1. BioPharma 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. Family of Spondyloarthropathies AS Undifferentiated Spondylo- arthropathy Juvenile Spondylitis IBD Associated Arthritis Psoriatic Arthritis Reactive Arthritis SAPHOAcute Ant. Uveitis

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

7.  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 Spondyloarthopathies (SpA)

8.  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 naillesions (onycholysis, dystrophy, pitting). SpA: Associated Extraarticular Features

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

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-B27 Khan 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. Modified New York Criteria for AS  Clinical criteria  Low back pain and stiffness for >3 mo, which improves with exercise, but is not relieved by rest  Limited lumbar spine motion: in sagittal and frontal planes  Limitations of chest expansion (age/sex standardized)  Radiographic criteria: Requires EITHER Bilateral sacroiliitis  Grade 2 or Unilateral sacroiliitis  Gr 3 Definite AS =  1 clinical plus 1 radiographic criteria Probable AS = 3 clinical criteria and no radiologic criteria or 1 radiologic criterion and no clinical criteria van der Linden S, et al. Arthritis Rheum. 1984;27:361-368.

19. Ankylosing Spondylitis Differentiating Inflammatory vs Mechanical Back Pain Inflammatory Back PainFeaturesMechanical Back Pain Prolonged > 60min.AM StiffnessMinor < 45 min. Early AMMax. Pain/StiffnessLate in day Improves SymptomsExercise/activityWorsens Symptoms ChronicDurationAcute or Chronic 9-40 yrs.Age at Onset20-65 yrs. Sacroiliitis, Vertebral ankylosis, syndesmophytes RadiographsOsteophytes, malalignment

20.  Diagnosis is usually delayed 5-7 years.  Mean 7.5 years from onset of LBP to XRay sacroiliitis  Incidental diagnosis often made on XRAYs (pelvis, LS or thoracic spine, CXR).  Diagnosis suggested by extraspinal manifestations: enthesitis, uveitis (30-40%), peripheral oligoarthritis  Rarely Late diagnosis with Complications: Spinal fusion, fracture, cauda equina syndrome, restrictive lung disease, aortic insufficiency DX of ANKYLOSING SPONDYLITIS

21. 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 Findings Probability of SpA (%) Low back pain5% Inflammatory LBP 14% SpA Features* 1-2 >3 30-70% >90% XRay Evidence >90% (AxialDz) HLA-B27>90% (Axial+Periph)

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

25. Ankylosing Spondylitis: X-rays

26. Sacroiliitis grade II bilat. Sclerosis Erosions

27. Special maneuvers:

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

30. Tragus to Wall Distance Patient stands, heels and buttocks against the wall, the head is placed back as far as possible, keeping the chin horizontal J Brandt, J Sieper

34. Enthesopathy  Periosteal new bone formation Bone McGonagle D. Arthritis Rheum. 1999;42:1080-1086.  Subchondral bone inflammation and resorption Tendon ©ACR 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

35. 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

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

37. 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)

38. 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

39. Chlamydial Arthritis  More than 50% of Reiter’s patients have Abs to Chlamydia  Chlamydial Ags by RNA or DNA probes found in joints  May account for up to 10% of all EARLY Arthritis patients  C. Trachomatis > C. psittaci or C. Pneumoniae (erythema nodosum, pneumonia, myocarditis)  Manifestations similar to Reiters, < 50% B27+; and ~15% have no urogenital sxs.  Dx: Sxs + serology or PCR probe  Rx: doxycycline > 3 mos. to eradicate infx and decrease sequelae

40. Post-Dysenteric Outbreaks of Reiters  Epidemics of known arthritogenic bacteria  < 20% of HLA-B27(+) persons develop incomplete ReA  Fewer develop complete ReA syndrome  Pts w arthritis more likely to be HLA-B27 negative in some studies  Shigellosis: 0.2-2% of patients develop ReA  often diarrhea resolves before arthritis appears  Salmonella: 1-3% develop ReA (6-12% seen?)  Like Shigella, arthritis more likely in HLA-B27 or HLA-B7 (+)  Other cross reactive Ags: Bw22, B40, B42, or B60

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

42. KB: keratoderma blenorrhagicum

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

45. What is the diagnosis? a)Bad manicure b)Rheumatoid arthritis c)Psoriatic arthritis d)Erosive OA

46. 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%

47. Classification of Psoriatic Arthritis TypeKey Clinical FeaturesIncidence Asymmetric polyarthritis or oligoarthritis Morning stiffness, DIP and PIP involvement, nail disease,  4 joints involved 40% Symmetric polyarthritis Symmetric polyarthritis, RA-like distribution, but RF negative 25% Spondylitis Inflammatory low back pain, sacroilitis, axial involvement, 50% HLA-B27+ 20% Distal interphalangeal joint disease Nail changes, often bilateral joint involvement 15% Arthritis mutilans Destructive form of arthritis, telescoping digits, joint lysis, typically in phalanges and metacarpals <5%

51. Pencil and Cup Deformity

52. PsA Dx Algorithm Established Cutaneous Psoriasis Widespread Pain Joint PainBack Pain Fibromyalgia Inflammatory LBP? 1.Morning Stiffness/Pain 2.Improved with activity 3.Chronicity No Mechanical LBP Xray SI, LS, Cx spine Psoriatic Spondylitis Inflammatory Arthritis? 1.Squishy swollen jts 2.Red tender joints 3.AM Stiffness > 45 min 4.Chronicity > 6 wks Symmetric? Yes No RF? RA Yes No Rheumatoid-like Psoriatic arthritis Look for: Mono/oligoarthritis Enthesitis Dactylitis Psoriatic Arthritis Yes No Inflam. OA Crystal arthritis Undiff. SpA Yes Osteoarthritis No Yes

53. 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

54. 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!

