BOTTOM LINE

Axial Spondyloarthritis (“Ankylosing spondylitis, AxSpA”) is an inflammatory arthritis affecting the axial skeleton, particularly the sacroiliac joints, onset in patients <40 years old with insidious chronic inflammatory back pain and sometimes peripheral arthritis. HLAB27 is often positive, but this should not be used as a screening test for ankylosing spondylitis. Patients can manifest other features of the seronegative spondyloarthritis spectrum like uveitis, psoriasis and inflammatory bowel disease. Comorbidities include increased prevalence of cardiovascular disease. Treatment starts with NSAIDs, and if needed, TNF, IL17, or JAK inhibition.
[🕑12 minute read]

TERMINOLOGY

Term	Definition
Spondyloarthritis, “SpA”	General term describing inflammatory arthritis of the spine, sacroiliac joints, sternoclavicular joints, and peripheral joints. Specific examples include psoriatic spondyloarthritis, enteropathic spondyloarthritis, Axial spondyloarthritis (ankylosing spondylitis), reactive arthritis.
Peripheral SpA	SpA involving predominantly peripheral joints. Sounds paradoxical; an example would be a young HLAB27+ male with some asymptomatic radiographic sacroiliitis but symptomatic swollen peripheral joints and dactylitis.
Axial spondyloarthritis, “AS” “AxSpA”	Axial spondyloarthritis (formerly ankylosing spondylitis) characterized by x-ray evidence of bilateral sacroiliitis (“radiographic sacroiliitis”), higher frequency of HLA-B*27 positivity and uveitis. Can manifest peripheral inflammatory arthritis, dactylitis, and enthesitis.
Radiographic axial SpA (axSpA)	AS with X-ray evidence of sacroiliitis.
Non-radiographic axial SpA (nr-axSpA)	AS with no evidence of sacroiliitis on X-ray, but evidence typically apparent on MRI.

• In clinical practice, there is little pragmatic distinction between radiographic and non-radiographic AxSpA.
• AxSpA patients may retrospectively have 4-9 years of inflammatory back pain before radiographic sacroiliitis.
• ~5-10% of patients with nr-AxSpA develop radiographic sacroiliitis after 2 years and ~20% after ~5 years.

EPIDEMIOLOGY

• Canadian (Ontario) Population
  • Incidence 14-16/100,000 yearly
  • Prevalence 200/100,000 (0.2%)
• Sex ratio
  • Radiographic axSpA:  2x more prevalent in males than females
  • Non-radiographic axSpA: male/female ratio roughly equal
• Age at onset:
  • early adolescence or early adulthood; very unlikely to onset in age >40 years
  • Older patients more likely to have degenerative arthritis to explain chronic back pain
• Risk factors
  • Genetic:
    • A first-degree relative increases risk 20X, heritability 77%
    • MHC-Genes, including: HLA-B*27, other HLA-B and HLA-D genes
    • Non-MHC genes, including: ERAP1, ERAP2, IL23R
  • Environmental
    • Microbiota: Possible associations with specific gut bacteria, including Klebsiella
    • Mechanical stress: Causing and perpetuating enthesitis in pathogenesis of SpA
    • Current smoking

CLINICAL FEATURES

—Axial Manifestations

HISTORY

Back pain is common, but AxSpA is rare
80% of general population experience back pain exacerbation in lifetime;
Only 0.2% of the general population have AxSpA

	“Inflammatory” back pain	“Mechanical” back pain
Age at  onset	<40 years	Any age, common >40 years
Rapidity of onset	Insidious	Variable, may be acute (ex: injury)
Morning stiffness	>60 minutes	<30 minutes
Pain waking from sleep overnight	Frequent, awaking 2nd half of night	Absent
Effect of exercise	Improvement	Worsening
Effect of rest	Worsening	Improvement
Spinal mobility	Loss in all planes	Decreased flexion
Alternating buttock pain	Present (in early disease)	Absent
NSAID response	Often some symptom response	Variable

Several overlapping classification criteria for “Inflammatory” back pain exist; sensitivity and specificity are around ~80%.
Hence, not every AxSpA patient has inflammatory back pain, and patients without AxSpA can have inflammatory back pain.

