Ankylosing Spondylitis

Meet the patient

A 26-year-old software engineer has had low-back and buttock pain for nine months. It is worse at 4 am, waking him, and eases only after a hot shower and a walk. His pain moves between the two buttocks. He has a stiff back for an hour each morning, and his right eye was red and painful for a week last month — his GP called it conjunctivitis.[1]

Three questions decide his next decade, and they decide every ankylosing-spondylitis consult: is this back pain inflammatory or mechanical? (the single discriminator question — worse with rest, better with exercise — does most of the work), is the X-ray normal when the disease is already active? (MRI catches the years the plain film misses), and what will preserve his spine and his sight? (continuous NSAIDs and physiotherapy, a biologic when those fail, and an ophthalmology review for every red eye). The clinical skill is recognising inflammatory back pain early — because most back pain in the community is mechanical, and the cost of missing AS is a fused spine and permanent disability.[1]

What ankylosing spondylitis is — the seronegative prototype

Ankylosing spondylitis is a chronic, progressive inflammatory disease of the axial skeleton — the sacroiliac joints and spine — and of the entheses, the sites where tendons, ligaments and joint capsules insert into bone. It is the prototype of the seronegative spondyloarthropathies.[1]

The word "seronegative" is doing a specific job — it means BOTH rheumatoid factor AND antinuclear antibodies are absent, in deliberate contrast to rheumatoid arthritis. If either is positive, rethink the diagnosis.[1]

The core pathological process is enthesitis — inflammation at the enthesis — which evolves into erosion, repair, new-bone formation and finally ankylosis (bony fusion of a joint). That sequence — inflammation then ossification — is the whole story of the bamboo spine, and it explains the central paradox of the disease: anti-inflammatory therapy controls the symptoms but does not reliably halt the new bone that fuses the spine.[1]

AS is now understood as the radiographic end of a single continuous spectrum called axial spondyloarthritis (axSpA):[3]

• Non-radiographic axial spondyloarthritis (nr-axSpA) — active sacroiliitis on MRI (bone-marrow oedema) but a normal plain pelvic X-ray.
• Radiographic axial spondyloarthritis (r-axSpA), classical AS — definite sacroiliitis on plain X-ray (bilateral grade 2 or unilateral grade 3 or more).[1]

The two are not different diseases; nr-axSpA may — but does not always — progress to AS over years. The clinical skill is requesting the right imaging (plain X-ray plus MRI of the sacroiliac joints) and escalating to a biologic when conventional therapy fails — while remaining alert to the extra-articular emergencies: acute anterior uveitis, spinal fracture in a fused spine, cauda equina syndrome.[1]

The family — the seronegative spondyloarthropathies

The seronegative spondyloarthropathies share a unifying set of features and are grouped because of overlapping genetics, clinical pattern and pathology.[1]

[1]

The shared features — the high-yield list: inflammatory back pain and sacroiliitis (often bilateral in AS); an asymmetric, predominantly lower-limb oligoarthritis; enthesitis (especially the Achilles tendon and plantar fascia insertions — heel pain); dactylitis ("sausage digit"); HLA-B27 association and a positive family history; acute anterior uveitis; mucocutaneous features (psoriasis, oral ulcers, keratoderma, balanitis, nail dystrophy); and RF negative, ANA negative — seronegative.[1]

The diagnostic criteria — modified New York and ASAS 2009

Two criteria sets coexist, and knowing when each applies is itself examinable.[1]

Modified New York criteria (1984) — for established AS

The modified New York criteria diagnose established AS once X-ray sacroiliitis is already present. Diagnosis requires the radiographic criterion plus at least one clinical criterion.[2]

• Radiographic criterion: sacroiliitis on X-ray graded bilateral grade 2 or more, OR unilateral grade 3 or more.
• Clinical criteria (any one): (1) low back pain and stiffness for more than 3 months that improves with exercise but is not relieved by rest; (2) limitation of motion of the lumbar spine in both the sagittal and frontal planes; (3) limitation of chest expansion relative to normal values corrected for age and sex.[1]

The mNY sacroiliitis radiographic grade is reproduced verbatim because examiners reward it:[1]

[1]

ASAS 2009 criteria — capturing the disease the X-ray misses

The ASAS 2009 criteria for axial spondyloarthritis capture the patient whose plain X-ray is normal — that is, nr-axSpA.[3]

