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Slide 1-

Seronegative Spondyloarthritides Kathryn Dao, MD Presbyterian Hospital Arthritis Consultation Center July 24, 2008
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Goals Define the spondyloarthritides Review the pathophysiology Recognize clinical presentations Discuss differential diagnoses List possible diagnostic tools Identify available therapeutics
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The “SERONEGATIVE” in Seronegative Spondyloarthritis refers to the absence of: Rheumatoid factor HLA-B27 ESR ANA choices a+b choices a+b+d
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Group of diseases characterized by: Inflammatory axial skeleton involvment (e.g, sacroiliitis and spondylitis) Asymmetric peripheral arthritis Enthesopathy Inflammatory eye disease Overlapping mucocutaneous features Spondyloarthritides: Definition Occurring in the absence of serum rheumatoid factor
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Nomenclature Classic papers used the term spondylitis deformans to designate all types of spinal arthritis– stiffness and deformity affecting the spine. Confusion as can be due to congenital conditions, infection, degenerative or inflammatory changes Thus, intepretation of historical data may not be as accurate R. Bloom and P. Smith. Skeletal Radiol 1992;21:111-114.
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Historical background “A layer of new bone may be seen covering the whole length of the dorsal and lumbar spine as if some soft liquid osseous material had been poured over them, and this had subsequently hardened.” --- Connor 1694 1694 Connor: French graveyard, skeleton with unusually straight vertebrae with fused articulations and “bony” ligaments 1884 Strumpell: 2 cases of “gradual and painless ankylosis of entire spinal column and hip joints” in hospitalized patients 1892 Bechterew- upper dorsal type case complicated by meningeal and spinal cord involvment “Bechterew’s disease” 1898 Marie- described the entity as separate from all other types of arthritis involving the spine P. Zorab. Proceedings of the Royal Society of Medicine 1961;54:415-20.
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Historical background 1920s roentgenographic findings of sacroiliitis and syndesmophytes 1930s-1950s discovery of human skeletons from Bronze Age, Egyptian times (4500 B.C.), Viking ships (10 A.D.) with ankylosing spondylitis; Could this be a variant of RA? 1940-50s Discovery of the human leukocyte antigens (HLAs) and characterization of the MHCs 1960s- American Rheumatism Association (ARA) recognized the spondyloarthropathies as a distinct group of inflammatory arthritis 1973 Association found between HLA-B27 and the spondyloarthropathies P. Zorab. Proceedings of the Royal Society of Medicine 1961;54:415-20.
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Spondyloarthritides: The Spectrum IAVB
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The Role of HLA-B27 Spondyloarthritis
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CASE STUDY 42 y.o. BM presents with a 20 year history of inflammatory back pain—wakes him up at night, gets better with activity, uveitis, and progressive stiffening of his upper back and neck. SI joint films revealed bilateral sacroiliitis, spinal x-rays showed syndesmophytes. HLA-B27 was negative. Does this patient have ankylosing spondylitis? YES
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Pathogenesis Etiology/pathogenesis unclear Interplay of genetic, immunologic and environmental factors Interaction between MHC-I molecule HLA-B27 with T cell response believed to be key in pathogenesis. 94% of AS patients are HLA-B27+(OR 161 [CI 113-230]) Bacterial infections may trigger events M Tc HLAB27 Intense Inflammatory response Ag TCR McMichael A and Bowness P. Arthritis Res 2002;4 (suppl 3):S153-8.
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Role of HLA-B27 Has a role in presenting protein antigens that have been synthesized in the cell (viral, tumor, self-derived) to cytotoxic T-cells HLA-B27 individuals are less efficient at elimination of intracellular organisms (e.g, Chlamydia) and certain enteric bacteria Unclear if disease susceptibility is due to presentation of an arthritogenic peptide vs. failure to eliminate intracellular organisms vs. itself acting as a source of Ag 25 different subtypes have been identified: B*2705, B*2704, B*2702 or B*2707 have accounted for most of the spondyloarthritides McMichael A and Bowness P. Arthritis Res 2002;4 (suppl 3):S153-8.
