The Spondyloarthropathies

1. The Spondyloarthropathies Kathryn Dao, MD Arthritis Center September 15, 2005

2. Objectives • Identify the different spondyloarthropathies • Beware of misconceptions • Know the clinical features • Be familiar with treatment options

3. 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

4. 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)

5. ReactiveArthritis JuvenileSpondylitis Acute Ant. Uveitis SAPHO PsoriaticArthritis AS UndifferentiatedSpondylo-arthropathy IBD AssociatedArthritis Family of Spondyloarthropathies

6. Evolution of Undifferentiated SpA to AS n = 88 initially n = 54 after 10 yrs Definite radiological sacroiliitis: after 9-14 yrs Mau et al. J Rheumatol 1988;15:1109

7. Spondyloarthopathies (SpA) • Spondyloarthropathy: several criteria have been proposed • Key Features: • Inflammatory axial arthritis (sacroiliitis and spondylitis) • Peripheral arthritis (often asymmetric and oligoarticular) • Enthesitis • HLA-B27 positivity • XRay evidence of erosions + hyperostosis (reactive bone) • Extra-axial, Extra-articular Features

8. SpA: Associated Extraarticular Features • 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).

9. Spondyloarthopathies ESSG Criteria* Inflammatory Spinal Pain Synovitis (Asymmetrical or Predominantly lower limbs) OR • 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 PLUS (One or more of the following:) * European Spondyloarthropathy Study Group Criteria for Spondyloarthropathy, 1991 Sensitivity 78-88%; Specificity 92-95% Dougados M, et al. Arthritis Rheum. 1991 Oct;34(10):1218-1227.

10. 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

11. 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?

12. 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

13. Clinical Associations with HLA-B27Khan MA. Ann Int Med 2002

14. Ankylosing Spondylitis

15. Ankylosing Spondylitis in USA

16. Unlike children, adults who are diagnosed with AS have SI joint involvement early in the disease (True/False)?

17. 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

18. Ankylosing SpondylitisDifferentiating Inflammatory vs Mechanical Back Pain

19. 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

20. Spinal Limitation Functional limits Night Pain LBP Stiffness Fatigue Spinal Immobility Symptoms Aortitis Restrictive lung Heart block Ocular Skin/nail Enthesitis Extra-articular Manifestations Chronic Uveitis IBD Sacroiliitis Hip involvment Spondylitis Disease Progression Periph.arthritis Bamboo Spine AS complications Drug toxicity Comorbidities Pain Functional limitation Fracture Death Morbidity Mortality Spectrum of AS Onset Early Moderate Severe

23. Ankylosing Spondylitis: X-rays

24. Lumbar Flexion (Schober) Result: 0.5 cm (normal > 4 cm) 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 J Brandt, J Sieper

28. Enthesopathy Inflammatory Rheumatoid arthritis Ankylosing spondylitis Reiter's syndrome Psoriatic arthritis Inflammatory bowel disease Lyme disease Late‑onset Pauciarticular JRA Leprosy Mechanical/Degenerative Trauma Osteoarthritis Metabolic/Endocrine DISH Acromegaly Fluorosis Retinoid therapy Hypoparathyroidism Hyperparathyroidism POEMS syndrome X‑linked hypophosphatemia Tendon Bone • Periosteal new bone formation • Subchondral bone inflammation and resorption ©ACR McGonagle D. Arthritis Rheum. 1999;42:1080-1086.

29. 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

30. Reactive arthritis have been associated with all the following except: a) Chlamydia b) Ureaplasma c) Campylobacter d) Gonorrhea

31. 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)

32. 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

33. Sausage Digits = periostitis + enthesitis + synovitis. Seen in SpA, JRA, MCTD • GU involvement • Urethritis • Prostatitis • Orchitis • Balanitis • Vaginitis • Cervicitis

34. KB: keratoderma blenorrhagicum

36. 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 Reactive Arthritis: Treatment • Antibotic TX (doxycycline, ciprofloxacin) x3 mos indicated with proven ReA • Abx do not affect outcome of Shigella, Salmonella infection

37. What is the diagnosis? • Bad manicure • Rheumatoid arthritis • Psoriatic arthritis • Erosive OA

38. 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%

39. Classification of Psoriatic Arthritis

43. Pencil and Cup Deformity

44. 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

45. 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!

47. 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, Tbc Khan MA. AR.;20: 909, 1977 Maksymowych WP. ARD 54:128, 1995

48. 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

49. SpA: Therapeutic Options • 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?

50. NSAIDs • 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!