• Entry criterion: back pain (3 months or more) with onset under 45 years.
• Then either arm:
  • Imaging arm: sacroiliitis on imaging (X-ray high grade, or active inflammation on MRI) PLUS at least one SpA feature.
  • Clinical arm: HLA-B27 positive PLUS at least two other SpA features.
• The 11 SpA features: inflammatory back pain; arthritis; enthesitis (heel); uveitis (anterior); dactylitis; psoriasis; Crohn disease or ulcerative colitis; good response to NSAIDs; family history of SpA; HLA-B27 positive; elevated CRP.
• Sensitivity about 83 percent overall, 97 percent with HLA-B27-positive disease; specificity 84 to 94 percent (the imaging arm is more specific).[1]

The ASAS 2011 criteria for peripheral spondyloarthritis apply when peripheral disease (arthritis, enthesitis or dactylitis) dominates: entry is peripheral disease plus at least two of psoriasis, prior infection, HLA-B27 or sacroiliitis on imaging — or one of those four plus two further features.[5]

Criteria for inflammatory back pain

The two inflammatory-back-pain criteria sets are examiner favourites.[1]

• Calin criteria (1977) — requires 4 of 5: age of onset under 35; duration over 3 months; insidious onset; morning stiffness; improvement with exercise. (High sensitivity, modest specificity.)
• ASAS (Berlin) criteria (2006) — requires 2 of 4: morning stiffness over 30 minutes; improvement with exercise not with rest; back pain waking the patient in the second half of the night; alternating buttock pain. (Sensitivity 70 percent, specificity 81 percent.)[1]

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How common, who, and why HLA-B27 is necessary but not enough

AS is the commonest inflammatory rheumatic disease in young men, and its global prevalence closely tracks the population carriage of HLA-B27.[1]

• Prevalence: about 0.1 to 0.4 percent of European adults; 0.5 percent in the USA; 0.1 to 0.2 percent in India; rare in Japan and sub-Saharan Africa (low HLA-B27 carriage).
• HLA-B27 carriage in the general population: about 8 percent of white Europeans and Americans, up to 14 percent in some Northern European groups; 6 to 8 percent in North India, but only 1 to 2 percent in South India and Japan, and near zero in Australian Aboriginal, African and Inuit populations — explaining the geography of AS.
• Among HLA-B27-positive individuals, only about 1 to 5 percent develop AS; in those with an affected first-degree relative the risk rises to about 10 to 20 percent.[1]

Sex ratio: historically quoted as 3 to 1 male to female; modern series are closer to 2 to 1. Women are increasingly recognised because their disease is milder, more peripheral, less radiographically advanced, and chronically under-diagnosed.[1]

Age of onset: the typical patient is in the late teens to mid-thirties; onset over 45 years excludes the ASAS axSpA entry criterion and should prompt a search for another cause (DISH, malignancy, fracture, infection).[1]

Risk factors. HLA-B27 is the dominant genetic factor (explains about 30 percent of total heritability). Subtypes: B-star-2705 (whites, Africans, Indians), B-star-2704 (Chinese, Japanese, Thai), B-star-2702 (Mediterranean), B-star-2707 are disease-associated; B-star-2706 (South-East Asia) and B-star-2709 (Sardinia) are protective. Additional loci include ERAP1, ERAP2, IL23R, TNFRSF1A, RUNX3 and KIF21B — together over 100 loci.[1]

Why the spine fuses — the enthesis and the bone-formation paradox

AS is fundamentally a disease of the enthesis. The enthesis is a mechanically stressed transition zone — fibrocartilage over mineralised fibrocartilage over subchondral bone. Mechanical stress, microdamage and gut antigens in a genetically susceptible host trigger a sterile inflammatory cascade at the enthesis, which then secondarily involves the adjacent joint, such as the sacroiliac joint.[1]

The classic morphological cascade in the spine:[1]

1. Enthesitis at the annulus fibrosus attachment to the vertebral rim.
2. Erosion of the vertebral corner — the Romanus lesion ("shiny corner" on lateral X-ray).
3. Repair with new bone — the syndesmophyte grows in the direction of the annulus fibrosus, delicately and symmetrically (in contrast to the bulky, asymmetric, flowing new bone of DISH).
4. Bridging of adjacent vertebrae becomes the bamboo spine.
5. In the sacroiliac joint, the same erosion-sclerosis-ankylosis sequence produces bilateral symmetric sacroiliitis.[1]

The inflammatory infiltrate is rich in CD4 and CD8 T lymphocytes, macrophages, mast cells and innate lymphoid cells, producing a TNF-alpha and IL-17A-rich milieu. IL-23 (from entheseal-resident gamma-delta T cells and type-3 innate lymphoid cells) drives IL-17A and IL-22, which promote both inflammation and pathological osteoproliferation.[1]