• Joint pattern
  • Sacroiliac pain:
    • Typically, dull gluteal pain, difficult to localize, with occasional involvement along iliac crest or greater trochanteric region
  • Chest wall:
    • Thoracic spine involvement with enthesitis at the costo-sternal and manubrial joints
    • Presents as chest wall pain and tenderness
  • Enthesitis:
    • Can present as tenderness at the costosternal junctions, spinous processes, iliac crests, greater trochanters, ischial tuberosities, tibial tubercles, Achilles tendon, or plantar fascia
    • Osteophytosis (bone spurs) may develop at sites of chronic enthesitis
    • May mimic fibromyalgia and be difficult to differentiate; ultrasound may be helpful to confirm enthesitis (in the hands of a skilled, experienced, and properly equipped rheumatologist-sonographer)

EXAM: Exam Maneuvers (usually late findings, not often done in day-to-day clinic)
Demonstration of back exam from RheumTutor.com: MSK Examination Videos 

• Occiput-to-wall:
  • Normal = 0cm. If heels and scapulae touch wall, occiput should touch wall
• Chest expansion:
  • Normal ≥5cm, abnormal <2.5cm
• Schober test (modified):
  • Normal ≥4.5cm.
  • Patient standing: mark at level of PSIS (dimples of Venus) and mark at 10cm above. Patient in maximal forward spinal flexion: distance between marks should increase ≥4.5cm
• Lateral flexion, Finger-fibula distance:
  • normal 0cm.
  • Distance finger travels when bending sideways: >10cm

—Peripheral MSK Manifestations

• Peripheral arthritis (27%)
  • Most frequently hips or shoulders; also, ankles, knees, TMJ, and SC joints
• Enthesitis (35%)
  • Ex: Achilles enthesitis, lateral or medial elbow epicondylitis
• Dactylitis (6%)
  • Diffuse swelling of toes or fingers

—Extra-articular Manifestations

• Anterior Uveitis (23%)
  • Eye pain, photophobia and blurry vision. Usually unilateral.
  • Recurrence common but permanent vision impairment is rare.
  • Associated with longer disease duration and HLA-B*27 genotype
  • Responds to topical steroids; can benefit from methotrexate and monoclonal antibody TNF inhibitors
• Bowel inflammation (4%)
  • Presents similar to inflammatory bowel disease (Crohn’s or Ulcerative colitis)
  • 50% have endoscopic ileal or colonic mucosal inflammation (often asymptomatic)
• Psoriasis (10%)
  • Psoriasis more often associated with peripheral arthritis
• Cardiovascular
  • Increased risk of cardiovascular disease: myocardial infarction, stroke, peripheral vascular disease, venous thromboembolism.
  • Rare, but described: aortitis, aortic root dilatation, aortic regurgitation
• Respiratory
  • Extra-parenchymal: Restrictive lung disease from chest wall restriction
  • Parenchymal: rare, but reported upper lobe predominant fibrosis
• Genitourinary:
  • Non-gonococcal urethritis
• Other:
  • Osteopenia, vertebral fracture, spinal cord impingement, rare IgA nephropathy and renal amyloid, depression

INVESTIGATIONS:

Bloodwork

• CBC: Hb may be low due to underlying colitis, inflammation, NSAID use
• ALT: May be elevated if comorbid fatty liver
• Cr: May be elevated due to NSAID use
• ESR, CRP: Elevated in 50-70% of radiographic SpA, 30% in non-radiographic axSpA

—HLA-B27

Prevalence of AxSpA in general population (US)	0.5%	0.5% of the general population have AxSpA
Prevalence of HLA-B27 in general North American population	6% (~5%)	6% of the general population are HLA-B27 positive
Prevalence of HLA-B27 in North American AxSpA population	95%	95% of people with AxSpA are HLA-B27 positive
Percentage of HLA-B27 individuals with AS	5%	Only 5% of HLA-B27 positive individuals have AxSpA
Likelihood of developing AxSpA if HLA-B27+	LR 9.0	Likelihood of having AxSpA is increased if HLA-B27 positive

HLA-B27 is not a good screening test for AxSpA in all-comers, because back pain is so common in the general population, but only ~5% of the HLA-B27 population have AxSpA.

HLA-B27 positive test can be helpful in selected patients with high-pre-test probability (ex: inflammatory back pain in a patient <40 years-old with enthesitis, uveitis, and elevated CRP).