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HLA molecules are believed to have evolved in response to environmental stressors (e.g, viral infections) 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 10%. there is 20-30% risk to 1st degree relatives with AS No justification to test asymptomatic relatives! B27 increases risk of SPONDYLITIS and UVEITIS McMichael A and Bowness P. Arthritis Res 2002;4 (suppl 3):S153-8. Spondyloarthritis
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Frequency of HLA-B27 McMichael A and Bowness P. Arthritis Res 2002;4 (suppl 3):S153-8.
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I N F L A M M A T I O N ENTHESITIS (TENO-) SYNOVITIS Dactylitis BONE REMODELING BONE REACTIVE SCLEROSIS & RESORPTION (EROSIONS) NEW BONE FORMATION & ANKYLOSIS PATHOLOGY OF SPONDYLOARTHRITIS Subchondral tissue become granulomatous and infiltrated by inflammatory cells FIBROCARTILAGE REPLACES NORMAL TISSUE
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Epidemiology of AS Males are affected more often than females (3:1) Disease pattern vary by sex (men more severe disease with predominant axial manifestation, women less severe with peripheral joints more commonly involved) Studies of siblings and twins suggest 16-50% genetic risk, concordance rate of monozygotic twins 75% Age of first spondylitic symptom: 15-40 y.o. German study 3000 patients – 4% <15 y.o, 90% 15-40 y.o, 6% >40 y.o. German rheumatologic database (n=8776) found mean age of onset was 28.3 years Sieper J et al. Ann Rheum Dis 2002:61(suppl III):iii8-18.
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Ankylosing Spondylitis in USA Khan MA. Ann Intern Med. 2002; 136:896-907
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Underwood & Dawson. Brit J Rheumatol 1995; 35: 1074-7 “5% of back pain sufferers may have a mild form of AS that may never progress to definite ankylosis, but for whom treatment as if they had AS may be of benefit”. 313 back pain sufferers filled questionnaire 46/313 (15%) had LBP (mean age 38.6 yrs) 33 were examined & 27 had x-ray of SI joints 2 had definite AS, and 18 had other features of SpA (ESSG) Prevalence of AS/Axial SpA among patients with chronic LBP in General Practice
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CASE STUDY 28 y.o. BM with a history of psoriasis and a family history of back and joint pain described pain and swelling of his right knee for the last 3 weeks after he had returned from a ski vacation with “the boys.” Of note, he has had a history of back pain himself which he attributes to playing football and other sports since high school; he noted that one of his toes on his right foot was swollen 6 months ago—he does not remember which one.
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Which should not be considered in the differential diagnoses? a) Gonococcal arthritis b) Internal derangement of the knee c) Systemic lupus erythematosus d) Gout e) Seronegative spondyloarthritis g) Osteoarthritis h) Rheumatoid arthritis
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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
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Prevalence of AS & Related SpA (%) Khan MA. Ann Intern Med. 2002;136:896-907. Epidemiology
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Saraux et al. J Rheumatol. 1999; 26:2622-7. Overall prevalence of RA = 0.62% (0.86 in F, 0.32 in M) Minimum (based on the initial group (3189)) = 0.53% Overall prevalence of SpA = 0.47% (0.53 in F, 0.41 in M ) Minimum (based on the initial group (3189)) = 0.41% CONCLUSION: RA & SpA are nearly equally prevalent in Brittany, France SpA is as common in women as in men. Prevalence of RA & SpA in Brittany, France
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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 Rudawaleit M, et al. Ann Rheum Dis 63:535, 2004; Khan M. Rheumatology, 2003; Underwood, Dawson. Br J Rheum 35:1074, 1995
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Chronic Low Back Pain Inflammatory back pain LR 3.1 Disease Probability Axial SpA/Pre-rad. AS Elevated ac. phase reactants LR 2.5 Heel pain (enthesitis) LR 3.4 Peripheral arthritis LR 4.0 Dactylitis LR 4.5 Acute anterior uveitis LR 7.3 Positive Family history LR 6.4 Good response to NSAIDs LR 5.1 HLA-B27 LR 9.0 MRI LR 9.0   3.1 x 7.3 = 22.3 (LR product) 5 % Rudwaleit M, et al. Arthritis Rheum 2005; 52:1000-8
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Ankylosing Spondylitis
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Making the Diagnosis
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Ankylosing Spondylitis Differentiating Inflammatory vs Mechanical Back Pain
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1. Clinical components: (a) Low back pain and stiffness for more than 3 months which improves with exercise, but is not relieved by rest. (b) Limitation of motion of the lumbar spine in both the sagittal and frontal planes (c) Limitation of chest expansion relative to normal values correlated for age and sex 2. Radiological component: Sacroiliitis grade > 2 bilaterally or grade 3-4 unilaterally Modified NY Classification Criteria for AS (1984) Definite AS if the radiological criterion is associated with at least 1 clinical criterion. Probable AS if: 1) Three clinical criteria present 2) radiologic criterion is present wtihout any sign or symptoms satisfying the clinical criteria (other sources of sacroiliitis should be considered) van der Linden et al., Arthritis Rheum 1984;27:361 Van der Linden S, Valkenburg HA, Cats A. Arthritis Rheum 1984;27:361-8.
