# Ankylosing Spondylitis and Axial Spondyloarthritis

## Introduction

Axial spondyloarthritis encompasses a clinical spectrum ranging from non-radiographic axial spondyloarthritis, in which sacroiliac inflammation is detectable only by MRI, to ankylosing spondylitis, also termed radiographic axial spondyloarthritis, in which structural damage is evident on conventional radiographs. HLA-B27 is the strongest genetic risk factor, present in approximately 90 percent of patients with ankylosing spondylitis. The disease predominantly affects young adults with onset before age 45, and the male-to-female ratio is approximately 2 to 3 for ankylosing spondylitis but approaches 1 to 1 for non-radiographic axial SpA. A diagnostic delay averaging 7 to 10 years from symptom onset remains a persistent clinical challenge, making early recognition critical. The IL-17 and IL-23 cytokine pathways are central to the pathogenesis of axial SpA.

## Pathogenesis

### Genetics

HLA-B27 is present in approximately 90 percent of patients with ankylosing spondylitis compared to approximately 8 percent of the general population, yet only about 5 percent of HLA-B27-positive individuals develop the disease. HLA-B27 subtypes influence disease susceptibility, with B*27:05 being the most common disease-associated subtype worldwide, while B*27:06 and B*27:09 may confer protection. Beyond HLA-B27, more than 100 risk loci have been identified, including IL-23R, ERAP1, IL-1A, RUNX3, and TBX21. ERAP1 risk variants demonstrate epistatic interaction, conferring disease risk only in HLA-B27-positive individuals.

### Pathophysiologic Mechanisms

Several hypotheses explain how HLA-B27 contributes to disease. The misfolding hypothesis proposes that misfolded B27 heavy chains within the endoplasmic reticulum trigger the unfolded protein response, leading to IL-23 production by macrophages. The homodimer hypothesis suggests that free heavy chain dimers expressed on cell surfaces activate NK cells and T cells through KIR3DL2 receptor engagement. The arthritogenic peptide hypothesis postulates that B27 presents unique self-peptides that trigger autoimmune CD8-positive T cell responses.

The IL-23/IL-17 axis plays a central role in disease pathogenesis. IL-23 produced by entheseal resident cells activates type 3 innate lymphoid cells and gamma-delta T cells, which in turn produce IL-17, driving both inflammation and new bone formation. Mechanical stress at entheses, the sites of highest biomechanical loading including the sacroiliac joints, spine, and heel, determines the preferential localization of disease. The gut-joint axis is supported by the finding of subclinical gut inflammation in 50 to 60 percent of ankylosing spondylitis patients, along with gut dysbiosis and altered microbiome composition.

### Enthesitis: The Primary Lesion

The enthesis, the site where tendons and ligaments insert into bone, represents the primary target of inflammation in spondyloarthritis. The entheseal organ concept recognizes the complex structure of the enthesis, including fibrocartilage, entheseal bone, and adjacent bursae. Resident immune cells including type 3 innate lymphoid cells and gamma-delta T cells at entheses can be activated by IL-23 and mechanical stress. The pathologic cascade proceeds from enthesitis through bone erosion to new bone formation in the form of syndesmophytes and ultimately to ankylosis.

<image>A detailed anatomical cross-section of a spinal enthesis showing the pathogenesis of axial spondyloarthritis. Show the vertebral body with the annulus fibrosus insertion site (enthesis) at the vertebral corner. Illustrate three stages: (1) Normal enthesis with fibrocartilage, mineralized zone, and bone. (2) Early inflammation: IL-23 from macrophages activating resident ILC3 and gamma-delta T cells at the enthesis; IL-17 production; neutrophil infiltration; bone marrow edema in adjacent vertebral corner. (3) Late stage: Erosion of vertebral corner followed by new bone formation (syndesmophyte) bridging the disc space. Label all cell types, cytokines (IL-23, IL-17, TNF), and structural changes. Include an inset showing the MRI appearance of bone marrow edema at the vertebral corner.</image>

## Clinical Features

### Inflammatory Back Pain

The ASAS criteria for inflammatory back pain require at least 4 of 5 features: age of onset before 40, insidious onset, improvement with exercise, no improvement with rest, and nocturnal pain that improves upon getting up. Alternating buttock pain reflects sacroiliac joint inflammation. Morning stiffness exceeding 30 minutes is characteristic. A robust response to NSAIDs distinguishes inflammatory from mechanical back pain. Inflammatory back pain has a prevalence of approximately 5 percent in the general population, of whom approximately 15 percent have axial spondyloarthritis.