56. 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

57. 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

58.  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? SpA: Therapeutic Options

59.  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! NSAIDs

60.  Consider DMARDs when:  Antiinflammatory therapy is insufficient to control Sxs  Progression of inflammatory axial disease  Active persisent polyarthritis  Uncontrolled extra-articular disease  But Which DMARD?  None shown to be effective at Axial disease  None FDA approved for AS, SpA  MTX indicated in psoriasis – not psoriatic arthritis –Hepatotoxicity Issues  Reliance on anecdotes and RA experience NSAID Resistant AS/SpA

61.  Gold - no proven benefit!  Intramuscular (aurothioglucose, aurothiomalate)  Auranofin 238 AS pts:no effect on Axial dz; but +effect on MD global, function  Primarily studied in psoriatic arthritis > AS > Reactive  Hydroxychloroquine  Controlled and uncontrolled trials in psoriatic arthritis, suggesting some efficacy.  Azathioprine: Uncontrolled and controlled trials in ReA and psoriatic arthritis  MTX: no benefit in AS  Beneficial in psoriasis and psoriatic arthritis Ineffective DMARDs

62. Conclusion Spondyloarthropathies  Inflammatory arthropathies  Share genetic, clinical and radiologic features  Ag driven immune response causing symptoms  New therapies allow for more effective management of these diseases

63. Methotrexate in AS and Psoriatic Arthritis  AS 1  51 Pts, MTX 7.5 mg/Napr vs Naproxen/Placebo x 12 mos  Negative results (only MD global improved)  AS 2  31 patients, 7.5 mg/week for 6 months, placebo controlled  Significantly more patients had good response with MTX than placebo (53% vs 13%, P=0.019)  Psoriatic arthritis 3  37 patients, 12 weeks, prospective  Improvements only in physician assessment of joint activity and skin area 1 Altan L, et al. Scand J Rheumatol. 2001;30:255-259. 2 Gonzalez-Lopez L, et al. Arthritis Rheum. 2002;46(suppl). Abstract 1134. 3 Willkens RF, et al. Arthritis Rheum. 1984;27:376-381.

64. Sulfasalazine in SpAs: AS, PsA, and ReA  619 patients  Axial disease (n=187)  Peripheral articular (n=432)  SSZ 2 gr/day vs Placebo  36 weeks  Results:  Axial – no SSZ response  Peripheral – favor SSZ (P=0.0007)  SSZ effective for peripheral arthritis of SpAs Clegg DO, et al. Arthritis Rheum. 1999;42:2325-2329.

65. Pamidronate in AS  Bisphosphonate bone-resorption inhibitor  84 AS patients, active disease refractory to NSAIDs  Randomized, double-blinded assignment  Infusion 60 mg vs 10 mg PAM q mo for 6 mo  Significant improvement in axial symptoms in the 60 mg group vs 10 mg group  No significant difference in joint pain or CRP/ESR  Well-tolerated, low withdrawal rate Maksymowych WP, et al. Arthritis Rheum. 2002;46:766-773.

66. Thalidomide in AS Huang F, et al. Arthritis Rheum. 2002;47:249-254.  26 AS patients  12-month, open-label trial; 200 mg/day  80% had improvement >20% in 4 of 7 indices  9 patients became pain free Wei JC, et al J Rheumatol 2003; 30: 2627  13 Males with resistant AS  24 weeks, open-label trial; 200 mg/d  3 withdrew for rash  2 Lost to follow-up  8/10 improved?? BASDAI, BASFI, ESR (not CRP)  Acts by decreasing expression of TNF and other proinflammatory genes?

67. Rationale for TNF Therapy in Spondyloarthropathies  SpA Primary Pathology = Enthesitis  McGonagle D, etal. Curr Opin Rheum 11:244, 1999  Transgenic mice overexpressing TNF  develop enthesitis and arthritis resembling AS w/ axial skeletal kyphosis & ankylosis with inflammatory & fibrotic change @ end plates, entheses  Crew MD, et al. J Interferon Cytokine Res. 18:219, 1998  Localization of TNF in Sacroiliac joints  Stone M, et al. Arthritis Rheum 2000 [abstract]  Osteoclasts and Synoviocytes in PsA express RANKL - Ritchlin C, et al. ACR 2001  Therapeutic benefit of TNF inhibition in AS & PsA

68. Pre-infusionPost-infusion Stone M et al. Arthritis Rheum 2000 (abstract). 2 Days Use of Infliximab in Spondyloarthropathy: Efficacy

69. BASDAI  The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) measures disease activity based on 6 self- administered questions relating to:  Fatigue  Spinal pain  Peripheral arthritis  Enthesitis  Morning stiffness : 2 questions (meaned) Average 1- 5/6; range 0-10 Garrett S, et al. J Rheumatol. 1994;21:2286-2291.

70. ASAS 20 Preliminary Response Criteria AS Patient global VAS Patient Pain VAS Patient Pain VAS Function (BASFI) Stiffness (BASDAI) Improvement of 20% AND 10 units in at least 3 domains No worsening in remaining domain Anderson et al Arthritis Rheum 2001:44:1876-886 ASAS Partial Remission: < 20 in all 4 domains