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Time (years) Back pain Back pain Radiographic sacroiliiits Back pain Syndesmophytes Radiographic stage Early Diagnosis of Spondyloarthritis Pre-radiographic stage (axial undiff. SpA) Rudwaleit M, Khan MA, Sieper J. Arthritis Rheum. 2005; 52:1000-1008.
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Spondyloarthropathies Amor Criteria 1990 Amor B, et al. Rev Rheum Mal Osteoartic. 1990;57:85-89. Sens = 85%, spec 90%
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ESSG* Classification Criteria for SpA (*European Spondylarthropathy Study Group) Alternating buttock pain Sacroiliitis (x-rays) * Positive family history Psoriasis Inflammatory bowel disease Urethritis / acute diarrhea in the preceding 4 weeks Heel pain (enthesitis) Inflammatory Back Pain Synovitis Plus one of the following: Asymmetrical Lower extremities Dougados M, et al. Arthritis Rheum 1991;34:1218 *without sacroiliitis: sens =77%, spec 89% with sacroiliitis: sens = 86%, spec 87% OR
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ENTHESITIS The characteristic feature of AS and spondyloarthritides Inflammation at sites where tendons, ligaments or joint capsules attaches to the bone: primarily affects the sacroiliac joints & the axial skeleton in AS, but extra-articular or juxta-articular bony tenderness occurs from enthesitis at many other sites (e.g. costosternal junctions, spinous processes, greater femoral trochanters, iliac crests, ischial tuberosities, tibial tubercles, heels, etc.) Khan MA; Rheumatology. Eds. Hochberg M. London, Mosby. 3rd ed. 2003
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Enthesitis 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 Reactive arthritis 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 DDx:
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Spectrum of AS Early Severe Moderate Onset
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Lumbar Flexion (Schober) A mark is placed at L5, measure 10 cm cephalad and place another mark. Have the patient bends forward as far as possible with knees extended, the difference is recorded. Normal is >5 cm J Brandt, J Sieper
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Wall to Tragus 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
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Ankylosing Spondylitis: Radiographic findings
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Ankylosing Spondylitis: Arrange the following from early to late x-ray findings: Ankylosis (bamboo spine) Shiny vertebral corners (Romanus sign) with squaring of the vertebral bodies Sacroiliitis Syndesmophyte formation Sacroiliitis >> Romanus sign/squaring of vertebral bodies >> Syndesmophytes >> Ankylosis
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Sacroiliitis
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CT scan of sacroiliitis early and late stages
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QUIZ What is the patient’s diagnosis? “DISH”
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DISH: diffuse idiopathic hyperostosis Found typically in Caucasian males aged 50-75 years Ossification of anterior longitudinal ligament It is an enthesopathy – with thick bulky osteophytes Usually involves four contiguous vertebral bodies Disc height is maintained in affected area Involvement of SI joints excludes DISH The left side of spine in thoracic area typically remains uninvolved (lack of ossification because of pulsations of aorta)
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Severe Spinal Complications from AS Spinal stiffness/ankylosis in kyphotic position Spinal fractures (10-20%) axial/T spine; increased 6-8 fold Cauda equina synd. (arachnoiditis)
Slide 49-

Extra-Axial Manifestations
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Ocular (25-40%): uveitis, conjunctivitis Heart (29%): AI, heart block, aortitis Lung (10%): ILD, apical fibrosis, aspergilloma Kidney (14%): amyloidosis, nephritis, IgA nephropathy Bones: osteoporosis – bone resorption > bone formation Associated Extraarticular Features
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Gastrointestinal: oral ulcerations, asymptomatic gut inflammation, symptomatic colitis Genitourinary: urethritis, vaginitis, balanitis Cutaneous: keratoderma blennorrhagicum, psoriasis or nail lesions (onycholysis, dystrophy, pitting). Periarticular: tendonitis, dactylitis (sausage-digit) Associated Extraarticular Features Mortality: 1.5-4 fold increase  Amyloidosis, fractures, cardiovascular, gastrointestinal bleeding, pulmonary diseases, colon cancer, violence, alcohol