The bone-formation paradox is the central teaching point. Anti-inflammatory therapy (NSAIDs, TNF inhibitors) controls inflammation and symptoms but does not reliably halt radiographic progression — new bone keeps forming. Current understanding implicates the Wnt or beta-catenin pathway: inflammation upregulates DKK-1 and sclerostin (Wnt antagonists), which then fall as inflammation resolves, removing the brake on osteoblasts and permitting syndesmophyte formation. This is why suppressive therapy alone cannot prevent ankylosis.[1]

The earliest lesion is bone-marrow oedema on MRI — visible on STIR or T2 fat-saturated sequences as bright signal in the subchondral bone of the sacroiliac joint. It precedes plain X-ray changes by several years and is the basis on which nr-axSpA is diagnosed.[4]

How HLA-B27 drives disease — three hypotheses

The mechanism by which HLA-B27 causes AS is one of the great unsolved problems in immunology. Three non-mutually-exclusive hypotheses:[1]

1. Arthritogenic-peptide hypothesis — HLA-B27 presents a bacterial or self peptide to CD8 T cells that cross-reacts with an entheseal self-antigen.
2. Misfolding and the unfolded-protein response — HLA-B27 folds slowly in the endoplasmic reticulum, accumulating misfolded heavy chains that trigger the UPR and downstream IL-23 production.
3. Free heavy-chain or cell-surface homodimer hypothesis — HLA-B27 heavy-chain homodimers on the cell surface engage KIR3DL2 on NK and Th17 cells, expanding the IL-17-producing Th17 compartment independent of peptide presentation.[1]

The clinical picture — inflammatory back pain and the extra-articular triad

The cardinal feature is inflammatory back pain, and recognising it is the single highest-yield clinical observation — because most back pain in the community is mechanical (worse with activity, better with rest).[1]

The typical patient is a young man (under 40) with insidious-onset low-back and buttock pain present for more than 3 months, worse at rest and at night (often waking the patient in the second half of the night), relieved by exercise and movement, with morning stiffness of more than 30 minutes (often 1 to 2 hours). It may alternate between the two buttocks — a key distinguishing feature from mechanical pain.[1]

Other axial and chest-wall features: deep sacroiliac pain; reduced spinal mobility in all planes; reduced chest expansion from enthesis-driven costovertebral and sternocostal inflammation causing restrictive chest-wall mechanics (the lungs stay structurally normal — the problem is mechanical); late cervical involvement with progressive loss of rotation and extension; and a kyphotic deformity in advanced disease — the "question-mark" posture with fixed forward gaze.[1]

Peripheral musculoskeletal features: an asymmetric, predominantly lower-limb oligoarthritis (hip, knee, ankle) — and hip involvement is the strongest predictor of poor functional outcome; enthesitis at the Achilles tendon insertion and the plantar fascia origin ("heel pain") is highly characteristic; dactylitis ("sausage digit"); and arthritis of the shoulder.[1]

The extra-articular triad — EYES

Every system is examinable, and the mnemonic EYES clusters the high-yield extras.[1]

[1]

Acute anterior uveitis (AAU, iritis) — classically unilateral, acute onset, painful red eye with photophobia, lacrimation and blurred vision, and it may precede the spinal symptoms by years. It is a medical emergency — untreated attacks cause posterior synechiae, glaucoma and cataract.[1]

Cardiovascular: aortic regurgitation (aortic root dilatation and aortitis) in about 2 to 10 percent, conduction defects (first-degree AV block, complete heart block, bundle-branch block), and an increased risk of ischaemic heart disease and stroke from chronic inflammation accelerating atherosclerosis. Respiratory: apical pulmonary fibrosis that can cavitate and be colonised by Aspergillus or mycobacteria (often mistaken for TB), and a restrictive defect from chest-wall ankylosis. Renal: secondary (AA) amyloidosis — the most serious renal complication, presenting as proteinuria, nephrotic syndrome or renal failure (biopsy shows apple-green birefringence with Congo red) — and IgA nephropathy.[1]

Neurological: cauda equina syndrome — late, due to expansion of the lumbosacral spinal canal by chronic dural inflammation, presenting with progressive lower-limb weakness, sensory disturbance, saddle anaesthesia and sphincter dysfunction; atlantoaxial subluxation with cervical cord compression; and spinal fracture with cord injury. Gastrointestinal: clinical or subclinical inflammatory bowel disease (Crohn, UC) in 5 to 10 percent. Constitutional: fatigue is a major, often disabling symptom; low-grade fever and weight loss may occur.[1]

