3Sampaio-Barros PD J Rheumatol 2001;28:560-65 4Lee w et al. Ann Rheum Dis 2007;66:633-8

Self-Reported AS Symptoms and Quality-of-Life Concerns* While there is no burden-of-illness data available for SpA in general, there is data available – specifically European studies – on symptom burden in AS. As with most rheumatic diseases, the severity of AS symptoms varies greatly among patients and over time.1 Ward assessed the importance of quality-of-life (QOL) issues of 175 AS patients using both a cross-sectional survey of health status and the Medical Outcomes Study Short Form 36 Health Survey (SF-36). The figure above highlights the seven greatest QOL concerns reported in the study.2 AS is associated with a relatively early age of onset, thus the impact of pain, fatigue, and progressive disability on the individual’s lifestyle, career, family, and social life are likely to be long term and far reaching. Daily pain and stiffness are common, as reported in 70% of patients, and 81% of AS patients who have lost most of their spinal mobility become restricted within the first 10 years.3-5 The AS Life-Impact Study, a cross-sectional, QOL study sponsored by the Spondylitis Association of America, was conducted to learn more about the long-term outcomes of people with AS and the impact of the disease on their daily lives. 2,384 adults with AS were surveyed by mail The outcomes of the study reinforce the burden of illness of AS; an abstract has been submitted to ACR and submission for publication to follow Chorus AM, et al. Employment perspectives of patients with ankylosing spondylitis. Ann Rheum Dis. 2002;61:693-699. Ward M. Health-related quality of life in ankylosing spondylitis: a survey of 175 patients. Arthritis Care Res. 1999:12(4):247-255. Barlow JH, Wright CC, Williams B, Keat A. Work disability among people with ankylosing spondylitis. Arthritis Care Res. 2001;45:424-430. Ward M. Quality of life in patients with ankylosing spondylitis. Rheum Dis Clin North Am. 1998;24(4):815-827. Carette S, Graham D, Little H, Rubenstein J, Rosen P. The natural disease course of ankylosing spondylitis. Arthritis Rheum.1983 Feb;26(2):186-190. *7 greatest QOL concerns reported Ward M. Arthritis Care Res. 1999

Prognosis of AS Following factors at presentation indicate increased disease severity Hip arthritis — odds ratio (OR) 23 Sausage-like finger or toe — OR 8 Poor response to NSAID — OR 8 High ESR (>30 mm/h) — OR 7 Limitation in range of motion @ lumbar spine — OR 7 Oligoarthritis — OR 4 Onset less than 16 years of age — OR 3 If no factor is present: mild outcome is likely (sensitivity 93%, specificity 78%) If hip is involved or 3 other factors are present, severe disease is predicted: sensitivity 50%, specificity 98%

Proportion of Patients (%) AS Burden of Disease: % of Male Patients with Disability (Steinbrocker > II) RA (n=11,643) AS (n=5,581) 60 53 * P<0.0025 * 48 * 44 * 39 38 40 35 31 29 25 Proportion of Patients (%) 22 20 <41 41-50 51-60 61-70 >70 Years Zink A, et al. J Rheumatol . 2000;27:613 - 22.

Proportion of Patients (%) AS Burden of Disease: % of Female Patients with Disability (Steinbrocker >II) RA (n=38,180) AS (n=2,487) 80 * P<0.0025 60 60 46 44 42 40 33 34 Proportion of Patients (%) 28 26 * 20 16 20 <41 41-50 51-60 61-70 >70 Years Zink A, et al. J Rheumatol . 2000;27:613 - 22.

Disease duration at retirement Early Retirement in AS AS patients 3 times more likely to become disabled1 31% after 20 years in Dutch study 36% after 20 years in French study Survey of 100 Norwegian AS patients2 (mean age: 42 years, disease duration: 16.5 years) 26% of patients were retired2 15.6 42.9 6.4 36.1 20 40 60 Disease duration at retirement Retirement age Years Men Women 96.2% retired due to AS P<0.02 Do you categorize patients as having mild, moderate, severe disease? Do you use some other method to categorize patients – early disease, established disease? How do you currently assess a patient’s likelihood of progression in AS? Do you believe that earlier intervention with biologics leads to better clinical outcomes? If treated early and aggressively, do you believe that the natural course of AS can be altered? 1Boonen A Clin Exp Rheumatol 2002;20(suppl 28):S23-S26. 2Gran JT et al. Br J Rheumatol 1997;36:766-71