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REACTIVE ARTHRITIS
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REACTIVE ARTHRITIS Acute inflammatory arthritis occuring 1-4 weeks after infectious event (GU, GI, idiopathic) TRIAD: aseptic arthritis + urethritis (vaginitis) + conjunctivitis (classic triad found in < one-third of pts) Usually asymmetric oligoarticular + extraarticular Sxs Arthritis recurrent in 15-30%, more in chlamydia associated arthritis 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
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REACTIVE ARTHRITIS Conjunctivitis may occur in the same time as flares of arthritis Average duration of arthritis 4-5 months; 2/3 will have mild musculosketal symptoms for more than a year Recurrence more common with chlamydia-induced reactive arthritis (15-30%) Decreasing incidence in the HIV era (condom use) HIV itself can produce a reactive type of arthritis (in Zambia rate of spondyloarthritis is 180/100,000 in HIV infected individuals– 12 times higher than non-HIV persons)
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COMMON PATHOGENS Enteric Infections Shigella flexneri (0.2-2%) Salmonella typhimurium, S. enteritidis (1-3%) Yersinia enterocololitica, Y. pseudotuberculosis Campylobacter jejuni Clostridium difficile Urogenital Infections Chlamydia trachomatis, C. pneumoniae Ureaplasma Urealyticum BCG when instilled into the bladder (for treatment of bladder carcinoma) Infectious Triggers for Reactive Arthritis
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GU involvement Urethritis Prostatitis Orchitis Balanitis Vaginitis Cervicitis Sausage Digits = periostitis + enthesitis + synovitis. Seen in SpA, JRA, MCTD
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KB: keratoderma blenorrhagicum
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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
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Psoriatic Arthritis
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PSORIATIC ARTHRITIS (PsA) Chronic inflammatory arthropathy in setting of psoriasis Sites of psoriasis: scalp, ears, gluteal fold, umbilicus, perineum, palms, soles, nails, extremities Nail changes: pitting, dystrophy, onycholysis 1-5% of US population has Psoriasis: 5-42% of these develop psoriatic arthritis Frequency of PsA increases with disease severity and duration (estimated 350-400,000 patients in USA) Skin precedes nails, but 15% will have arthritis before skin disease Course: chronic, destructive arthritis in 30-50%
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Types of psoriasis: Guttate Pustular Plaque Erythrodermic
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8/21/2021 2:26:14 PM 62 Classification of Psoriatic Arthritis
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Subtypes of Psoriatic Arthritis
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Pencil and Cup Deformity
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PsA Dx Algorithm Established Cutaneous Psoriasis Widespread Pain Joint Pain Back Pain Fibromyalgia Inflammatory LBP? Morning Stiffness/Pain Improved with activity Chronicity Mechanical LBP Xray SI, LS, Cx spine Psoriatic Spondylitis Inflammatory Arthritis? Squishy swollen jts Red tender joints AM Stiffness > 45 min 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 Yes Osteoarthritis No Yes
Slide 66-

IBD-associated Arthritis
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IBD-associated Arthritis 5-39% 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, erythema nodosum, uveitis, pyoderma gangrenosum Gut disease may be asymptomatic for years
Slide 68-

IBD-associated Arthritis 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 Sacroiliitis is related to the duration of the disease
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TESTING for the Spondyloarthritides
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Laboratory HLA-B27 Patients may have normal ESR/CRP despite active disease 1991 multicenter study of 191 patients with AS Serum ALP may be elevated, normochromic anemia Spearman correlation coefficent (based on disease activity) =0.06-0.48 PPV = 0.15-0.69 Spoorenberg A. et al. J Rheumatol. 1999;26(4):980-4.
