Ankylosing Spondylitis

Ankylosing spondylitis (AS) is a chronic, progressive inflammatory arthropathy characterized by inflammation of the axial skeleton, leading to progressive spinal fusion and significant functional impairment. It is the most common form of seronegative spondyloarthropathy and predominantly affects the sacroiliac joints and lumbar spine, with potential extension to the thoracic and cervical spine. The prevalence ranges from 0.1-1.4% in North American and European populations, with a male-to-female ratio of approximately 2-3:1; onset typically occurs in the second to fourth decade of life. The disease has profound clinical significance for USMLE examinations due to its strong association with HLA-B27, distinctive radiographic findings, and the emergence of biologic therapies that have dramatically altered outcomes. Early recognition and aggressive management are essential to prevent disability, preserve spinal mobility, and screen for extra-articular manifestations that can affect multiple organ systems.

The pathophysiology of AS centers on an aberrant immune response in HLA-B27–positive individuals. HLA-B27 is present in >90% of AS patients compared to 4-8% of the general population, establishing it as the strongest genetic association with any human disease. The mechanism involves both classical and unconventional HLA-B27 presentations: (1) arthritogenic peptide hypothesis—HLA-B27 presents bacterial peptides (from Klebsiella pneumoniae, Proteus, Shigella, or Yersinia) that cross-react with self-antigens in the spine and entheses, (2) HLA-B27 homodimer formation creating novel epitopes that activate CD8+ T cells, and (3) impaired folding of HLA-B27 in the endoplasmic reticulum triggering unfolded protein responses and IL-23 pathway activation. CD8+ T cells specific for HLA-B27–presented peptides infiltrate the sacroiliac joints and spinal tissues, initiating chronic inflammation. Importantly, only 5-10% of HLA-B27–positive individuals develop AS, indicating that additional genetic and environmental factors are necessary.

Beyond HLA-B27, the IL-23 signaling pathway emerges as critical in AS pathogenesis. Genome-wide association studies (GWAS) have identified numerous genes involved in the IL-23 pathway (IL23R, IL12B, STAT3, TYK2) as conferring disease susceptibility. IL-23, produced by dendritic cells and macrophages in response to bacterial antigens or endoplasmic reticulum stress, promotes differentiation of naive CD4+ T cells toward Th17 effector cells. These Th17 cells produce IL-17A and IL-17F, which amplify inflammation by stimulating synovial fibroblasts, osteoblasts, and endothelial cells to produce TNF-α, IL-6, IL-8, and other inflammatory mediators. IL-17 also promotes bone resorption through RANKL upregulation and inhibits bone formation through Wnt/β-catenin pathway suppression, contributing to the paradoxical combination of bone loss and new bone formation seen in AS. This IL-23/IL-17 axis represents the primary pathogenic mechanism distinct from TNF-α–driven spondyloarthropathy, explaining the clinical benefit of IL-17 inhibitors in AS.

AS distinctively targets the entheses—fibrous insertions of tendons, ligaments, and joint capsules into bone. The anatomic proximity of entheses to cortical bone and their relative avascularity create a microenvironment prone to inflammation. Chronic enthesitis leads to: (1) progressive erosion of cortical bone at insertion sites, (2) inflammatory granulation tissue formation, and (3) gradual replacement with fibrous tissue and ultimately bony ankylosis. This process is mediated by TNF-α and IL-17–driven activation of osteoclasts and erosion of the mineralized fibrocartilage. Simultaneously, bone morphogenetic proteins (BMPs) and Wnt/β-catenin signaling are activated in response to inflammation, promoting heterotopic ossification and new bone formation—a paradoxical phenomenon unique to spondyloarthropathies. Over time, the syndesmophytes (vertical bony bridges connecting vertebral bodies) progressively fuse adjacent vertebrae, converting the spine into a rigid "bamboo spine" configuration. The combination of progressive spinal fusion with osteoporosis (from chronic inflammation and reduced mobility) creates a mechanically fragile spine susceptible to fracture from minor trauma.

Beyond HLA-B27 and IL-23 pathway genes, GWAS have identified susceptibility loci in genes encoding molecules involved in immune regulation (ERAP1, ERAP2, which process HLA-B27 peptides), TNF-α signaling, autophagy (ATG16L1), and IL-6 signaling. These multiple genetic contributions explain disease heterogeneity. Environmental triggers include bacterial infections—particularly gastrointestinal pathogens (Salmonella, Shigella, Yersinia, Campylobacter) and urogenital infections (Chlamydia trachomatis)—that may initiate the initial immune response in genetically susceptible individuals through molecular mimicry or direct antigen presentation. The role of the intestinal microbiota is increasingly recognized; dysbiosis and altered intestinal barrier function may facilitate bacterial translocation and chronic stimulation of mucosal immunity.

