1. Ankylosing Spondylitis
LCDR Paul Kruszka, MD USPHS

2. 37 year old male with back pain
Past medical history significant for only left sided inguinal hernia repair in 1995
Social history: not tobacco, less than one drink daily, married, 2 children, professional U.S. Coast Guard officer.
Family History: negative

3. HPI
19 Mar 98: First visit (age 26) for right buttock pain that radiates to right thigh. Worse with walking. Physician’s exam normal. Treated with heat and ibuprofen.
28 Jul 04: 2nd visit for back pain. Daily occurrence of left lumbar, gluteal and posterior thigh pain, worse at end of day. Normal exam. Physician noted differential DDX to include herniation of the nucleus pulposus (HNP) and spinal stenosis.

4. HPI 2005: deployed overseas
11 Jun 07: Intermittent right and left buttocks pain radiating to bilateral feet. Treated with ibuprofen.
27 Sep 07: L-spine x-ray- erosions and sclerosis bilateral sacroiliac (SI) joints. Radiologist concerned about anklylosing spondylitis.
27 Sep 07: MRI L-spine - degenerative changes
01 Jul 08: PCS move

5. HPI
31 Oct 08: Patient reports 10 years of back pain, improved as day goes on and with exercise. Pain is located in bilateral buttocks radiating to posterior thighs.
31 Oct 08: HLA B27 positive, ANA negative, ESR 1 mm/hr and rheumatoid factor negative.
21 Jan 09: Humira recommended by rheumatologist at National Naval Medical Center

6. Back Pain
2nd most common symptomatic visit to physicians, next to upper respiratory infections.
70% of all adults have back pain.
Only 14% have an episode that lasts more than 2 weeks.
Deyo RA, Rainville J, and Kent DL. What Can the Medical History and Physical Examination Tell Us About Low Back Pain? In: Simel DL and Rennie D. The Rational Clinical Examination. McGraw-Hill Companies 2009;

7. Prevalence of Ankylosing Spondylitis
The estimated prevalence is 0.2% to 1.2%
Among adults with chronic low back pain: prevalence is about 5%

8. Ankylosing spondylitis
Greek: “ankylos” = bent
“spondylos” = spinal vertebra
Chronic inflammatory disease of axial skeleton causing back pain and progressive stiffness
Peak age years
Three times more prevalent in men

9. Spondyloarthritis
Ankylosing spondylitis (AS) belongs to group of disorders that share a predilection to cause inflammation at enthesis and an association with HLA-B27
Other members of spondyloarthritis (SpA) family: reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel disease

10. Pathogenesis Strong link between AS and HLA-B27
Relative Risk if 1st degree relative with AS: 16 to 94
Twin studies concordance of AS: 63% for identical twins
90% of risk estimated to be genetic
Only small percentage of HLA-B27 individuals in population suffer from a SpA (3-8% of Americans HLA-B27 positive), suggesting that other genetic and environmental factors may play a role

11. HLA-B27 Major histocompatability complex (MHC) class I allele
Presents peptides from intracellular pathogens for recognition by T-cell receptors of CD8+ T cells
Pathogenic link between HLA-B27 and AS elusive despite association of over 30 years

12. HLA-B27
Prevalence: 8% Caucasians; 4% African Americans; % Japanese
Northern Scandinavia: 24% HLA-B27 positive; AS prevalence: 1.8%
Bowness P HLA-B27 in health and disease: a double-edged sword. Rheumatology 2002; 41:

13. Pathophysiology
Characterized by chronic inflammation and progressive ankylosis
Commonly accepted that inflammation is driving force for structural damage in AS
Current research shows that tumor necrosis factor (TNF) is important cytokine contributing to inflammation in AS.
Maksymowych W. Imaging in Spondyloarthritis. In: Lopez-Larrea C. and Diaz-Pena R. eds. Molecular Mechanisms of Spondyloarthropathies Landes Bioscience and Springer Science Media.

14. Pathophysiology
Hallmark of structural abnormality in AS is bony ankylosis.
No molecular explanation for ankylosis.
Ankylosing Spondylitis. Wikipedia: accessed 07 Feb 10 at:

15. Natural History Poorly documented in literature
Variable severity of symptoms and radiographic progression
Slow speed of disease progression
Until recently, lack of validated outcome measure
No motivation to study AS until Anti-TNFs arrived on scene
Average age of onset: 25 years
Mean time between diagnosis and onset of symptoms: 8.6 years
Average age of retirement 39.4 years
Mean disease duration at retirement: years
AS cause of work cessation: 96%
Gran JT and Skomsuoll JF. The outcome of Anklosing Spondylitis: a study of 100 patients. Brit J Rheum. 1997;36:

16. History - Inflammatory back pain
Onset before age 40 years
Insidious onset
Improvement with exercise
No improvement with rest
Pain at night (with improvement upon arising)
Patient has a 25% probability of having ankylosing spondylitis if four of five of the above symptoms are present, assuming a 5% prevalence of AS among patients with chronic low back pain.
Kruszka PS. Ankylosing Spondylitis. In: Ebell MH, Ferenchick G, Smith M, Barry H, Slawson D, Shaughnessy A, Forsch R, Li S, Wilkes M, Usatine R, eds. Essential Evidence. John Wiley and Sons: Hoboken, NJ, 2009.