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Imaging Radiographs- inexpensive, readily available, poor sensitivity (see changes after 1-9 years of symptoms) CT- high radiation exposure, good to detect sclerosis, erosions, ankylosis MRI-expensive, most sensitive to detect early changes: bone marrow edema and effusions Bone scintigraphy/SPECT- may help in equivocal cases; sens/spec questionable
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Imaging Radiograph (L-spine, AP pelvis, SI joints) Grade 2-4 sacroiliitis Equivocal Grade I sacroiliitis Normal MRI CT or MRI Bone scan Equivocal Multifocal disease suspected No further studies Koehler et al. Rheumatolgy 2000;39;360-8.
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Assessment and Monitoring Dz Need to assess baseline disease activity and therapeutic responses Tools designed to measure aspects of disease: BASMI, BASDAI, BASFI, BASRI, BASG and Dougados functional index (Note: standardization and validation lacking)
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WHO/ILAR Core Domains for AS van der Heijde et al J Rheumatol 1999;26:951-4; ASAS workshop Gent, Oct 2002 fatigue DC-ART = disease controlling antirheumatic therapy SM-ARD = symptom-modifying antirheumatic drugs (NSAIDS)
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Assessment in Ankylosing Spondylitis International Working Group (ASAS): 20 Preliminary Response Criteria AS Anderson et al Arthritis Rheum 2001:44:1876-886 ASAS Partial Remission: < 20 in all 4 domains
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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.
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Bath Ankylosing Spondylitis Functional Index (BASFI) Indicate your level of ability during the last week: (easy to impossible) Putting on your socks without help or aids Bending forward from the waist to pick item from floor without aid Reaching up to a high shelf without help or aid Getting up from armless chair without using hands or other help Getting up off the floor without help from lying on your back Standing unsupported for 10 minutes without discomfort Climbing 12-15 steps without use of handrail or walking aid Looking over your shoulder without turning your body Doing physically demanding activities Doing a full days activities at home or at work
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Other Patient Reported Outcomes Total Back Pain — VAS Score Nocturnal Back Pain — VAS Score Patient Global — VAS Score
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Objectives: 1. relieve pain, stiffness, fatigue 2. maintain physical and psychosocial function Management of Disease
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Management Options for AS/Spondyloarthritides: Appropriate Patient Selection Before beginning treatment for AS, ask: Is the disease active? What aspect of AS are we treating?
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Nonpharmacologic measures Patient education, joint protection, maintenance of function and posture (Ankylosing Spondylitis Association, Arthritis Foundation) Lifestyle modification: Exercise, rest, physical therapy, diet, vocational counseling, smoking cessation Splints, braces and corsets—not helpful Pharmacologic therapies: Analgesic agents: too little too late NSAIDs - Mainstays of therapy Corticosteroids - rarely used; rarely effective DMARDs: (SSZ, MTX) for peripheral disease Biologics: (anti-TNF therapies) SpA: Therapeutic Options
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Effective: inflammatory back pain, spinal stiffness, peripheral arthritis, enthesopathy No evidence that NSAIDs inhibit disease progression ACR2003 Wanders, van der Heijde: celecoxib Rx pts less progression FDA-approved NSAIDs for AS: phenylbutazone indomethacin (-SR), enteric coated acetylsalicylic acid, naproxen, sulindac, diclofenac. Anecdotal reports & few studies suggest that specific NSAIDs may be more effective: Phenylbutazone (100 mg tid-qid): risk of agranulocytosis indomethacin: especially in long acting form. CNS Sx? diclofenac: as effective as Indocin, less toxic? LFTs! NSAIDs
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COX-2 Inhibitors in AS Celecoxib taken regularly (not on PRN basis) slowed radiographic progression of AS1 mSASSS = modified Stoke Ankylosing Spondylitis Spinal Score. 1. Wanders A. et al. Arthritis & Rheum 2005;52(6):1756-65. 2. Van der Heijde et al. Arthritis & Rheum 2005;52(4):1205-15. P=0.02 Mean change Etoricoxib was superior to naproxen over 1 year2 P<0.05
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Consider DMARDs when: Anti-inflammatory therapy is insufficient to control Sxs Active persisent polyarthritis Uncontrolled extra-articular disease But Which DMARD? None shown to be effective with Axial disease None FDA approved for AS, SpA MTX indicated in psoriasis/ peripheral psoriatic arthritis (hepatotoxicity issues) Reliance on anecdotes and RA experience NSAID Resistant AS/SpA
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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, but may make psoriasis worse Azathioprine: Uncontrolled and controlled trials in ReA and psoriatic arthritis Leflunomide: no benefit in spondylitic process Ineffective DMARDs
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Methotrexate in AS and Psoriatic Arthritis AS1 51 Pts, MTX 7.5 mg/Napr vs Naproxen/Placebo x 12 mos Negative results (only MD global improved) AS2 31 patients, 7.5 mg/week for 6 months, RDBPCT Significantly more patients had good response with MTX than placebo (53% vs 13%, P=0.019) AS3 34 patients with axial disease prior NSAID failure, open study, 1 year MTX 12.5 mg IM qweek, 91% (n=31) finished study 53% (n=18) responders but most with peripheral arthritis, axial measures unchanged Psoriatic arthritis4 37 patients, 12 weeks, prospective Improvements only in physician assessment of joint activity and skin area 1Altan L, et al. Scand J Rheumatol. 2001;30:255-259. 2Gonzalez-Lopez L, et al. J Rheumatol. 2004;31(8):1568-74. 3 Sampaio-Barros, et al. Scan J Rheumat 2000; 29*3):160-2 4Willkens RF, et al. Arthritis Rheum. 1984;27:376-381.