HLA-B27 is present in >90% of AS patients and is the dominant genetic risk factor. However, its presence is neither necessary nor sufficient for disease development, as only 5-10% of HLA-B27–positive individuals develop clinically evident AS. The association is strongest in patients with early-onset disease and family history. HLA-B27 testing has high negative predictive value—absence of HLA-B27 essentially excludes AS as a diagnosis. Certain HLA-B27 subtypes (B*2705 in Caucasians) carry higher disease risk than others.

Family history and twin studies demonstrate significant genetic contribution: concordance in monozygotic twins is approximately 90%, while sibling recurrence risk is 8-10%. GWAS have identified >40 non-HLA susceptibility loci, predominantly involving IL-23 pathway genes (IL23R, IL12B, STAT3, TYK2, TNFAIP3, IKBKG) and TNF-α signaling. These multiple genetic hits explain variable penetrance and disease severity. ERAP1 and ERAP2 variants modulate peptide presentation to HLA-B27, influencing disease risk. Autophagy-related genes (ATG16L1) suggest impaired handling of intracellular bacteria in pathogenesis.

Antecedent or concurrent infections with gram-negative enteric bacteria (Salmonella, Shigella, Yersinia enterocolitica, Campylobacter jejuni) or urogenital pathogens (Chlamydia trachomatis, Ureaplasma urealyticum) are associated with AS development or flares. The mechanism involves molecular mimicry—bacterial epitopes cross-react with HLA-B27–presented self-peptides. Reactive arthritis represents an intermediate phenotype where infection-triggered inflammation mimics AS but typically resolves. The temporal relationship between infection and arthritis onset suggests that in genetically susceptible individuals, microbial triggers can initiate pathogenic T cell and B cell responses.

Subclinical inflammatory bowel disease (IBD) or IBD-like intestinal inflammation is present in 5-25% of AS patients without clinical symptoms. Dysbiosis—altered microbiota composition—has been documented in AS, with reduced bacterial diversity and decreased abundance of short-chain fatty acid (SCFA)–producing commensals. Impaired intestinal barrier function, demonstrated by increased zonula occludens-1 (ZO-1) dysfunction and elevated fecal calprotectin, may facilitate bacterial translocation and perpetual mucosal immune activation.

Smoking is associated with worse radiographic progression and more severe disease phenotype. Male sex confers 2-3-fold higher risk compared to females, though females may present with more axial symptoms and diagnostic delay. Higher body mass index has been associated with elevated inflammatory markers. Trauma may exacerbate spinal inflammation in susceptible individuals.

The cardinal symptom of AS is inflammatory back pain (IBP), which distinguishes AS from mechanical back pain. Patients typically report insidious onset of deep, poorly-localized pain in the sacroiliac region or lower lumbar spine, often bilateral and symmetric. Key distinguishing features include: (1) morning stiffness lasting >30 minutes (often 1-2 hours), which improves with activity and heat but worsens with rest—this contrasts with mechanical pain that typically improves with rest; (2) pain worse in the second half of the night, prompting patients to awaken and move around; (3) improvement with exercise and NSAIDs, reflecting the inflammatory rather than degenerative nature; and (4) insidious onset before age 40, often in young adults in their 20s and 30s. The inflammatory pattern results from nocturnal accumulation of inflammatory mediators and increased TNF-α and IL-17 production, with mobilization and heat helping to mobilize inflammatory exudate.

As disease progresses, inflammation ascends the spine, leading to mid-thoracic and eventually cervical involvement. Patients develop progressive loss of lumbar lordosis and thoracic kyphosis, culminating in the characteristic "bamboo spine" or "poker spine" appearance on radiographs. This structural progression correlates with progressive limitation in spinal flexion, extension, and lateral bending. In advanced disease, patients adopt a characteristic posture with forward head position and thoracic hyperkyphosis to maintain horizontal gaze—the "question mark" posture. Cervical spine involvement can lead to atlantoaxial subluxation in severe cases, with risk of myelopathy. Chest wall involvement (costovertebral joints, manubriosternal joint, costochondral junctions) can cause pleuritic chest pain and restrict chest expansion, potentially affecting pulmonary function testing with reduced forced vital capacity.

Approximately 30% of AS patients develop peripheral joint arthritis (polyarticular or oligoarticular), which typically affects large joints in an asymmetric pattern: hips, shoulders, knees, and ankles. Hip involvement occurs in 20-30% of patients and is a significant predictor of worse prognosis and functional impairment; early hip disease is associated with younger age at disease onset and elevated inflammatory markers. Peripheral arthritis in AS typically appears early in disease course and can be intermittent. Thoracic outlet syndrome and carpal tunnel syndrome may develop secondary to cervical or thoracic spine disease and inflammation.