Other Disease Manifestations in AS Eyes (Acute Anterior Uveitis) Up to 40% Lungs (Restrictive Lung Disease, Apical Fibrocystic Disease) Heart (Aortic Insufficiency, Heart Block) 3% to 10% Kidneys (Amyloidosis) Gut (Inflammatory bowel disease, Microscopic inflammatory lesion) Extra-articular sites may be affected in AS. The most common of these is acute anterior uveitis, which occurs in up to 40% of patients.1-6 Approximately 20% to 70% of AS patients have microscopic evidence of gut inflammation and 6.5% develop Crohn’s disease during the course of their disease. Up to 10% of patients with AS may have psoriatic skin involvement. Banares A, Hernandez-Garcia C, Fernandez-Gutierrez B, Jover JA. Eye involvement in the spondyloarthropathies. Rheum Dis Clin North Am. 1998 Nov;24(4):771–784. Khan MA: Ankylosing spondylitis: Clinical features. In: Hochberg M, et al (Editors). RHEUMATOLOGY (3rd Edition), London, Mosby: A Division of Harcourt Health Sciences Ltd. 2003. Khan MA. Update on spondyloarthropathies. Ann Intern Med. 2002;136:896-907. Smale S, Natt RS, Orchard TR, Russell AS, et al. Inflammatory bowel disease and spondyloarthropathy. Arthritis Rheum. 2001 Dec;44(12):2728-2736. De Vos M, Mielants H, Cuvelier C, Elewaut A. Long-term evolution of gut inflammation in patients with spondyloarthropathy. Gastroenterology. 1996;110:1696-1703. Lautermann D, Braun J. Ankylosing Spondylitis – Cardiac manifestations. Clin Exper Rheum. 2002;6(suppl 28):S11-S115. Skin (Psoriasis & Nail Changes) Microscopic involvement 20-70% 6.5% have Crohn’s Disease Up to 10% Dactylitis Cauda Equina Syndrome Osteopenia, Osteoporosis Spinal Fracture

Spectrum of AS Early Moderate Severe Courtesy of J. Cush, MD

Late Complications of AS Skeletal Complications Bamboo spine Osteoporosis Spinal fractures Fused hips and shoulders Fused ribs: reduced chest wall expansion Non-skeletal Complications Heart: valvular (aortic and mitral) regurgitation, conduction abnormalities, diastolic dysfunction Lung: apical fibrosis, restrictive lung disease Kidney: amyloidosis Neurological: cauda equina syndrome, spinal cord compression

Aortic Dilatation in AS Aortic regurgitation seen in 3.5% of patients after 15yrs; 10% at 30 yrs, and is associated with peripheral arthritis Warning signs: None! Be aware of the complication Treatment: medical management. In severe cases: valve replacement Bergfeldt Am J Med 1988;85:12-18, Bulkley & Roberts Circulation 1973;48:1014-27

Heart & Lung Disease in AS Conduction abnormalities (heart block) & diastolic dysfunction seen in a minority of patients with long-standing AS Whether these changes are more common in AS compared to general population, is controversial. One Swiss study found no increased prevalence1 Pulmonary manifestations of long-term AS: Interstitial lung disease, upper lobe fibrosis, reduced chest expansion (due to fused ribs and restricted chest cage movement) Warning signs: New onset of shortness of breath, cough, palpitations, missed heart beats, swelling on legs Treatment: pacemaker, diuretics, vasodilators, bronchodilators etc Ankylosing spondylitis and heart abnormalities: do cardiac conduction disorders, valve regurgitation and diastolic dysfunction occur more often in male patients with diagnosed ankylosing spondylitis for over 15 years than in the normal population? Brunner F, Kunz A, Weber U, Kissling R. Department of Physical Medicine and Rheumatology, Balgrist University Hospital, Forchstrasse 340, 8008 Zurich, Switzerland. florian.brunner@balgrist.ch The objective of this study was to determine the rate of selected cardiac pathologies (conduction disorders, valve regurgitation and diastolic dysfunction) in patients with long-standing ankylosing spondylitis (AS) and compare the results with the prevalence in the normal population. A rheumatologic (structured questionnaire interview) and cardiac evaluation (resting electrocardiography and echocardiography) was performed in 100 male subjects with AS and a disease duration of more than 15 years. The rates for conduction disorders, aortic and mitral valve regurgitation and diastolic dysfunction were compared with the corresponding results in the literature among the normal population. In patients with long-standing AS there was no increased rate for valve regurgitation (mitral and aortic valve) and for arrhythmia. Diastolic dysfunction occurred more often in patients with long-standing AS. However, this might be caused by the presence of other cardiovascular risk factors such as age and hypertension. According to these results, a cardiologic evaluation with echocardiography should not be recommended routinely in patients with long-standing AS. To confirm these results, a large prospective study with patients with long-standing AS and with a matched control group should be performed in the future. 1Lang U et al. Eur J Med Res 2007;12(12):573-81