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Clegg etal, ArthRheum 42:2325 Sulfasalazine in SpAs Chen J and Liu C. J Rheumatol 2006;33(4):722-31. 2006 Metaanalysis Review of 11 randomized trials, total 895 patients; treatment ranged 12 weeks to 3 years Found that ESR and AM stiffness favored SSZ over placebo Benefits found in those with peripheral arthritis No benefits in physical function, pain, spinal mobility, ehtesitis, patient and physican global assessment
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Sulfasalazine in SpAs 1999 trial- VA multicenter RDBPCT 619 patients, SSZ 2 g/day vs placebo X 36 weeks % of responders n=187 n=432 Clegg DO, et al. Arthritis Rheum 1999;42(11)2325-9.
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Pamidronate in the Management of AS Bisphosphonates inhibit inflammation and suppress cartilage/bone erosion In a randomized, double-blind, controlled trial, n=84, IV pamidronate (60 mg/mo vs 10 mg/mo, 6 doses) reduced BASDAI by 35%, significant improvements in other indices, but no change in ESR, CRP Higher withdrawals in the 10mg/mo group SE: arthralgias, myalgias Maksymowych WP, et al. Arthritis Rheum. 2002;46:766-773.
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Thalidomide in the Management of AS Thalidomide inhibits TNF weakly but not IL-1, IL-61 12-month open-label trial: 200 mg/d, 30 patients, 50% had 50% improvement in 4/7 indices2 ESR and CRP significantly improved2 SE review, 22 studies (1981-2001): 1.3% on high dose had reversible perineuropathy1 Drowsiness, dizziness, headaches, N/V, no phocomelia (57% female)1 1. Davis JC Jr, et al. Rheum Dis Clin North Am. 2003;29:481-494. 2. Huang F, et al. Arthritis Rheum. 2002;47:249-254. 3. Breban M, et al. Arthritis Rheum. 1999;42:580-581. 4. Wei JC, et al. J Rheumatol. 2003;30:2627-2631. Studies on Thalidomide in AS
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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
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Braun J, et al. Arthritis Rheum. 1995;38:499-505. TNF- mRNA in Sacroiliac Biopsy Role of TNF- in AS
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Study design Phase III, randomized, multicenter, double-blind, placebo-controlled study Patients Assigned to etanercept 25 mg twice weekly (n=138) or placebo (n=139) for 24 weeks Concomitant meds Stable doses of NSAIDs, oral steroids or DMARDs 1° outcome Percentage of patients achieving ASAS 20 at weeks 12 and 24 2° outcome Percentage of patients achieving higher ASAS responses and safety of etanercept Davis JC Jr, et al. Arthritis Rheum. 2003;48:3230-3236. Etanercept in AS
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Etanercept in AS: Patient Characteristics Davis JC Jr, et al. Arthritis Rheum. 2003;48:3230-3236.