17. Mathematics Pre-test odds = prevalence/(1-prevalence) = 5%/95% = 0.05
Likelihood ratios (LRs) = sensitivity/(1-specificity)
Onset before 40: 1.12
Morning stiffness: 2.56
Improvement with exercise: 2.62
Post-test odds = pre-test odds x likelihood ratios = 0.05x1.12x2.56x2.62 =
0.37
Post-test probability = post-test odds/(post-test odds + 1) =
0.37/1.37 = 27%
Sackett DL. Evidence-Based Medicine: How to Practice and Teach EBM 2nd Edition. London 2000: Churchill Livingstone.

18. Exam
Schober test
Lateral spine flexion test
Chest expansion test

19. Schober’s test Make a mark between two posterior superior iliac spines
Make another mark 10 cm above first mark
Have patient bend at waist
Distance between two marks normally if greater than 15 cm

20. Chest expansion Measured at level of 4th intercostal space.
The difference between maximum inspiration and expiration is measured
An expansion less than 2.5cm is abnormal

21. Lateral spinal flexion
Heel and back against wall
Measure distance from middle finger to floor
Bend sideways without bending knees and repeat measurement
Greater than 10cm is normal

22. Radiographic Diagnosis
X-ray is standard for diagnosing sacroiliitis and differentiating AS from undifferentiated spondyloarthritis (SpA)
Poor sensitivity in early stages of disease
Braun J. and van der Heijde D. Imaging and scoring in ankylosing spondylitis. Best Pract Clinn Rheumatol ; 16(4):

23. Grade 1 Blurring of the joint margins

24. Grade 3
Severe erosions with widening of joint space +/- ankylosis

25. Grade 4
Complete ankylosis

26. MRI Most sensitive imaging for detection of inflammation.
Ankylosing Spondylitis. Wikipedia: accessed 07 Feb 10 at:

27. Differential Diagnosis
Rheumatoid arthritis - predominantly affects peripheral joints and is rheumatoid factor positive.
Psoriatic arthritis - usually accompanied by skin and nail disease
Reactive arthritis - follows a genitourinary or intestinal infection (“Can’t pee, can’t see, can’t bend at the knee”)
Inflammatory bowel disease arthritis - usually follows GI symptoms.

28. The Modified New York Criteria
One clinical criterion
Inflammatory back pain
Limitation of mobility of the lumbar spine
Limitation of chest expansion
Radiologic criterion
Radiologic sacroiliitis of grade 2 bilaterally
Radiologic sacroiliitis of grade 3-4 unilaterally
Van der Linden SM, Valkenburg HA, Cats A. Evaluation of the diagnostic criteria for ankylosing spondylitis: a proposal for modification of the New York criteria. Arthritis Rheum 1984;27:361-8.

29. History and Physical Tests (assuming pretest probability 5%)
Clinical Finding
LR+
LR-
Probability of disease present
Probability of disease absent
Morning stiffness > 30 minutes
2.56
0.5
12%
2.5%
Improves with exercise but not rest
2.62
0.6
2.9%
Alternating buttock pain
3.1
0.7
14%
3.7%
Anterior spine flexion < 5cm
2.6
0.1
0.7%
Lateral spine flexion < 10cm
6.8
26%
3.6%
Kruszka PS. Ankylosing Spondylitis. In: Ebell MH, Ferenchick G, Smith M, Barry H, Slawson D, Shaughnessy A, Forsch R, Li S, Wilkes M, Usatine R, eds. Essential Evidence. John Wiley and Sons: Hoboken, NJ, 2009.