The differential — and the discriminator question

A young person with back pain is not always AS. The discriminator that does most of the work is one question: is the pain worse with rest and better with exercise? — yes points to AS.[1]

Mechanical or degenerative low back pain is the commonest mimic — acute onset, worse with activity, better with rest, no morning stiffness, no night pain, normal inflammatory markers, normal SI imaging. Lumbar disc herniation is radicular, dermatomal, worse on sitting, with a positive straight-leg raise and neurological signs. Lumbar spinal stenosis is an older patient with neurogenic claudication. Diffuse idiopathic skeletal hyperostosis (DISH, Forestier disease) affects older men (over 50), with flowing ossification along the anterolateral spine (at least 4 contiguous vertebrae), normal SI joints, normal inflammatory markers and no HLA-B27 association — the bone is bulky and asymmetric, versus the delicate symmetric syndesmophytes of AS. Fibromyalgia is widespread pain with fatigue and sleep disturbance, normal inflammatory markers and normal imaging.[1]

The SpA family themselves overlap: psoriatic arthritis (skin or nail psoriasis, asymmetric sacroiliitis, DIP involvement, pencil-in-cup); reactive arthritis (1 to 4 weeks after GI or GU infection, oligoarthritis, enthesitis, dactylitis, mucocutaneous features); IBD-associated arthritis (axial pattern mirrors AS; peripheral pattern mirrors the bowel flare). Infectious sacroiliitis (pyogenic, tuberculous) is unilateral, severe, with systemic upset and raised CRP — TB should be considered where TB is endemic.[1]

The bedside round — the named measurements

A focused examination is the single most reliable bedside tool in established AS. Always assess spinal mobility, chest expansion, SI-joint provocation, entheses, eyes, heart, chest, skin, peripheral joints and neurology.[1]

Modified Schober test (lumbar flexion). The patient stands erect; mark the midpoint of a line joining the two posterior superior iliac spines (about L5); mark a second point 10 cm above; ask the patient to flex forward as far as possible; measure the new distance. An increase of less than 5 cm (final distance under 15 cm) indicates reduced lumbar flexion.[1]

Occiput-to-wall distance (Moll-Wright test). Patient stands with heels and back against a wall, head in natural position. Measure from the occiput to the wall. More than 5 cm indicates a fixed flexion deformity of the cervical and upper thoracic spine.[1]

Chest expansion. Measure at the fourth intercostal space (or just below the axillae) at maximal inspiration minus maximal expiration. Less than 2.5 cm indicates reduced chest-wall mobility — an early sign. Cervical rotation, lateral lumbar flexion (fingertip-to-floor), and intermalleolar distance (reflecting hip mobility) complete the set. The BASMI combines five measurements — cervical rotation, tragus-to-wall distance, lumbar flexion (modified Schober), lumbar side flexion, and intermalleolar distance — into a 0 to 10 score of spinal mobility.[1]

SI-joint provocation — Gaenslen test (pain in the SI joint on the extended side), FABER or Patrick test (pain in the SI joint or hip), and pelvic compression or distraction tests. These are sensitive but poorly specific — use to support, not to confirm.[1]

Investigations — MRI changes the game

No single test diagnoses AS. Diagnosis is clinical plus imaging, with HLA-B27 and inflammatory markers in a supporting role.[1][3]

Plain X-ray of the sacroiliac joints follows the pathological cascade: blurring of the subchondral bone plate; erosions and juxta-articular osteoporosis; sclerosis (especially on the iliac side, which has thinner cartilage); joint-space narrowing, then partial ankylosis, then complete ankylosis. The process is classically bilateral and symmetric.[1]

Plain X-ray of the lumbar and thoracic spine shows the Romanus lesion (shiny corner) — erosions with sclerosis at the anterosuperior vertebral corner (the enthesitis lesion, an early finding); squaring of vertebral bodies (erosion of the normal anterior concavity); syndesmophytes — delicate, vertical bony outgrowths bridging adjacent vertebrae along the annulus fibrosus; the bamboo spine (late); the dagger sign (ossification of the supraspinous and interspinous ligaments on the AP view); and the trolley-track sign (three vertical lines on AP from ossified ligaments and facet joints).[1]