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Etanercept in AS: Percent of patients achieving ASAS responses at 24 wks Davis JC Jr, et al. Arthritis Rheum. 2003;48:3230-3236
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Davis JC, et al. Poster presented at: EULAR 2004; June 9-12, 2004; Berlin, Germany. Weeks 0 20 40 60 80 100 BL 4 8 12 16 20 24 Patients (%) Etanercept Placebo 74% 43% 48 Open Label Extension: Patients With ASAS 20 Response
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Etanercept in AS: Conclusions Primary outcome (ASAS 20) achieved by 57% patients on etanercept at 24 weeks (22% on placebo, P<0.0001) Statistically significant improvement in ASAS 50 and 70, BASDAI, and spinal mobility in the etanercept group Response to treatment was sustained over time in open-label extension Etanercept was well tolerated (SE: URTI and injection site reaction) URTI=upper respiratory tract infection.
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Study design Phase III, randomized, multicenter double- blind, placebo-controlled study Patients Assigned to infliximab 5 mg/kg (n=201) or placebo (n=78) for 24 weeks Concomitant meds Stable doses of NSAIDs, tramadol, or acetaminophen; all others discontinued 1° outcome Percentage of patients achieving ASAS 20 at week 24 2° outcome Improvement in BASFI, BASMI, CRP, QOL, productivity (VAS 0-10), MRI van der Heijde D, et al. Poster presented at: EULAR 2004; June 9-12, 2004; Berlin, Germany. Infliximab in AS
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Infliximab in AS: Patient Characteristics Stable doses of NSAIDs were permitted No DMARDs or corticosteroids were permitted van der Heijde D, et al. Poster presented at: EULAR 2004; June 9-12, 2004; Berlin, Germany.
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Infliximab in AS: Percent of patients achieving ASAS responses at 24 wks van der Heijde D. et al. Arthritis Rheum 2005;52:582-91
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Median % Improvement Median Improvement (%) from Baseline in MRI Activity Score (STIR/Gd) at Week 24 Mean Improvement 12.6% 53.8% - + SD + 104.88% + 47.36% p < 0.001 Braun J., et al. Oral Presentation; ACR 2004.
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Pre-infusion Post-infusion Stone M et al. Arthritis Rheum 2000 (abstract). 2 Days Use of Infliximab in Spondyloarthropathy: Efficacy
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Infliximab in AS: Conclusions Primary outcome (ASAS 20) achieved by 61% of patients on infliximab at 24 weeks (19% on placebo, P<0.001) 22% achieved ASAS partial remission in the infliximab group and productivity score improved by 62% Response to treatment was sustained over 3 years without concomitant DMARDs Infliximab was well tolerated (SE: URTI and infusion reaction 2.7%; equal to placebo) Infliximab improved MRI activity by 73%
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ASAS 20 Response: Adalimumab Phase III Week 12 Week 24 van der Heijde ACR 2005
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Risks and Relative Contraindications of Anti-TNF Treatment: Lessons Learned From RA Experience Positive PPD, history of untreated TB Current active infection Chronic recurrent infections History of decompensated CHF, lymphoma Systemic lupus erythematosus Demyelinating conditions: MS, optic neuritis
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SPARTAN Modifications of ASAS Guidelines for Use of TNF Inhibitors
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SPARTAN Modifications of ASAS Guidelines for Use of TNF Inhibitors
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Osteoporosis in AS Prevalence of vertebral osteoporosis in AS is between 20% to 60%1 Relative risk of fractures is 6 times in early AS compared with controls2 Risk factors: disease duration, severity, male sex Major etiologic factors: pro-inflammatory cytokines and spinal immobility No studies on treatment of osteoporosis in AS: ? role of pamidronate, anti-TNF 1. Bessant R, Keat A. J Rheumatol. 2002;29:1511-1519. 2. Mitra D, et al. Rheumatology. 2000;39:85-89.
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Summary: Spondyloarthritides Beware of the pitfalls: these disease are more common than previously thought and are often diagnosed late, causing significant functional disability Consider the differential diagnosis Recognize the role of labs/imaging Traditional therapies provide symptomatic control, DMARDs have no role in spinal disease Osteoporosis is common in AS Anti-TNF- therapy improves symptoms and productivity with the potential to modify structural outcomes in AS
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Conclusion Spondyloarthridites Inflammatory arthropathies Share genetic, clinical and radiologic features Ag driven immune response causing symptoms New therapies allow for more effective management of these diseases