### Axial Disease Progression

Sacroiliitis is the earliest and most consistent finding, typically presenting bilaterally. Spinal involvement ascends from the lumbar to thoracic to cervical regions. The structural progression follows a predictable sequence: squaring of vertebral bodies, syndesmophyte formation, and ultimately the bamboo spine of complete spinal ankylosis. Reduced spinal mobility is quantified by the Schober test (with less than 5 centimeters of expansion indicating restriction), chest expansion (with less than 2.5 centimeters being abnormal), and occiput-to-wall and tragus-to-wall distances. Cervical involvement produces loss of lordosis, fixed flexion deformity, and inability to look forward.

### Peripheral Manifestations

Peripheral arthritis occurs in approximately 30 percent of patients and is characteristically asymmetric, oligoarticular, and lower extremity predominant. Enthesitis, particularly at the Achilles tendon insertion and plantar fascia origin, is a hallmark of spondyloarthritis, with additional common sites including the costochondral junctions and ischial tuberosities. Dactylitis, or sausage digits, is more common in psoriatic arthritis but can occur in ankylosing spondylitis. Hip involvement affects up to 25 to 50 percent of patients and carries significant functional impact, potentially requiring arthroplasty.

### Extra-articular Manifestations

Acute anterior uveitis is the most common extra-articular manifestation, affecting 25 to 40 percent of patients, and presents as unilateral, recurrent, and alternating episodes that are strongly HLA-B27 associated. Treatment involves topical glucocorticoids and cycloplegic drops, and TNF inhibitors, particularly adalimumab and infliximab, reduce recurrence rates more effectively than etanercept. Inflammatory bowel disease affects 5 to 10 percent of patients overtly, while subclinical gut inflammation is detectable in 50 to 60 percent. Psoriasis is present in 10 to 25 percent of SpA patients. Cardiovascular manifestations include aortitis, aortic regurgitation in 1 to 10 percent, and conduction abnormalities including atrioventricular block. Apical pulmonary fibrosis is a rare late finding. Osteoporosis is paradoxically common despite the new bone formation that characterizes the disease, and vertebral fractures, including chalk-stick fractures through syndesmophytes, represent a serious complication. IgA nephropathy and AA amyloidosis are rare renal complications.

## Diagnosis

### 2009 ASAS Classification Criteria for Axial SpA

The classification criteria apply to patients with age of onset before 45 years and back pain of at least 3 months duration. Two arms are available. The imaging arm requires sacroiliitis on imaging, either meeting radiographic modified New York criteria or showing active inflammation on MRI as bone marrow edema, plus at least one SpA feature. The clinical arm requires HLA-B27 positivity plus at least two SpA features. SpA features include inflammatory back pain, arthritis, enthesitis, uveitis, dactylitis, psoriasis, IBD, good response to NSAIDs, family history of SpA, HLA-B27, and elevated CRP.

### Imaging

Radiographic sacroiliitis is graded according to the modified New York criteria: grade 0 is normal, grade 1 is suspicious changes, grade 2 demonstrates sclerosis with some erosions, grade 3 shows erosions with sclerosis and partial ankylosis, and grade 4 indicates complete ankylosis. Classification requires bilateral grade 2 to 4 or unilateral grade 3 to 4 changes. Radiographic changes may take 7 to 10 years to develop, limiting the utility of conventional radiography for early diagnosis.

MRI of the sacroiliac joints is the gold standard for early detection. Active inflammation appears as bone marrow edema on STIR or T2 fat-saturated sequences. Structural changes including erosions, fat metaplasia, sclerosis, and ankylosis are visible on T1-weighted sequences. The ASAS definition of a positive MRI requires bone marrow edema highly suggestive of SpA present in at least 2 consecutive slices or at least 2 lesions on a single slice. Spine radiographs may demonstrate Romanus lesions at vertebral corners, squaring, syndesmophytes, the bamboo spine, Anderson discovertebral lesions, and the trolley-track sign. Ultrasound is useful for assessing peripheral enthesitis, with Power Doppler indicating active inflammation.