Spinal cord injury in AS Osteoporosis is common in AS Spinal BMD can be falsely increased due of new bone formation – femoral BMD measurement recommended Patients with AS suffer spinal fractures at an increased rate with minimal trauma (lifetime incidence 4%-18%) Incidence of spinal cord injury increased > 10-fold when compared to the general population of Finland Compression of the spinal cord at atlanto-axial level can occur with paraparesis or tetraparesis Warning signs for fracture: sudden onset of new severe back pain after stable disease Warning signs for spinal cord injury: new onset sensory or motor symptoms (tingling, numbness, weakness, bladder/bowel involvement)

Cauda Equina Syndrome in AS Neurological complications are rare (2%) in AS Cauda equina syndrome is very rare complication, seen in long standing AS Affects nerve roots from lumbar & sacral spine May be secondary to inflammation of the covering of the spinal cord (called arachnoiditis) Warning signs: Slowly progressive pain, numbness in the saddle distribution, bowel/bladder incontinence Rarely, muscle weakness symptoms seen Diagnosed by imaging (CT, MRI) Treatment: recently, surgery (laminectomy, lumbo-peritoneal shunt) has been shown to be effective Lumboperitoneal shunt for treatment of dural ectasia in ankylosing spondylitis. Dinichert A, Cornelius JF, Lot G. Neurosurgery, Hôpital Lariboisière, 2 rue Ambroise Paré, 75010 Paris, France. antoine@dinichert.com Neurological complications of ankylosing spondylitis (AS) are reported in 2.1% of patients. Cauda equina syndrome (CES) is rare and occurs at the ankylosing stage. MRI and CT of the lumbar spine show a cauda equina deformation with dural ectasia and bony erosion. We report three patients with AS presenting with progressive CES. These patients underwent lumboperitoneal shunting (LPS) surgery. The motor deficit improved in all cases. We suggest that CES develops from arterial pulsation of the CSF on a dural sac with reduced elasticity and that LPS reduces these intradural pressure shock waves. A meta-analysis by Ahn et al. [Ahn NU, Ahn UM, Nallamshetty L, et al. Cauda equina syndrome in ankylosing spondylitis (the CES-AS syndrome): meta-analysis of outcomes after medical and surgical treatments. J Spinal Disord 2001;14:427-33] concludes that surgical treatment has a better outcome than conservative or no treatment. Adding our 3 patients to this analysis, it appears that LPS for CES in AS is more efficient than laminectomy. LPS is a routine procedure for a rare indication, which promises improvement or atleast a stabilization of this disabling evolution of the disease.

Mortality in Ankylosing Spondylitis Mortality in AS is slightly increased (1.5 times the normal population) Major causes are: Cardiovascular disease Pulmonary diseases Spinal fractures Violence, alcohol Gastrointestinal bleeding Amyloidosis, nephritis Colon cancer Myllykangas-Luosujarvi R et al. Br J Rheumatol 1998; 37:688 (N = 71) Lehtinen K. Ann Rheum Dis 1993; 52:174 (N = 398) Khan MA et al. J Rheumatol 1981; 8:86 (N = 56) Radford EP et al. NEJM 1977; 15:297 (N = 836)

In Conclusion: Late stage complications of Ankylosing Spondylitis can involve skeleton as well as internal organs Skeleton: Bamboo spine, osteoporosis Heart: valve disease, conduction abnormality, heart contractility reduced Lungs: Apical fibrosis, restrictive lung & chest-wall disease Kidneys: amyloidosis Neurological system: spinal cord injury and cauda equina syndrome Early detection by recognizing warning signs is the key All complications are treatable with symptomatic treatment Whether anti-TNF agents can prevent/treat these complications remains to be seen

With determination, you can achieve anything! Mr. KM on Mount Hood, OR, at 11,000 feet, May 2003