MRI of the sacroiliac joints is the cornerstone for nr-axSpA. STIR or T2 fat-saturated sequences show high-signal bone-marrow oedema (osteitis) indicating active inflammation — the earliest lesion, preceding X-ray by years. T1-weighted sequences show structural damage (erosions, fat metaplasia, ankylosis). The ASAS or OMERACT consensus definition of active sacroiliitis on MRI requires bone-marrow oedema highly suggestive of SpA, visible on at least two consecutive slices or on a single slice if more than one lesion is seen. Plain X-ray shows only the late consequence; MRI changes the game for early diagnosis.[4]

HLA-B27 is positive in about 90 percent of patients with AS — supportive, not diagnostic. About 8 percent of the general population are HLA-B27-positive but never develop AS, and a negative result does not exclude AS (especially in non-white populations). CRP and ESR are elevated in about 50 to 70 percent of active disease — a normal CRP does not exclude AS. RF and ANA are negative (the definition of "seronegative").[1]

Pre-biologic screen: tuberculosis (interferon-gamma release assay or Quantiferon-TB Gold plus chest X-ray), hepatitis B and C, HIV, full blood count and liver function; an ECG if there is cardiac involvement before a TNF inhibitor.[1]

Disease-activity scores — reproduced verbatim

ASDAS (Ankylosing Spondylitis Disease Activity Score), preferred as ASDAS-CRP.[8]

ASDAS-CRP equals 0.12 times the square root of back pain, plus 0.06 times the duration of morning stiffness, plus 0.07 times CRP in mg per L, plus 0.12 times peripheral pain or swelling, plus 0.06 times patient global on a 0 to 10 scale. (Back pain, peripheral pain and patient global are 0 to 10 patient-reported scales; morning stiffness is 0 to 10.)[1]

Disease-activity bands: under 1.3 inactive disease; 1.3 to under 2.1 moderate; 2.1 to under 3.3 high; 3.3 or more very high. Clinically important improvement is a change of 1.1 or more; major improvement is a change of 2.0 or more.[1]

BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) — six 0 to 10 patient questions (fatigue, spinal pain, joint pain or swelling, enthesitis, morning-stiffness severity and duration), averaged; a BASDAI over 4 on two occasions supports starting a biologic. BASFI is the 10-item functional measure; BASMI the spinal-mobility measure.[1]

First-line — continuous full-dose NSAIDs plus physiotherapy

NSAIDs are first-line for symptom control, and — at full anti-inflammatory dose, given continuously rather than on demand — may slow radiographic progression (a modest effect, strongest for patients with elevated CRP). Try two different NSAIDs over 4 weeks before declaring failure.[7][8]

| NSAID | Dose | Frequency |[7][8] |---|---|---| | Naproxen | 500 mg oral | twice daily | | Diclofenac | 50 to 75 mg oral | twice to three times daily | | Indometacin | 25 to 50 mg oral | three times daily (often favoured for AS) | | Ibuprofen | 400 to 800 mg oral | three to four times daily | | Celecoxib | 100 to 200 mg oral | twice daily (COX-2 selective) | | Etoricoxib | 60 to 90 mg oral | once daily (COX-2 selective; not available in USA) |

[1]

Add a proton-pump inhibitor (omeprazole 20 mg daily) for patients with GI risk. Avoid NSAIDs in significant renal impairment (CKD stage 3B or worse), severe heart failure, active peptic ulcer, anticoagulation, late pregnancy (after 28 to 30 weeks — premature closure of the ductus arteriosus and oligohydramnios), and prior NSAID hypersensitivity.[1]

Physiotherapy and exercise are non-negotiable. Daily stretching, postural exercises, spinal-mobility drills, swimming and deep-breathing exercises to maintain chest expansion are as important as drugs. Supervised group physiotherapy or hydrotherapy is cost-effective and is the only intervention with long-term outcome benefit on mobility. Smoking cessation is mandatory — it reduces progression and improves biologic response.[1]

The biologics — TNF first, IL-17 second

For persistent high disease activity despite an adequate NSAID trial — operationalised as ASDAS 2.1 or more (or BASDAI over 4) on two occasions — a biologic DMARD is indicated.[6][8][10]

TNF inhibitors (first-line biologic)

