Seronegative Spondyloarthropathies

Genetic drivers (non-modifiable)

• HLA-B27: the dominant susceptibility allele; heritability of ankylosing spondylitis is very high, yet only a minority of B27-positive people ever develop disease — so the allele is necessary-ish but not sufficient. Risk varies by subtype (B*27:05 confers risk; B*27:06 and B*27:09 appear not to), which is why prevalence tracks ancestry (high in Northern European and Native American populations, low in those of African descent).
• Non-HLA polymorphisms: ERAP1 variants (peptide trimming for MHC class I loading) act epistatically — they raise risk only in HLA-B27–positive individuals, elegant support for the peptide-presentation model. IL23R and IL12B variants tie the same genetics to the IL-23/IL-17 axis targeted by therapy.
• Family history: a first-degree relative with SpA, psoriasis, uveitis, or IBD is the single most useful stem clue after B27 status.
• Sex: male predominance for radiographic axial disease and bamboo-spine progression; women present more often with non-radiographic axial SpA, peripheral arthritis, and enthesitis, and are frequently diagnosed late.
• Age: onset almost always before 45; new inflammatory back pain after 45 should push you toward malignancy, infection, or DISH.

Environmental/microbial triggers

• Antecedent infection: enteric (Salmonella, Shigella, Yersinia, Campylobacter) or urogenital (Chlamydia trachomatis) infection 1–4 weeks before reactive arthritis.
• Barrier disease: clinically apparent or subclinical gut inflammation and cutaneous psoriasis serve as the mucosal/epidermal "launch sites" for IL-23–driven entheseal inflammation.
• HIV: associated with severe reactive arthritis and explosive psoriatic arthritis — check HIV status in a young patient with fulminant SpA.

Modifiable risk factors examiners plant

• Smoking: accelerates radiographic progression, worsens function, and blunts TNF-inhibitor response — counseling is part of the ACR/SAA/SPARTAN axial spondyloarthritis guideline's non-pharmacologic package.
• Obesity: increases psoriatic arthritis risk and reduces the odds of achieving minimal disease activity.
• Mechanical entheseal stress: repetitive load at high-stress entheses (Achilles, plantar fascia) helps explain the Koebner-like site selection.

• HLA-B27 molecular mimicry: HLA-B27 presents microbial antigens (from Gram-negative bacteria like Klebsiella, Shigella, Salmonella, Yersinia, Chlamydia) that cross-react with self-antigens on joint and entheseal tissues, triggering aberrant CD8+ T cell responses
• Enthesitis as pathologic hallmark: Inflammation initiates at tendon and ligament insertion sites (entheses) rather than synovium, leading to characteristic bone erosion and new bone formation; TNF-α and IL-23 pathways drive this unique pattern
• Innate immune activation: Loss of regulatory T cell function and increased IL-17 production from γδ T cells and innate lymphoid cells perpetuate chronic inflammation independent of traditional adaptive immunity
• Altered microbiota and gut permeability: Dysbiosis and increased intestinal permeability (even in seronegative SpA without inflammatory bowel disease) allow bacterial lipopolysaccharide translocation, activating toll-like receptors and promoting Th17 differentiation
• HLA-B27 misfolding hypothesis: Intracellular accumulation of misfolded HLA-B27 molecules triggers unfolded protein response, activating stress kinases and amplifying IL-23-mediated inflammation

Axial Manifestations

• Inflammatory back pain: Insidious onset of morning stiffness lasting >30 minutes (often >1 hour), improves with activity/exercise, worsens with rest—typically worse in second half of night; eventually leads to spinal fusion and kyphotic deformity with restricted spinal mobility
• Sacroiliitis: Bilateral and symmetric buttock pain radiating to posterior thighs; early radiographic finding; diagnosed by imaging and reproduced by physical examination maneuvers (Gaenslen test, FABER test)
• Cervical spine involvement: Less common but clinically significant; can lead to atlantoaxial subluxation and myelopathy

Peripheral Manifestations

• Asymmetric oligoarthritis: Typically affects knees, ankles, and feet; less symmetric than rheumatoid arthritis
• Dactylitis ("sausage digit"): Swelling of entire digit from simultaneous synovitis and tenosynovitis; considered a clinical hallmark
• Plantar fasciitis and Achilles tendinitis: Enthesitis manifestations; often precede or accompany joint involvement

Extra-Articular Features (Vary by Subtype)