30. Diagnosis and treatment algorithm for AS
4 of 5 criteria: 1) onset of back pain before age of 40 yrs 2) insidious onset, 3) persistence for at least 3 months, 4) associated with morning stiffness, or 5) improvement with exercise? No
Consider another diagnosis
Yes
25% probability of having AS assuming 5% prevalence of AS in chronic low back pain.
Anterior spine flexion of < 5 cm (Schober’s test) and chest expansion of < 2.5 cm increase probability of diagnosis but are often absent in ear disease.
Yes
Order sacroiliac x-ray. Is the radiologic criterion o grade 2 sacroiliitis bilaterally or grade 3 or 4 unilaterally satisfied?
Definite diagnosis; treat as AS No
Patient still has possible early AS. Order HLA-B27.
Positive
Negative
Patient has a 80% chance of having early AS. Consider a trial of NSAIDs and physical therapy or a rheumatologist referral
Patient has less than 3% chance of having AS. Consider another diagnosis.
Kruszka PS. Ankylosing Spondylitis. In: Ebell MH, Ferenchick G, Smith M, Barry H, Slawson D, Shaughnessy A, Forsch R, Li S, Wilkes M, Usatine R, eds. Essential Evidence. John Wiley and Sons: Hoboken, NJ, 2009.

31. Limitations of criteria for AS
Radiographic evidence may not show up for years.
Restriction of spinal mobility also may be a late finding.

32. A case for early diagnosis
In the past, treatment options were limited to physical therapy and NSAIDs.
In the past, a delay in diagnosis did not affect patient due to lack of highly effective therapeutic medications.
Recently, tumor necrosis factor  (TNF) blocking agents have shown a strong response.
AS patients with short disease duration and good functional status respond better to TNF blocking agents.
Rudwaleit M, Khan MA, and Sieper J. The challenge of diagnosis and classification in early ankylosing spondylitis. Do we need new criteria? Arth Rheum (4):

33. Extra-axial manifestations
Cross sectional study of 100 Norwegian patients with average duration of 17 years
Peripheral arthritis 40%
Anterior uveitis 33%
Aortic insufficiency 14%
Gran JT, Skomsvoll FJ. The outcome of Ankylosing Spondyliis: A study of 100 patients. British Journal of Rheum 1997;36:

34. Treatment Summary
Use NSAIDs and physical therapy as first-line therapy
Tumor Necrosis Factor  blocking agents (anti-TNFs) provide rapid and effective improvement in pain and function.
Total hip arthroplasty and spinal surgery are of value in selected patients

35. Rehabilitation and Physical Therapy
A review of six randomized and quasi-randomized trials with a total of 561 participants showed that group and individual physical therapy leads to significant improvement in relief of symptoms and physical function.
Dagfinrud H, Hagen KV, Kvien TK. Physiotherapy interventions for ankylosing spondylitis (Cochrane Review). The Cochrane Library 2007 Issue 1. Chichester, UK: John Wiley and Sons, Ltd.

36. NSAIDs
Numerous studies show that NSAIDs provide rapid improvement in back pain and physical function
Toxic side-effects on GI tract
A 2 year RCT (n=215) showed reduced radiographic progression in AS patients treated with continuous (celecoxib) compared to on demand treatment.
Wanders A, van der Heijde D, Landewe R, Behier JM, Calin A, Olivieri I, Zeidler H. Nonsteroidal anti-inflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis. Arthritis and Rheumatism (6):

37. Ant-TNFs Anti-TNFs provide excellent and quick symptomatic relief
Withdrawal of anti-TNFs often results in relapse
Long-term anti-TNF decelerates but does not inhibit structural deterioration in patients with AS.
Long term side effects unknown

38. Regression of spinal inflammation
A RCT of 20 patients, 9 randomized to infliximab infusions at 0,2,6 and 11 weeks and 11 patient received placebo
MRI active lesions improved 60% in the infliximab group and deteriorated by 21% in the placebo group
Conclusion: significant regression of spinal inflammation seen in MRI scores of infliximab group
Braun J, Baraliakos X, Golder W, Brandt W, Rudwaleit M, Listing J et al. Magnetic resonance imaging examinations of the spin in patients with ankylosing spondylitis, before and after successful therapy with infliximab: evaluation of a new scoring system. Arthritis Rheum (4):

39. Radiographic progression for anti-TNFs
Study
Number
Mean mSASSS change from baseline to year 2
P value
Etanercept1
OASIS
257
175
0.9+/-2.5
1.0+/-3.2
0.996
Infliximab2
156
165
0.9+/-2.6
0.541
Adalimumab3
307
169
0.8+/-2.6
0.9+/-3.3
0.771
van der Heijde D, Landewe R, Eistein S, Ory P, Vosse D, Ni L et al. Radiographic progression of ankylosing spondylitis after up to two years of treatment with etanercept Arthritis Rheum 2008, 58:
van der Heijde D, Landewe R, Baraliakos X, Houben H, van Tubergen A, Wiliamson P et al. Ankylosing spondylitis Study for the Evaluation of Recombinant Infliximab Therapy Study Group: Radiographic findings following two yers of infliximab therapy in patients with ankylosing spondylitis. Arthritis Rheum 2008, 58:
van der Heijde D, Salonen D, Weissman BN, Landewe R, Maksymowych WP, Kupper Harmut et al. Assessment of radiographic progression in the spines of patients with ankylosing spondylitis treated with adalimumab for up to 2 years. Arthritis Research and Therapy 2009, 11:R127.

