Low Back Pain and the Seronegative Spondyloarthropathies Scott R. Burg, D.O. Orthopaedic and Rheumatologic Institute Cleveland Clinic

Spondyloarthropathies (SPA) A group of common inflammatory rheumatic disorders characterized by: Axial and/or peripheral arthritis, enthesitis, dactylitis Potential extra-articular changes such as uveitis and skin rash

Common Genetic Predisposition HLA-B27 gene Association varies widely among various SPAs and ethnic groups Environmental factors seem to be triggering the diseases in genetically predisposed

Radiographic Hallmark Sacroilitis

SPA Characterized by: Sacroilitis Inflammatory back pain Peripheral arthropathy Absence of rheumatoid factor/CCP and subcutaneous nodules Enthesitis Extra spinal involvement (eye, heart, lung and skin) HLA-B27 At least 6 other genes associated with ankylosing spondylitis identified to date

Inflammatory Low Back Pain Assumed to be characterized by inflammation of SIJ and lumbar spine Young age of onset Continuous pain > 3 months Morning stiffness Pain improving on activity

Inflammatorty Back Pain Unilateral or bilateral Alternates from side to side Responds well to NSAIDs

Sacroilitis and Inflammatory Low Back Pain Prevalence 50%

F.D. Hart Quarterly Journal of Medicine, 1949 A frequent feature of the pain and stiffness was the aggravation caused by immobility. Waking in the morning stiff and in pain, the patient gradually became more supple during the day, feeling at his best from the afternoon until bedtime. One patient noted that by frequent exercise, his condition was kept in check, but confinement to bed for any cause made him worse. Another woke himself up (every 2 hours) throughout the night to exercise his spine as otherwise, he suffered unduly in the morning.

IBP in USA Present in 6% General back pain 20% Performs well as case ascertainment tool for those who seek care SPA in 1%, what constitutes the gap?

IBP Concept Distinguishing feature in all criteria sets developed to identify AS and SPA Criteria sets share several key clinical features Diverge on genetic indicators and radiographic parameters

Value of IBP Concept in Primary Care Setting Defines a group at risk for SPA or AS Defense of further diagnostic testing i.e. imaging or genetic tests Negative tests in IBP any justification for NSAID’s or biologics to treat symptoms or prevent SPA or AS

Spondyloarthropathies (SPA) Ankylosing spondylitis (AS) Reactive arthritis (REA) Psoriatic arthritis (PSA) SPA associated with inflammatory bowel disease (IBD) Undifferentiated SPA (USPA) Juvenile onset spondyloarthritis

Ankylosing Spondylitis (AS) Most common and most typical 0.2-1.2% of Caucasian population. Variability based on regional, genetic and environmental factors Lower male to female ratio (2-3.1) based on recent epidemiologic studies Higher in HLA-B27 populations

Diagnosis of AS Delayed As long as 8 years Longer delays in females

Diagnostic and Classification Criteria European spondyloarthropathy study group (ESSG) Assessment in Spondyloarthritis International Society (ASAS) proposed new set of diagnostic criteria enabling identification of SPA before structural changes occur in the spine

MRI Changes now included in new classification criteria of early axial SPA Major tool diagnostically

AS Symptoms Early adulthood Dull pain buttock / lower lumbar area Morning stiffness relived on exertion worsened on inactivity Enthesitis Inflammation at bone insertion sites of ligaments or tendons Pain of enthesopathy varies and depends on affected location Frank arthritis 25-35% involving large joints in asymmetrical fashion Neck pain with increased ROM later manifestation

Dactylitis (Sausage Digit) PSA REA Joint and tenosynovial inflammation

Other Clinical Features of AS Acute anterior uveitis – 30% often antedates spondylitis AI, CHF, aortitis, angina, pericarditis, conduction deficits Dyspnea, cough, hemoptysis = pulmonary fibrosis

Reactive Arthritis (REA) Arthritis 2-4 weeks after urogenital or enteric infection often in presence of HLA B27 antigen Risk 50% higher in HLA-B27 positive HLA B-27 positive associated with severity and chronicity Enthesitis 70% of patients Heel spur and pain Achilles tendonitis Knee synovitis with large effusions Dactylitis typical