Imaging: X-rays

—X-RAY SACROILIAC JOINT

Should be done for all patients with suspected AS. Each SI joint can be graded.

• Example images (Radiopaedia.org)
• In AxSpA, sacroiliitis is usually bilateral and symmetric, starting at the lower 2/3’s of the SI joint on the iliac side
• AxSpA patients may retrospectively have 4-9 years of inflammatory back pain before radiographic sacroiliitis.
• ~5-10% of patients with nr-axSpA develop radiographic sacroiliitis after 2 years,
  ~20% after ~5 years.
• Risks for radiographic progression: baseline radiographic damage, smoker, high ESR or CRP
• Older patients may develop subchondral sclerosis (usually iliac side) due to osteoarthritis; remember that new onset AxSpA is unlikely in >40-year-old patient

—X-RAY WHOLE-SPINE

Not routinely required. Only 3-5% of AxSpA patients have spinal changes without SI joint changes

Destructive Lesions: Andersson lesion, irregularity/erosion central portion of vertebral endplate

Proliferative Lesions:

1. Inflammation/ossification at insertion of annulus fibrosis (the corners of vertebral bodies) results in “Shiny corners” on the vertebrae (Romanus lesion)
2. Further inflammation/ossification at these corners causes squaring of vertebral bodies
3. Gradual ossification of outer layers of annulus fibrosis forms bony bridges between vertebrae called syndesmophytes
4. Syndesmophytoses between multiple vertebrae causes ankylosis (Bamboo spine)

AxSpA syndesmophytes are symmetrical, thin, and elegant.
Psoriatic or reactive syndesmophytes are bulky, asymmetric and look like “jug-handles”

Imaging: MRIs

—MRI SACROILIAC JOINT:

Needed if compelling clinical picture but X-rays of SI joints show only Grade 0-1 changes

Example images (Radiopaedia.org)

MRI Protocol:

Semi-coronal images of sacroiliac joint with STIR (short tau inversion recovery) or T2wFS (T2-weighted fat-suppression) sequences demonstrate water content, indicating bone marrow edema

T1w (T1-weighted) sequences demonstrate fat content, useful for assessing structural lesions corresponding to the bone marrow edema lesions

Active inflammatory lesions light up as “osteitis” or “bone marrow edema” (BME) on STIR images with corresponding dark lesions on T1-weighted images

• POSITIVE MRI FOR SACROILIITIS IN AxSpA (ASAS 2016 Criteria)
  • 2 BME lesions on same MRI slice, or
  • one lesion in same quadrant of SI joint on at least 2 consecutive slices
• OTHER STRICTER PROPOSED CRITERIA
  • Definitive active lesion
    • BME in ≥4 SI joint quadrants at any location, or
    • BME at same location in ≥3 consecutive slices
  • Definitive structural lesion
    • Erosion ≥3 SI joint quadrants or same location for ≥2 consecutive slices, or
    • Fat lesion ≥5 SI joint quadrants or same location for ≥3 consecutive slices, or
    • Presence of a deep (i.e. >1cm) fat lesion

NOTES on MR of SI joint:

Structural lesions without concomitant bone marrow edema (BME) does not suffice for definition of positive MRI for sacroiliitis

BME lesions are not specific for ankylosing spondylitis and MRIs must be interpreted in clinical context

BME may be observed in up to 23% of patients with mechanical back pain, 7% asymptomatic patients

• Differential for sacroiliitis on MRI
  • Osteitis condensans ilii:
    • triangular-shaped area of sclerosis on iliac side, can be found incidentally in women who have given birth with mechanical back pain.
  • Septic sacroiliitis:
    • X-rays can be normal in first weeks of infection; changes do not respect anatomical borders and can cause proximal para-sacroiliiac inflammation (ex: iliopsoas muscle)
  • Fracture:
    • Insufficiency fractures causing BME; fracture line may not be always visible
• Differential for hyperostosis in spine
  • DISH (diffuse idiopathic skeletal hyperostosis):
    • Flowing hyperostosis of anterior longitudinal ligament of at least 4 vertebral bodies more commonly in obese diabetic men >50 years old.
    • More often found on the right side of the spine, contralateral to heart and aorta.