The TNF inhibitors are equivalent in efficacy; choice is often dictated by comorbidity.[1]

| Agent | Dose and route | Notes |[1] |---|---|---| | Adalimumab | 40 mg subcutaneous every 2 weeks | Monoclonal antibody; effective for AAU and IBD | | Etanercept | 50 mg subcutaneous weekly | Fusion protein; avoid for AAU and IBD | | Infliximab | 5 mg/kg IV every 6 to 8 weeks (loading at weeks 0, 2, 6) | Monoclonal; effective for AAU and IBD | | Golimumab | 50 mg subcutaneous monthly | Convenient; effective for AAU and IBD | | Certolizumab pegol | 400 mg at weeks 0, 2, 4, then 200 mg every 2 weeks (or 400 mg every 4 weeks) | Monoclonal; minimal placental transfer — preferred in pregnancy; effective for AAU and IBD |

[1]

Pre-biologic screen and contraindications. Screen TB (IGRA and CXR), HBV or HCV, HIV, full blood count, LFT, renal function, pregnancy test, and update vaccines. Contraindications include active infection (including untreated latent TB), demyelinating disease (multiple sclerosis — a relative contraindication to TNFi), moderate to severe heart failure (NYHA III or IV — caution with TNFi), recent or active malignancy (case by case), and live vaccines.[1]

IL-17 inhibitors (second-line biologic; first-line if TNFi is contraindicated)

[1]

Caution with IL-17 inhibitors: avoid in inflammatory bowel disease (case reports of new-onset or flared IBD); candidiasis (mucocutaneous); caution in latent TB (less reactivation than TNFi). JAK inhibitors (tofacitinib, upadacitinib, filgotinib) are approved in some regions for AS and share the antiviral or herpes-zoster cautions of the class.[1]

Switching. If the first biologic fails (at 12 to 16 weeks), switch to another class (TNFi to IL-17i or vice versa); about 40 to 50 percent respond to the second agent.[1]

What does NOT work — csDMARDs and systemic steroids for axial disease

Two negative rules carry as many marks as the positive ones.[6][10]

Conventional synthetic DMARDs (sulfasalazine, methotrexate) are NOT effective for axial disease — they are used only when there is peripheral arthritis that has failed NSAIDs. Sulfasalazine 2 to 3 g per day (screen for G6PD deficiency; warn of orange urine staining and reversible male infertility); methotrexate 7.5 to 25 mg weekly with folic acid 5 mg weekly (teratogenic — reliable contraception).[1]

Systemic (oral or IV) glucocorticoids are NOT recommended for axial disease — they are ineffective and high-toxicity. Intra-articular glucocorticoid injections (triamcinolone acetonide 40 mg into the SI joint under imaging, or into a peripheral joint or enthesis) are useful for focal inflammation.[10]

Surgery and adjuncts

Total hip replacement is the single best functional intervention in AS with hip arthritis — it dramatically improves mobility, pain and independence. Corrective spinal surgery — pedicle-subtraction osteotomy or vertebral-column decancellation — is reserved for severe kyphotic deformity that prevents forward gaze or severely impairs function; it is high-risk and confined to specialist spinal centres.[1]

Adjuncts: paracetamol and short-course weak opioids for pain (avoid chronic opioids); smoking cessation; osteoporosis prevention and treatment with calcium and vitamin D, and a bisphosphonate (alendronate 70 mg weekly) for documented osteoporosis. Vaccinate before biologics (pneumococcal, influenza, hepatitis B, COVID-19); avoid live vaccines (MMR, yellow fever, BCG, oral polio) while on a biologic.[1]

The five emergencies of ankylosing spondylitis

How AS patients come to harm — the preventable list

• Diagnostic delay — women and patients with peripheral-predominant disease are under-diagnosed for years; longer delay means more damage.[1]
• Missing nr-axSpA because the plain X-ray is normal — MRI is required.[4]
• Over-reliance on HLA-B27 — positive in 8 percent of the general population; negative does not exclude AS.[1]
• Assuming a normal CRP excludes AS — CRP is normal in 30 to 50 percent.[1]
• Missing a spinal fracture after minor trauma in a fused spine — image, immobilise.[1]
• Using csDMARDs or systemic steroids for axial disease — ineffective.[6][10]
• Using etanercept for uveitis or IBD — relatively contraindicated; choose a TNFi monoclonal.[10]
• Not screening for latent TB before a biologic — high reactivation risk.[1]
• Treating only pain, not function — physiotherapy is mandatory.[1]
• Continuing NSAIDs in CKD or late pregnancy.[1]