Inflammation at entheses other than the spine is common, manifesting as: (1) Achilles tendinitis or plantar fasciitis, presenting with heel pain exacerbated by weight-bearing and palpation over the insertion site, (2) anterior chest wall pain from costochondritis or manubriosternal joint involvement, (3) greater trochanter bursitis, and (4) iliac crest tenderness. Approximately 25-30% of AS patients develop uveitis (typically anterior, non-granulomatous), presenting with eye pain, photophobia, blurred vision, and red eye; uveitis may precede articular symptoms and warrant ophthalmology evaluation. Recurrent or chronic uveitis is associated with a worse prognosis. Psoriasis is present in 5-10% of AS patients (compared to 1-2% in general population), and the combination of psoriasis, arthritis, and enthesitis defines the broader psoriatic spondyloarthropathy phenotype. Inflammatory bowel disease (Crohn's disease or ulcerative colitis) coexists in 5-10% of AS patients; its presence may correlate with more severe axial disease. Oral ulcers are uncommon but can occur.

Constitutional symptoms including fatigue and low-grade fever may accompany active inflammation. Fatigue is often underappreciated but contributes significantly to disability and quality of life impairment. Unlike rheumatoid arthritis, AS typically does not cause systemic symptoms from extra-articular organ involvement, though cardiac and pulmonary complications (discussed under Complications) may develop insidiously.

Early AS may have minimal findings on standard musculoskeletal examination, as inflammation is primarily axial and may be subtle. Progressive disease demonstrates: (1) Schober test abnormality—measurement from a point 5 cm below the posterior superior iliac spine to 10 cm above; the normal increase in distance with lumbar flexion is <5 cm, reflecting reduced spinal mobility; (2) limited spinal extension and flexion, (3) reduced chest expansion (<2.5 cm measured at the fourth intercostal space), (4) sacroiliac joint tenderness to palpation, (5) positive FABER test (flexion-abduction-external rotation) if hip involvement is present, (6) tenderness over Achilles insertion and plantar fascia, and (7) anterior uveitis on slit-lamp examination if present. Late-stage disease may show kyphotic posturing, reduced spinal mobility resembling "wooden" rigidity, and neurological signs if cervical myelopathy develops.

Juvenile-onset AS (before age 16) is more common in males and often presents with peripheral joint involvement (particularly knees and hips) before axial symptoms develop; these patients tend to have more aggressive disease. Women with AS often present with peripheral joint involvement, neck pain, or atypical symptoms, leading to diagnostic delays; disease activity and functional impairment in women may be underestimated by standard measures. Some patients present with isolated peripheral arthritis or enthesitis without prominent axial involvement—the "non-radiographic axial spondyloarthropathy" phenotype, which has normal or near-normal plain radiographs but MRI evidence of spinal inflammation.

Diagnosis begins with recognition of inflammatory back pain characteristics: age <40 at onset, insidious onset, morning stiffness >30 minutes improving with activity, night pain, and improvement with NSAIDs. The ASAS criteria for inflammatory back pain (developed by the Assessment of Spondyloarthritis International Society) require ≥4 of 5 features: morning stiffness >30 minutes, improvement with exercise, awakening due to back pain in the second half of the night, buttock pain, and either elevated CRP or MRI signs of inflammation. Detailed family history is essential, as positive family history significantly increases pre-test probability. Temporal relationships with infections, systemic symptoms, eye symptoms, or GI complaints should be documented. Occupational and social factors affecting symptom severity and functional status should be assessed.

HLA-B27 testing is essential in the diagnostic evaluation and should be performed in any patient with suspected axial spondyloarthropathy. The test has >90% sensitivity in AS patients and is present in <8% of the general population, giving it high specificity for spondyloarthropathy. A negative HLA-B27 essentially excludes AS as a diagnosis and should prompt consideration of alternative diagnoses (mechanical back pain, fibromyalgia, seronegative RA with axial involvement). Conversely, HLA-B27 positivity alone is not diagnostic (5-10% of positive individuals develop AS) and must be interpreted in clinical context. Routine HLA-B27 screening in asymptomatic individuals is not recommended, as most will never develop disease.

Inflammatory markers (ESR and CRP) are non-specific but useful for disease assessment. Approximately 70% of AS patients have elevated CRP (>3 mg/L) or ESR at presentation, though 30% may have normal markers despite active disease. CRP is more specific to AS than ESR. Serial CRP and ESR measurement helps assess response to therapy and disease progression. Notably, inflammatory markers may not correlate with spinal inflammation on MRI or patient-reported symptoms, limiting their diagnostic utility. Severe elevation (ESR >100 mm/h, CRP >100 mg/L) should prompt

Immediate concerns first: any AS patient with new neck or back pain after even trivial trauma is assumed to have an unstable fracture of the fused spine until CT (± MRI) proves otherwise — immobilize in the patient's baseline deformity, not flat on a backboard, which can distract the fracture and injure the cord. Acute unilateral painful red eye requires same-day ophthalmology for topical glucocorticoids and cycloplegics.

Before any biologic: screen for latent tuberculosis (IGRA/PPD) and hepatitis B; TNF inhibitors are contraindicated in active infection, untreated latent TB, demyelinating disease, and NYHA class III–IV heart failure.

Surgical: total hip arthroplasty for structural hip disease; spinal osteotomy for disabling kyphosis preventing horizontal gaze; urgent stabilization for unstable fracture.