—MRI WHOLE SPINE

• May be useful if
  • High pre-test probability, inflammatory back pain in spine but normal/equivocal MR of SI joints (rare)
  • Evaluating other etiology of back pain
  • Assess for ongoing inflammation in patients on AxSpA treatment but still have back pain
  • Spondylitis in MRI for AS: spondylitis, inflammation of facet joints, aseptic spondylodiscitis
• POSITIVE FINDINGS FOR SPONDYLITIS IN AS:
  • Anterior or posterior spondylitis in at least 3 sites.

Other imaging

• Osteoporosis
  • Bone mineral density to screen for osteoporosis/osteopenia in adults patients risk: spine, pelvis, femoral neck

Nuclear Medicine Bone scans
Don’t order bone scans; neither sensitive nor specific for inflammatory SpA

DIAGNOSIS

Diagnosis of AxSpA can be made in a patient with inflammatory back pain onset under the age of 40 years-old; probability increases with additional spondyloarthritis features on history and exam (ex: uveitis, inflammatory arthritis/dactylitis/enthesitis, psoriasis, inflammatory bowel disease). Exam may show limitation in spinal movement and peripheral features of spondyloarthritis like peripheral joint swelling, dactylitis or enthesitis. Elevated CRP and HLA-B27 positivity can be supportive in right clinical context. X-rays should show sacroiliitis, and if not, and MR of SI joints can be performed if high enough pre-test probability. Lack of sacroiliitis on MR makes AxSpA extremely unlikely.

DIFFERENTIAL DIAGNOSIS

• Mechanical
  • Non-specific low-back pain, lumbago, muscle strain
  • Osteoarthritis, degenerative disc disease, sciatica or other impingement
  • Fracture, osteoporotic fracture
• Infection:
  • Septic arthritis of spine or SI joint.
• Other
  • Osteiitis condensans ilii: back pain, radiographic sclerosis on iliac side of SI joint post-pregnancy
  • DISH (diffuse idiopathic skeletal hyperostosis): ligamentous calcification/ossification around the spine
  • Fibromyalgia

CLASSIFICATION CRITERIA

AxSpA is a clinical diagnosis. Classification criteria are not meant as diagnostic criteria to diagnose disease in a single specific patient. Classification criteria are a standardized way of recruiting a well-defined homogenous population of patients in research studies in order to ensure comparability across studies of a heterogenous disease.

ASAS CRITERIA FOR AXIAL SPA (Sensitivity 82.9%, Specificity 84.4%)

In patients ≥3 months back pain and age of onset <45 years:

• Sacroiliitis on imaging AND ≥1 SpA Feature,
  OR
• HLA-B27 positive AND ≥2 other SpA features

SpA features

• Inflammatory back pain
• Peripheral inflammatory arthritis
• Enthesitis (heel)
• Uveitis
• Dactylitis
• Psoriasis
• Inflammatory bowel disease (Crohn’s, ulcerative colitis)
• NSAID response
• Family history SpA (1st/2nd° relative AS, reactive, uveitis, psoriasis, IBD)
• HLA-B27 positive
• Elevated CRP

Sacroiliitis in imaging

• Active (acute) inflammation on MRI high suggestive of sacroiliitis from SpA
• Definitive radiographic sacroiliitis according to modified New York Criteria

ASAS CRITERIA FOR PERIPHERAL SPA (Sensitivity 77.8%, Specificity 82.2%):  

• Peripheral inflammatory arthritis/enthesitis/dactylitis, PLUS
  • ≥1 SpA (uveitis, psoriasis, IBD, prodromal infection, HLAB27+, radiographic sacroiliitis), OR 
  • ≥2 other SpA features: inflammatory arthritis/enthesitis/dactylitis, inflammatory back pain, family history SpA

DISEASE MEASURES

• BASDAI
  Bath Ankylosing Spondylitis Disease Activity Index: 6 questions on patient-reported outcomes:
  • 1. Fatigue/tiredness
  • 2. Neck, back, hip pain
  • 3. Pain/swelling in joints other than neck, back, hip
  • 4. Discomfort to areas tender to touch or pressure
  • 5. Level of morning stiffness
  • 6. Duration of morning stiffness
• ASDAS
  Ankylosing Spondylitis Disease Activity Score
  • Components: BASDAI Questions 2, 3, 6; Patient global, CRP
  • ASDAS <1.3:               Inactive disease
  • ASDAS 1.3-2.0:           Low disease activity
  • ASDAS 2.1-3.4:           High disease activity
  • ASDAS >3.5:               Very high disease activity