### Laboratory

HLA-B27 testing is supportive but not diagnostic; approximately 10 percent of AS patients are HLA-B27 negative, and the negative predictive value alone does not exclude axial SpA. CRP and ESR are elevated in only 40 to 50 percent of patients, and normal values do not exclude active disease. Importantly, there are no disease-specific autoantibodies in axial SpA; RF, anti-CCP, and ANA are characteristically negative.

## Disease Activity Assessment

The BASDAI (Bath AS Disease Activity Index) employs 6 patient-reported questions covering fatigue, spinal pain, peripheral joint pain and swelling, enthesitis, and morning stiffness, scored on a 0 to 10 scale, with active disease defined as a score of 4 or greater. The ASDAS (AS Disease Activity Score) incorporates patient-reported outcomes combined with CRP and is the preferred composite measure, with inactive disease below 1.3, low activity between 1.3 and 2.1, high activity between 2.1 and 3.5, and very high activity above 3.5. The BASFI (Bath AS Functional Index) captures functional limitation, and the BASMI (Bath AS Metrology Index) provides objective spinal mobility measurements.

<image>A comprehensive imaging comparison for axial spondyloarthritis diagnosis. Show four panels: (1) AP pelvis radiograph showing bilateral sacroiliitis with grading system illustrated (Grade 0-4 on left and right SI joints). (2) Coronal STIR MRI of SI joints showing bright bone marrow edema (BME) on the iliac and sacral sides of the SI joints bilaterally, with arrows pointing to areas of active inflammation. (3) Lateral spine radiograph showing progressive changes: vertebral squaring, Romanus lesions (bright corners), syndesmophytes, and a segment of bamboo spine with complete bridging. (4) Sagittal STIR MRI of the spine showing corner inflammatory lesions (bright signal at anterior vertebral corners) and Andersson lesion (discovertebral destruction). Label all findings with annotations.</image>

## Management

### NSAIDs: First-Line Therapy

NSAIDs at full anti-inflammatory doses represent the first-line therapy for symptomatic axial SpA, as recommended by ASAS and EULAR. Effective regimens include naproxen 1000 milligrams daily, celecoxib 200 to 400 milligrams daily, and indomethacin 75 to 150 milligrams daily. Approximately 70 percent of patients achieve significant improvement with NSAIDs. The question of whether continuous NSAIDs slow radiographic progression remains unresolved; the Wanders study from 2005 suggested a possible benefit, but the ENRADAS trial in 2015 did not confirm this finding.

### Biologic Therapy

TNF inhibitors are the first-line biologic therapy for axial SpA failing NSAIDs. Adalimumab, infliximab, etanercept, golimumab, and certolizumab are all approved, achieving ASAS40 response rates of approximately 40 to 50 percent versus 15 to 20 percent for placebo. Infliximab and adalimumab are preferred when concomitant IBD or uveitis is present, as etanercept is less effective for these extra-articular manifestations. The RAPID-axSpA trial confirmed certolizumab efficacy in both radiographic and non-radiographic axial SpA.

IL-17A inhibitors represent an alternative first-line or second-line biologic option. Secukinumab at 150 milligrams monthly after loading was demonstrated effective in the MEASURE trials, achieving ASAS40 rates of approximately 40 percent. Ixekizumab at 80 milligrams every 4 weeks after loading was effective in the COAST trials. These agents are effective for axial disease, peripheral arthritis, enthesitis, and psoriasis but are contraindicated in patients with active IBD, as they may worsen or unmask inflammatory bowel disease. Bimekizumab, targeting both IL-17A and IL-17F, demonstrated efficacy in the BE AGILE trial and is approved for ankylosing spondylitis.