Extra-articular Features Urethritis Cervicitis Vulvovaginitis and salpingitis Prostatitis Oral ulcers, e. nodosum, conjunctivitis Cardiac involvement

Enteropathic Associated Arthritis (IBD) 10% of patients may antedate IBD Asymmetric, large joints, lower limb Occasional symmetrical, small joint polyarthritis

Spondyloarthritis and Sacroilitis Independent course compared to bowel disease Milder than AS HLA-B27 positivity Weaker than AS 25-60% of patients positive

Undifferentiated Spondyloarthropathy (USPA) Patients without criteria for well-defined SPA Fewer extra-articular changes Sacroilitis / spondylitis absent, or very mild after years of active disease Good prognosis

Juvenile Spondyloarthropathy Asymmetric Lower extremity peripheral Boys aged 7-16 years Enthesitis and dactylitis prominent Systemic manifestations frequent in juvenile than adult form

Psoriatic Arthritis (PSA) Develops in 5-40% of psoriasis patients Incidence 7.2 per 100,000/year Existing psoriasis patients prevalence rises from .2% of 7-40%

Arthritis in PSA Asymmetric in small and large joints Patterns include: Mutilans Peripheral oligoarthritis / polyarthritis Spondylitis DIP arthritis (fingers and toes >50%)

Back Pain in PSA Cervical spine disease common (>50%) Progresses in severity in parallel with disease of peripheral joints Sacroilitis – 20% of patients Spondylitis – 5% of patients

PSA Nails (83%) or skin precede or follow joint involvement Scalp, behind ears, umbilicus or gluteal folds Fatigue, iritis, uveitis

Biomarkers to Assess PSA CRP Matrix metalloproteinase-3 Circulating osteoclast precursors HLA-B27 represents axial disease sacroilitis and spondylitis

Conventional Radiography Important outcome domain in clinical trials of (ASAS) Recognition of early bone changes beneficial in patients early therapy response to disease progression Inexpensive, easy to generate Widely available and inexpensive; rapid and easily studied in randomized and blinded environments

Imaging Role in Sacroilitis MRI and CT – high sensitivity and better detection of early sacroilitis but cost prohibits use in routine diagnosis Plain radiograph initial diagnostic tool but large inter and intraobserver variations documented

Battistone, et. al. Oblique views not justifiable High specificity (97.8%) low sensitivity (54.4%)

Radiographic Hallmarks in SPA Erosions – earliest – iliac side Periostitis Bone proliferation at enthesis Normal bone mineralization

Progression of Erosive Disease Widening of joint Reparative bone laid down behind erosions Total fusion of SIJ (ankylosis)

Radiographs Poor sensitivity to soft tissue and bony changes in early SI disease Bony changes not evident until advanced stage of disease Reliability unsatisfactory and leads to therapy delays

Sacroiliac Joint Involvement in (SPA) Most common early clinical finding First manifestations of disease

Criteria for Classification of SPA ESSG Amor Criteria Modified New York Criteria Criteria sets all fall short as these all depend on presence of radiological sacroilitis (often appears late in disease course) Long delay exists between initial symptoms and establishing a diagnosis

Conventional Radiography Assess structural spine changes Document more chronic lesions Not sensitive to change over 2 years

Computed Tomography Superior to radiography Better definition of bone detail Soft tissue overlap, air, intestinal loops, feces absent Specific contrast windows Observer variation reduced Diagnostic CT performed supine with semicoronal slice and preferable to axial CT Overall view of cartilaginous joint facets and ligamentous part of SIJ Superior to MRI in detection of chronic bony changes in the ligamentous portion of the joint Considerable radiation exposure

CT Findings Comparable to chronic changes of MRI Better for evaluating joint space alteration Better demonstrating ossification of enthesopathies not always seen on MRI Cannot demonstrate present disease activity

Use of MRI in SPA Key tool for assessment of inflammation structural damage in AS

MRI Imaging method for earlier diagnosis of sacroilitis Identifies both inflammation and structural changes Radiographs only structural changes

MRI Compared to CT and Conventional X-RAY Detects active inflammatory change Visualizes soft tissue Chronic changes Early diagnosis of sacroilitis well before CT or radiography Monitoring disease activity