• Uveitis (especially anterior, acute): Most common extra-articular manifestation; can occur in 25-40% of ankylosing spondylitis patients; presents with photophobia, eye pain, and red eye
• Inflammatory bowel disease features: Crohn disease or ulcerative colitis in 5-10% of SpA patients; joint symptoms may precede GI symptoms
• Psoriasiform skin lesions: Psoriasis in 10-20% of patients; may be subtle (nail pitting, psoriatic plaques)
• Oral ulcers and genital ulcers: More prominent in Behçet syndrome variant
• Keratoderma blennorrhagicum: Hyperkeratotic lesions on palms/soles in reactive arthritis; pathognomonic when present
• Circinate balanitis: Shallow penile ulcers in reactive arthritis; often asymptomatic

Clinical Pearls

• Age at onset typically 15-35 years; male predominance (3:1 ratio)
• Symptoms often follow gastrointestinal infection (Shigella, Salmonella) or urogenital infection (Chlamydia) by 1-4 weeks
• HLA-B27 positivity increases axial involvement probability but is not diagnostic alone

• HLA-B27 testing: Highly sensitive (>90%) for ankylosing spondylitis and associated conditions; present in 6-8% of healthy Caucasian population, so positive test alone is insufficient for diagnosis; critical for classifying undifferentiated SpA
• Imaging—sacroiliac joints: Conventional X-rays show bilateral symmetric sacroiliitis; early changes include erosions and sclerosis; essential for diagnosis of ankylosing spondylitis; MRI detects inflammation before structural changes appear (better for early disease)
• Imaging—spine: Early changes include squaring of vertebral bodies, vertical ossification of intervertebral ligaments, and progressive fusion creating "bamboo spine" in advanced disease; cervical spine fusion carries myelopathy risk
• Laboratory markers: Elevated ESR and CRP during active disease; notably, rheumatoid factor and anti-CCP are negative (distinguishing feature); ANA typically negative
• Assessment of Spondyloarthritis International Society (ASAS) classification criteria: Requires HLA-B27 positivity PLUS either ≥2 SpA features (inflammatory back pain, arthritis, uveitis, dactylitis, psoriasis, inflammatory bowel disease, good response to NSAIDs) OR imaging evidence of sacroiliitis PLUS ≥1 SpA feature
• Ophthalmologic examination: Screen for uveitis even in asymptomatic patients given high association with anterior uveitis

Diagnostic Pearls

• Do NOT order HLA-B27 in patients with clear rheumatoid arthritis or positive rheumatoid factor (different disease)
• MRI sacroiliac joints is more sensitive than X-rays for detecting early inflammatory changes
• Presence of dactylitis or enthesitis should raise suspicion for SpA over rheumatoid arthritis

First-Line Therapy

• NSAIDs: Continuous (not as-needed) dosing is essential; naproxen 500 mg BID or indomethacin 75-100 mg daily in divided doses; use for at least 4-6 weeks before assessing efficacy; provide superior benefit in axial disease compared to peripheral disease; continue indefinitely in responders
• Physical therapy and exercise: High-impact, particularly spinal extension and posture exercises; critical for maintaining spinal mobility and preventing fusion-related disability; should be offered to all patients

Second-Line Therapy for Inadequate NSAID Response

• TNF-α inhibitors: First biologic class; dramatically alter natural history by slowing radiographic progression; particularly effective for axial disease
• Infliximab 5 mg/kg IV at weeks 0, 2, 6 then every 8 weeks
• Etanercept 50 mg SC weekly or 25 mg BID
• Adalimumab 40 mg SC every other week
• Preferred agents for ankylosing spondylitis with axial involvement
• IL-17 inhibitors: Secukinumab (2.5 mg/kg IV loading then monthly SC) or ixekizumab; newer agents with efficacy comparable to TNF inhibitors, particularly for axial and peripheral disease
• IL-23 inhibitors: Ustekinumab and risankizumab; emerging data supporting efficacy in SpA

Special Situations

• Uveitis management: Topical corticosteroids (prednisolone acetate 1% QID) and cycloplegia (tropicamide 1% TID) for acute episodes; consider biologic therapy if recurrent; TNF inhibitors particularly effective for uveitis prevention
• NSAID intolerance/GI bleeding: Switch to selective COX-2 inhibitor (celecoxib 200 mg BID) or add gastroprotection with proton pump inhibitor; consider biologics sooner
• Inflammatory bowel disease overlap: Biologics selection depends on