Special populations

Pregnancy and lactation. NSAIDs are safe in the first and second trimester but avoided after 28 to 30 weeks (premature closure of the ductus arteriosus, oligohydramnios); ibuprofen and diclofenac are low-risk in lactation. Anti-TNF monoclonal antibodies cross the placenta in the third trimester via FcRn, but certolizumab pegol lacks the Fc fragment and is the preferred anti-TNF in pregnancy and lactation (minimal placental transfer). Sulfasalazine is safe in pregnancy and lactation (continue; supplement folic acid 5 mg daily); note reversible male infertility — counsel men planning conception. Methotrexate, leflunomide and mycophenolate are absolutely contraindicated (teratogenic). If the SI joints and lumbar spine are fused, neuraxial anaesthesia may be technically difficult and the airway challenging if the cervical spine is fused — early anaesthetic review.[1]

Children (juvenile-onset AS or enthesitis-related arthritis, ERA). Enthesitis and asymmetric lower-limb oligoarthritis dominate; axial involvement appears 5 to 10 years later. Uveitis is usually acute and symptomatic (unlike the chronic asymptomatic uveitis of antinuclear-antibody-positive JIA). Treat with NSAIDs, physiotherapy and biologics.[1]

The elderly. Late-onset AS is rare; advanced silent disease discovered after a fracture is the typical scenario. NSAID toxicity (renal, GI, cardiovascular) is higher — prefer COX-2 selective agents at the lowest effective dose, and assess and treat fracture risk and osteoporosis.[1]

The immunocompromised or on-biologic host. Vaccinate before starting the biologic; avoid live vaccines while on it; screen for and treat latent TB and hepatitis B before a TNFi; hold the biologic during severe infection.[1]

Evidence, guidelines and the regional delta

The ASAS-EULAR 2022 recommendations frame modern management: treat-to-target (remission or low activity; ASDAS under 1.3); NSAIDs at maximum tolerated dose, continuously, first-line for all (trial at least two before declaring failure); physiotherapy for all; local glucocorticoid injections for focal inflammation (avoid systemic glucocorticoids); csDMARDs only for peripheral arthritis; biologic DMARDs (TNFi or IL-17i) for persistent high disease activity, switching class if the first fails; surgery (hip replacement, spinal osteotomy) for refractory structural disease; and treatment of comorbidity (cardiovascular risk, osteoporosis, IBD, psoriasis, uveitis).[7][8]

The ACR, SAA and SPARTAN 2019 recommendations (USA) strongly recommend NSAIDs (full dose, continuous) and physical therapy; conditionally recommend a TNFi or IL-17i for persistent active disease after NSAID failure; strongly recommend a TNFi monoclonal over etanercept when there is recurrent uveitis or IBD; conditionally recommend against systemic glucocorticoids and against csDMARDs for axial disease.[10]

NICE NG65 (UK, 2017) sets the biologic threshold at ASDAS 2.4 or more (or BASDAI 4 or more plus objective inflammation on CRP or MRI) on two occasions, mandates switching biologic at 12 weeks on inadequate response, and offers IL-17i if TNFi is contraindicated or failed.[11]

Controversies and the landmark paradox. NSAIDs may slow radiographic progression — the Wienands and Wanders analyses of the GESPIC and ALERT cohorts suggested a modest reduction in mSASSS progression with continuous versus on-demand NSAIDs, strongest in patients with elevated CRP; the effect is real but debated. IL-23 inhibitors (ustekinumab, risankizumab) failed in axSpA despite a strong IL23R genetic signal and dramatic efficacy in psoriasis and IBD — a landmark paradox that challenges the centrality of the IL-23 axis in established axial disease and focuses attention on the IL-17 arm downstream. TNF inhibitors and IL-17 inhibitors are roughly equivalent in efficacy (ASAS 20 response about 60 percent at 12 to 16 weeks).[8]

Secukinumab MEASURE 1 (NEJM 2015) — secukinumab 150 mg subcutaneously at weeks 0, 1, 2, 3 and 4 then monthly produced an ASAS 20 response in about 60 percent at week 16 versus 29 percent placebo — a pivotal registration trial.[9]

The mantra, and the mnemonic

[1]

The mantra: worse with rest, better with exercise, bilateral sacroiliitis — continuous NSAIDs, physiotherapy, and a biologic when those fail.[1][7]

Ward-round test — three stems, thirty seconds each

Stem 1 — the software engineer from the top of the topic (answer)