MRI Disadvantages Long examination times High cost Skilled staff Contraindications – i.e. pacemakers

TNF Agents Dramatic change in therapeutic strategies in AS Improvement of clinical disease activity correlates with reduction of acute skeletal change documented by post Gadolinium and Stir MRI exams

Blum (1996) and Hanly (1994) Prospective study MRI 100% specific in clinical sacroilitis IBP – 67% specific in early recognition of sacroilitis

MRI in AS Erosion of cartilaginous joint facets Concomitant edema and enhancement of joint and subchondral bone Changes on iliac side of joint Sacral involvement more frequent in AS

MRI in AS Early Diagnosis Sacral involvement Fatty marrow degeneration Joint space widening Pronounced subchondral sclerosis Only technique to detect actively inflamed lesions of SIJ and spine Gold standard for efficacy of TNF therapy in future

Ultrasonography Highly sensitive, non-invasive imaging technique for soft tissue involvement in SPA Entheses initial site of joint inflammation in SPA Enthesopathy often under-estimated Higher sensitivity than MRI for early signs of enthesitis

US in SIJ Involvement in SPA Fast Inexpensive Complements physical exam identifying origin of IBP

U.S. Only visualize superficial part of SIJ Cannot visualize cartilaginous portion Less sensitive detecting erosions Possible to diagnose active sacroilitis based on increased joint vascularization of posterior joint

Bone Scintigraphy Limited diagnostic value for diagnosis of established AS or early diagnosis of probable/suspected sacroilitis Sensitivity not higher than 50-55% Specificity about 80% Radiation exposure lower than CT but higher than plain radiography

PSA Radiographic Changes Entheseal bone formation Periostitis Entheseal erosions Diffuse bone based pathology

Ultrasound in PSA 25% more lesions found than on clinical exam alone Achilles abnormalities in 59.2% of PSA patients

PSA and Sacroilitis 25% in two series 78% in a third series Unilateral Axial and peripheral disease cause frequent and severe lesion Cartilaginous and ligamentous joint involvement Bony ankylosis less frequent than AS Bone eburnation of sacral and iliac surface more marked in PSA than AS

Reactive Arthritis (REA) and Sacroilitis 50% of patients symmetrical Minor changes in distal portion (synovial) Entheses in ligamentous part

Enteropathic ENSPA Protzer, et. Al. SPA in 10.7% of all CD and 14.4% of all UC patients 26.8% prior to GI symptoms 14.4% simultaneous

ENSPA and Sacroilitis Often bilateral Radiographically similar to AS More dominant involvement of ligamentous portion of joint than other forms

ENSPA and Imaging CT entheseal and ligamentous Frequent MRI inflammation at entheses

Undifferentiated Spondyloarthropathy (UPSA) Clinical and suggestive of SPA but not fulfilling diagnostic or classification criteria USPA versus AS lack of grade ≥ 2 bilateral or grade 3 unilateral sacroilitis on x-ray

Take Home Messages Radiological study of SIJ in SPA represents clinical and imaging challenges Integrated use of different imaging techniques is suggested to avoid misdiagnosis MRI technique of choice for f/u, given lack of ionizing radiation

Therapy of SPA Basic essential therapy NSAID’s and PT Management of AS Symptoms Signs Disease activity (severity) Functional status

Sulfasalazine (SZA) Control of peripheral joint involvement Reduce spinal stiffness No effect on enthesitis, spinal mobility or physical therapy

Methotrexate Modest effect on peripheral joints Studies at odds on spine

Systemic Corticosteroids Ineffective

Biphosphonates Modest effect Osteoporosis Inflammatory spinal symptoms

TNF Inhibitors Effective in suppressing inflammation with joint destruction Reduce pain Fail to slow new bone formation Administered early, drug free remission is possible

ASASD Axial SPA Criteria Minimum of 2 NSAID’s for 4 week minimum (previous 3 months) TNF blocker use earlier and for a minimum of 3 months

TNF Inhibitors in AS Infliximab Etanercept Adalimumab Goliumumap

Active SI Inflammation Reduced Infliximab, Etanercept, Adlmimab Reduce signs and symptoms even in advanced or total spinal ankylosis AS or PSA in patients therapied with Infliximab or Etanercept showed clinically relevant improvement