Skeletal — the emergencies

• Spinal fracture in the ankylosed spine: the fused, osteoporotic spine behaves like a long bone; even trivial trauma (a fall from standing, a low-speed collision) produces a transverse three-column fracture, most often cervical, with high risk of cord transection. Any new or changed neck/back pain after minor trauma in ankylosing spondylitis is a surgical emergency — plain films are unreliable across a fused, deformed spine, so obtain CT (MRI if cord injury or epidural hematoma is suspected) and immobilize in the patient's baseline kyphotic position, not flat.
• Atlantoaxial subluxation and cervical myelopathy: presents with occipital pain, hand clumsiness, hyperreflexia, gait change.
• Cauda equina syndrome: a late, insidious complication of long-standing ankylosing spondylitis with dural ectasia — saddle anesthesia, urinary retention; still evaluate emergently.
• Osteoporosis and vertebral compression fracture: paradoxical bone loss occurs despite syndesmophyte formation; DXA of the spine is falsely reassuring because ossification inflates apparent density.

Extra-skeletal

• Acute anterior uveitis: unilateral painful red eye with photophobia and consensual photophobia — an ocular urgency requiring same-day ophthalmology to prevent synechiae and vision loss.
• Aortitis: aortic root dilation causing aortic regurgitation, plus conduction disease from inflammation tracking into the membranous septum — a young man with ankylosing spondylitis and complete heart block needing pacing is a classic vignette.
• Restrictive lung disease: costovertebral fusion limits chest expansion; also apical fibrobullous disease that can mimic or harbor tuberculosis.
• Secondary AA amyloidosis: chronic serum amyloid A elevation → nephrotic-range proteinuria and renal failure; also IgA nephropathy.

Treatment-related

• NSAIDs: GI bleeding, AKI, hypertension, cardiovascular risk with continuous dosing.
• TNF inhibitors: reactivation of latent tuberculosis (screen with IGRA/TST plus chest radiograph before the first dose) and hepatitis B; serious bacterial and fungal infection; demyelinating disease; avoid in advanced heart failure.
• IL-17 inhibitors: mucocutaneous candidiasis, and possible worsening or new onset of inflammatory bowel disease — avoid when IBD coexists.

• Inflammatory versus mechanical back pain is the whole first step: age <45, insidious onset, pain worst in the second half of the night, morning stiffness >30 minutes, better with exercise and worse with rest. Mechanical back pain does the opposite — that inversion is the discriminator examiners reward.
• Normal sacroiliac radiographs do not exclude disease: the single best next step in a young patient with inflammatory back pain and normal films is MRI of the sacroiliac joints, which shows bone marrow edema years before erosion or sclerosis appears. Ordering HLA-B27 instead is the classic distractor — it is a probability modifier, never a diagnosis.
• Before the first dose of any TNF inhibitor, screen for latent tuberculosis (IGRA or TST plus chest radiograph) and hepatitis B. This is the most commonly tested "next step" in the treatment arm of a SpA vignette.
• Not all TNF inhibitors are interchangeable: the ACR/SAA/SPARTAN axial spondyloarthritis guideline favors monoclonal antibody TNF inhibitors (infliximab, adalimumab) over etanercept when recurrent uveitis or inflammatory bowel disease coexists, because etanercept does not prevent either. Similarly, avoid IL-17 inhibitors when IBD is present.
• Psoriatic arthritis versus rheumatoid arthritis: PsA takes the DIP joints, is asymmetric, brings nail pitting and onycholysis, dactylitis, and the "pencil-in-cup" deformity of arthritis mutilans. RA spares DIPs and hits MCP/PIP symmetrically with positive RF/anti-CCP.
• Reactive arthritis: "can't see, can't pee, can't climb a tree" — conjunctivitis, urethritis, oligoarthritis, plus keratoderma blennorrhagicum and circinate balanitis. Synovial fluid is sterile and inflammatory; treating a documented Chlamydia infection with doxycycline is correct for the infection and the partner, but antibiotics do not alter post-enteric reactive arthritis.
• Sulfasalazine and methotrexate work for peripheral arthritis only — they have no meaningful effect on axial disease or radiographic progression.
• Minor trauma plus a fused spine equals CT, not reassurance — an unstable transverse fracture is the emergency hiding in an otherwise benign-sounding stem.