The 26-year-old with nine months of early-morning back and buttock pain that eases after a walk, alternating buttock pain, an hour of morning stiffness, and a recent red painful eye. What is the diagnosis, and what is the first imaging? Model: This is inflammatory back pain in a young man with an extra-articular feature (acute anterior uveitis) — the classic presentation of ankylosing spondylitis or non-radiographic axial spondyloarthritis. Apply the ASAS (Berlin) inflammatory-back-pain criteria (morning stiffness over 30 minutes, improvement with exercise not rest, second-half-of-night pain, alternating buttock pain — he meets all four). The first imaging is a plain AP pelvis and dedicated sacroiliac joint views looking for bilateral symmetric sacroiliitis — but because a normal X-ray does not exclude early disease, MRI of the sacroiliac joints (STIR or T2 fat-saturated) is the next step to show bone-marrow oedema if the X-ray is normal (nr-axSpA). Send HLA-B27 and CRP (supportive; a normal CRP does not exclude AS). First-line is continuous full-dose NSAIDs (naproxen 500 mg twice daily) plus physiotherapy.[1][3]

Stem 2 — the red eye that is not conjunctivitis (answer)

A patient with known ankylosing spondylitis develops an acutely painful, photophobic, blurred-vision right eye. The GP called it conjunctivitis last month. What is it, and what do you do — including the drug choice that will change? Model: This is acute anterior uveitis — unilateral, painful, photophobic, blurred vision — not conjunctivitis. Refer urgently to ophthalmology within 24 hours for slit-lamp examination and a topical corticosteroid (prednisolone acetate 1 percent hourly while awake) plus a cycloplegic (homatropine 2 percent or cyclopentolate 1 percent) to prevent posterior synechiae. Untreated attacks cause synechiae, glaucoma and cataract. And if his recurrent uveitis is driving the choice of biologic, favour a TNF monoclonal antibody (adalimumab, infliximab, golimumab, certolizumab) — NOT etanercept, which paradoxically worsens or fails to control uveitis.[10]

Stem 3 — the fall in a fused spine (answer)

A 54-year-old with long-standing ankylosing spondylitis and a bamboo spine trips over a curb and now has neck pain. His X-ray shows no obvious fracture. The registrar wants to discharge him with analgesia. What is the right call? Model: This is a spinal-fracture emergency until proven otherwise. The rigid, osteoporotic, fused spine fractures easily — even minor trauma can produce a highly unstable (often cervical) fracture with high paraplegia and mortality, and plain X-rays are unreliable in a fused spine. Immobilise in-line (rigid collar, sandbags, manual in-line stabilisation), obtain whole-spine CT and MRI, and involve neurosurgery or spinal surgery. Do not discharge. Patients with AS should be counselled about this risk before any trauma.[1]

References

1. [1]Braun J, Sieper J. Ankylosing spondylitis Lancet, 2007.PMID 17448825
2. [2]van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria Arthritis Rheum, 1984.PMID 6231933
3. [3]Sieper J, Rudwaleit M, Baraliakos X, et al. The Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis Ann Rheum Dis, 2009.PMID 19433414
4. [4]Rudwaleit M, Jurik AG, Hermann KG, et al. Defining active sacroiliitis on magnetic resonance imaging (MRI) for classification of axial spondyloarthritis: a consensual approach by the ASAS/OMERACT MRI group Ann Rheum Dis, 2009.PMID 19454404
5. [5]Rudwaleit M, van der Heijde D, Landewé R, et al. The Assessment of SpondyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general Ann Rheum Dis, 2011.PMID 21109520
6. [6]van der Heijde D, Sieper J, Maksymowych WP, et al. 2010 Update of the international ASAS recommendations for the use of anti-TNF agents in patients with axial spondyloarthritis Ann Rheum Dis, 2011.PMID 21540200
7. [7]Regel A, Sepriano A, Baraliakos X, et al. Efficacy and safety of non-pharmacological and non-biological pharmacological treatment: a systematic literature review informing the 2016 update of the ASAS/EULAR recommendations for the management of axial spondyloarthritis RMD Open, 2017.PMID 28176966
8. [8]Ramiro S, Nikiphorou E, Sepriano A, et al. Efficacy and safety of biological DMARDs: a systematic literature review informing the 2022 update of the ASAS-EULAR recommendations for the management of axial spondyloarthritis Ann Rheum Dis, 2023.PMID 36270657
9. [9]Baeten D, Sieper J, Braun J, et al. Secukinumab, an Interleukin-17A Inhibitor, in Ankylosing Spondylitis N Engl J Med, 2015.PMID 26699169
10. [10]Ward MM, Deodhar A, Gensler LS, et al. 2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis Arthritis Care Res (Hoboken), 2019.PMID 31436026
11. [11]McCrum C Appraisal of Clinical Practice Guideline: NICE Guidance on Spondyloarthritis in over 16s: diagnosis and management [NG65] J Physiother, 2019.PMID 31477501