40. Prognosis
In a study of 51 patients over a 23 year period whose mean disease duration was 38 years:
74% of patients who had mild spinal restriction after 10 years did not progress to severe spinal restriction
81% with severe restriction of the spine were restricted in the first 10 years.
Pradeep DS, Keat A, and Gaffney K. Predicting outcome in ankylosing spondylitis. Rheum 2008;47(7):942-5.

41. Spinal cord injury
Odds ratio for clinically significant vertebral column fractures, as compared with rate in the general population: 7.7
Jabobs WB, Fehlings M. Ankylosing spondylitis and spinal cord injury: origin, incidence, management, and avoidance. Neurosurg Focus 2008;24(1):E12

42. Prognostic Factors Early age of onset Male gender Hip arthritis
Prevalence of any three of following with in 2 years of diagnosis:
ESR > 30 mm/hr
NSAID unresponsiveness
Limitation of lumbar spine movement
Sausage-like digits
Oligoarthritis
Smoking
Extra-articular features
Pradeep DS, Keat A, and Gaffney K. Predicting outcome in ankylosing spondylitis. Rheum 2008;47(7):942-5.

43. Adalimumab Trial Evaluating Long-Term Efficacy and Safety In AS (ATLAS)
Ongoing 5 year study that included initial 24 week RCT followed by open-label extension
Treatment Humira 40mg SQ QOW ($14,000/year)
24 week RCT: significant improvement compared with placedbo: BASDAI (P<0.001); BASFI (P<0.001), ASQOL (P<0.001), ASQOL (P<0.001), SF-36 PCS (P<0.001)
Of 315 patients enrolled in ATLAS, 288 participated in open-label extension and 82% presented 3 year outcome data
Mean changes from baseline through 3 years statistically significant
Van der Heijde DM, Revicki DA, Gooch KL, Wong RL, Kupper H, Harnam N, homposn C, Sieper J. Physical function, disease activity and health-relatd quality of life outcomes after 3 years of adalimumab treatment in patients with AS. Arthritis Res Ther. 2009;11(4):R124.

44. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
Please place a mark on each line below to indicate your answer to each question relating to the past week
1. How would you describe the overall level of fatigue/tiredness you have experienced?
NONE _____________________________________________ VERY SEVERE
2. How would you describe the overall level of AS neck, back or hip pain you have had?
3. How would you describe the overall level of pain/swelling in joints other than neck, back, hips you have had?
4. How would you describe the overall level of discomfort you have had from any areas tender to touch or pressure?
5. How would you describe the overall level of morning stiffness you have had from the time you wake up?
6. How long does your morning stiffness last from the time you wake up?
_____________________________________________
0 hrs ½ 1 1½ 2 or more hours

45. Bath AS Functional Index (BASFI)
Putting on your socks or tights without help or aids?
Bending forward from the waist to pick up a pen from the floor without an aid?
Reaching up to a high shelf without help or aids?
Getting up out of an armless dining room chair without using your hands?
Standing unsupported for 10 minutes without discomfort?
Climbing steps without using a handrail or walking aid?
Getting up off the floor without any help from lying on your back?
Looking over your shoulder woithout turning your body?
Doing physically demanding activities?
Doing a full day activities whether it be at home or work?

46. Van der Heijde DM, Revicki DA, Gooch KL, Wong RL, Kupper H, Harnam N, homposn C, Sieper J. Physical function, disease activity and health-relatd quality of life outcomes after 3 years of adalimumab treatment in patients with AS. Arthritis Res Ther. 2009;11(4):R124.

47. Van der Heijde DM, Revicki DA, Gooch KL, Wong RL, Kupper H, Harnam N, homposn C, Sieper J. Physical function, disease activity and health-relatd quality of life outcomes after 3 years of adalimumab treatment in patients with AS. Arthritis Res Ther. 2009;11(4):R124.

48. Bottom Line
Symptoms suggesting inflammatory back pain include: onset age 40, insidious onset, persistence of pain for 3 months, morning stiffness, improvement with exercise (SORT C)
Radiographic sacroiliitis confirms the diagnosis; however, these findings are often absent during early disease (SORT C)
In the presence of inflammatory back pain and negative x-rays, order HLA-B27 to increase the probability of early diagnosis (SORT C)
NSAIDs and physical therapy should be used as the first-line therapy, as they improve symptoms and function (SORT A)
Tumor necrosis factor blocking agents provide rapid and effetive improvement in pain and function and should be considered if NSAIDs and physical therapy are not effective (SORT A)

49. Strength of Recommendation Taxonomy (SORT)