TREATMENT

Non-pharmacologic

• Education
• Active physiotherapy, regular exercise
• Smoking cessation

Pharmacologic

• GOAL:
  • Maximize long-term health-related quality of life, prevent  structural damage, preserve/normalize function
• ASSESSMENTS:
  • Based on patient-reported outcomes, clinical findings, labs.
  • Serial MRI can re-assess disease activity, but only modest association exists between clinical measures and MRI inflammation; serial MRIs are costly and may cause delays.

—AXIAL DISEASE

• Initial
  • Physical therapy, group or individual self-management education
  • NSAIDs:
    • Active Axial SpA: continuous NSAIDs
    • Stable Axial SpA: PRN NSAIDs
  • Steroids: No role for systemic corticosteroids; rare and adjunctive radiology-guided local corticosteroid to SI joint for refractory isolated sacroiliitis may be considered

Expect peak response in 2-4 weeks. If inadequate efficacy with 2 different NSAIDs, and diagnosis of active AxSpA is certain, move onto subsequent therapy

• Subsequent, If true active axial disease, failure of serial NSAIDs (at least 2):
  • Either TNFi, IL-17i, or JAKi (no preferred first line of therapy)
    • If minimal response to subsequent therapy, consider switching to different mechanism of action
    • If good response to subsequent therapy but lost over time, consider switching within same mechanism of action
    • In Canada, only Upadacitinib and tofacitinib are approved for AxSpA; only as second line after failure of bDMARD.

If no treatment response, re-evaluate diagnosis and disease activity; consider comorbid osteoarthritis or other causes of back pain

—PERIPHERAL DISEASE

• Peripheral arthritis: csDMARDs (methotrexate, sulfasalazine, leflunomide); local corticosteroid
  • Ex: predominantly peripheral disease or residual peripheral disease despite controlled axial disease; csDMARDs have no role for axial joints
  • Surgery:
    • Hip arthroplasty may be required if refractory pain, disability, and radiographic structural damage

—COMORBID SPONDYLOARTHRITIS FEATURES

Comanage comorbidities with relevant subspecialists (opthalmology/optometry, gastroenterology, dermatology)

• Uveitis:
  • Favour TNFi monoclonal antibody
• Inflammatory bowel disease (concomittant or suspected):
  • Consider favouring TNFi monoclonal antibody or JAKi over IL-17i
• Significant Psoriasis:
  • Consider favouring IL17i

—OTHER COMORBIDITIES

• Cardiovascular:
  • Assess and treat underlying cardiovascular risk factors (ex: hypertension, dyslipidemia, diabetes)

Evaluating Treatment Response

• All patients
  • Regular-interval clinical evaluation (history, exam) with CRP
  • Use of ASDAS (less so a BASDAI) to quantify disease activity
  • Not recommended (or controversial): treating to a specific target ASDAS or other specific disease score target
• Patients with unclear disease activity on clinical evaluation
  • Axial disease:
    Repeat pelvic +/- spinal MRI to assess active bone marrow edema lesions and structural changes
  • Enthesitis:
    Consider entheseal ultrasound to confirm enthesitis (with a skilled, experienced, and properly equipped rheumatologist-sonographer)

PROGNOSIS

• Radiographic progression
  • Data limited: minimum 2-years are needed to assess radiographic progression; a 2-year placebo-controlled trial would be unethical
  • TNFi may possibly slow radiographic progression of AS
• Predictors of increased disease severity
  • Hip arthritis: OR 23
  • Dactylitis: OR 8
  • Poor efficacy of NSAIDs: OR 8
  • ESR >30 mm/h: OR 7
  • Decreased range of motion lumbar spine: OR 7
  • Oligoarthritis: OR 4
  • Onset < 16 years-old: OR 3
• Predictors of good response to TNFi
  • Increased CRP or ESR
  • Higher disease activity
  • Higher functional status
  • Younger age
  • HLAB27 positivity
• Morbidity, mortality
  • Higher prevalence of cardiovascular disease and vascular death, spinal cord injury
  • Possibly slightly higher risk of death from all causes (RR 1.64 [95% CI 1.49-1.80])

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