JAK inhibitors, specifically upadacitinib at 15 milligrams daily, demonstrated efficacy in the SELECT-AXIS trials, and the 2022 ACR/ASAS guidelines conditionally recommend JAK inhibitors after TNF inhibitor or IL-17 inhibitor failure.

| Drug Class | Axial Disease | Peripheral Arthritis | Enthesitis | Dactylitis | Uveitis | IBD | Key Consideration |
|-----------|:------------:|:-------------------:|:---------:|:----------:|:-------:|:---:|------------------|
| NSAIDs | **Yes** (first-line) | Yes | Yes | Partial | No | No (may worsen) | ~70% response rate; full anti-inflammatory doses |
| TNF inhibitors (mAbs: adalimumab, infliximab) | **Yes** | Yes | Yes | Yes | **Yes** | **Yes** | Preferred with concurrent uveitis or IBD |
| TNF inhibitors (etanercept) | Yes | Yes | Yes | Yes | **Less effective** | **No** | Avoid if concurrent IBD or recurrent uveitis |
| IL-17A inhibitors (secukinumab, ixekizumab) | **Yes** | Yes | Yes | Yes | Limited | **Contraindicated** (may worsen IBD) | Effective alternative to TNFi; avoid in active IBD |
| JAK inhibitors (upadacitinib) | **Yes** | Yes | Yes | Yes | Under study | Under study | Recommended after TNFi/IL-17i failure |
| Methotrexate | **No** | Modest | No | No | No | No | Not effective for axial disease |
| Sulfasalazine | **No** | Modest | No | No | No | No | Peripheral benefit only |
| IL-23 inhibitors | **No** (failed trials) | N/A (axial) | N/A | N/A | N/A | N/A | Major paradigm challenge |

### Agents NOT Effective in Axial SpA

Several agents that are effective in other rheumatic conditions have proven ineffective for axial spondyloarthritis. Methotrexate provides no benefit for axial disease, though it may help peripheral arthritis. Sulfasalazine similarly fails for axial disease but has a modest effect on peripheral arthritis. Systemic glucocorticoids are not recommended for chronic axial disease. IL-12/23 inhibition with ustekinumab failed in trials for ankylosing spondylitis. Perhaps most surprisingly, IL-23 inhibitors including risankizumab and guselkumab also failed in axial SpA trials, despite the central role of the IL-23/IL-17 axis in disease pathogenesis, representing a major paradigm challenge.

### Non-pharmacologic Management

Exercise is a cornerstone of axial SpA management, with supervised exercise programs demonstrating superiority over home exercise. Physical therapy encompassing stretching, strengthening, postural training, and aquatic therapy should be offered to all patients. Smoking cessation is important, as smoking accelerates radiographic progression and worsens clinical outcomes.

### Surgical Considerations

Total hip arthroplasty provides excellent outcomes for severe hip disease. Spinal osteotomy is reserved for severe fixed kyphosis but is a high-risk procedure requiring specialized centers. The risk of spinal fractures is important to recognize, as chalk-stick fractures through ankylosed spinal segments can occur with relatively minor trauma, warranting a low threshold for CT imaging after trauma in these patients.

## Key Clinical Pearls

- A diagnostic delay of 7-10 years is common; IBP in young patients (<45) should prompt axSpA evaluation
- MRI of SI joints can detect inflammation years before radiographic changes appear
- Etanercept is less effective than monoclonal anti-TNF antibodies for uveitis and IBD in axSpA
- IL-17 inhibitors can worsen or unmask IBD; avoid in patients with active Crohn's disease
- IL-23 inhibitors (guselkumab, risankizumab) have failed in axial SpA despite efficacy in PsA - a major paradigm challenge
- HLA-B27 testing is supportive but not diagnostic; 10% of AS patients are HLA-B27 negative

## References
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2. Ward MM, et al. 2019 Update of the ACR/SAA/SPARTAN Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis Rheumatol. 2019;71(10):1599-1613.
3. Taurog JD, Chhabra A, Colbert RA. Ankylosing spondylitis and axial spondyloarthritis. N Engl J Med. 2016;374(26):2563-2574.
4. Baeten D, et al. Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis (MEASURE). N Engl J Med. 2015;373(26):2534-2548.
5. van der Heijde D, et al. Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis (SELECT-AXIS 1). Lancet. 2019;394(10214):2108-2117.