Seronegative Spondyloarthropathies
Seronegative spondyloarthropathies are a group of chronic inflammatory rheumatologic disorders that are distinctive from rheumatoid arthritis. This group includes ankylosing spondylitis, reactive arthritis, psoriatic arthritis, and enteropathic arthritis.
Seronegative spondyloarthropathies have the following shared features:
- Seronegative = -ve rheumatoid factor and anti-CCP antibodies
- Associated with HLA-B27
- Shared manifestations (the As)
- Axial arthritis
- Asymmetrical arthritis
- Anterior uveitis
- Aortitis → aortic regurgitation
- Attachment inflammation (enthesitis)
- All sausage digits (dactylitis)
However, not every seronegative spondyloarthropathy presents with all of these “A” features. See the disease-specific sections below for further details.
Classification of spondyloarthropathies based on the predominantly involved joints:
| Type | Definition | Classic examples |
|---|---|---|
| Axial spondyloarthritis | Primarily affects the axial skeleton |
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| Peripheral spondylarthritis | Primarily affects the peripheral joints and/or entheses |
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Disclaimer
With the exception of ankylosing spondylitis, which is an axial spondyloarthritis by definition, the other seronegative spondyloarthropathies may affect the axial skeleton and/or peripheral joints.
Therefore, specialist management is often guided by the pattern of axial versus peripheral involvement. However, this is considered beyond a non-specialist level. For simplicity, this article presents management according to the specific condition, rather than the pattern of joint involvement.
Ankylosing Spondylitis
Causes and Risk Factors
The exact underlying cause remains unknown.
Risk factors: [Ref]
- HLA-B27 – most important genetic risk factor
- Males
- Family history
- Young age
- Onset of disease is often <30 y/o
- It is rare for ankylosing spondylitis to be diagnosed >45 y/o
Clinical Features
By definition, ankylosing spondylitis is an axial spondyloarthropathy +/- peripheral spondylarthritis
| Category | Subcategory | Clinical features |
|---|---|---|
| Axial manifestation (defining feature) | Early features | Gradual onset of inflammatory lower back pain and buttock pain (from the sacroiliitis)
Sacroiliitis can be demonstrated by:
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| Advanced features |
Reduced spinal mobility can be demonstrated by:
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| Extra-axial manifestation (variable) | Musculoskeletal |
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| Eye |
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| Cardiovascular |
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| Lungs |
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| GI |
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| Skin |
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Referral Criteria
Refer to rheumatology if a <45 y/o has back pain for >3 months with at least 4 of the following:
- Low back pain started <35 y/o
- Waking during the 2nd half of the night due to symptoms
- Buttock pain
- Improvement with movement
- Improvement within 48 hours of taking NSAIDs
- 1st degree relative with spondyloarthritis
- Current or past arthritis
- Current or past enthesitis
- Current or past psoriasis
If exactly 3 of the additional criteria are present, perform an HLA‑B27 test. Refer to rheumatology if HLA-B27 is +ve
Investigation and Diagnosis
Diagnostic work-up (for suspected ankylosing spondylitis):
| Investigation | Description | Findings in ankylosing spondylitis |
|---|---|---|
| Blood tests |
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| Imaging |
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Do NOT rule out a diagnosis solely on the basis of a -ve HLA-B27 result or normal CRP / ESR
Other investigation findings in ankylosing spondylitis:
| Investigation | Findings in ankylosing spondylitis |
|---|---|
| Spine X-ray [Ref] | Early findings:
Late findings:
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| Chest X-ray | Possible apical pulmonary fibrosis |
| Lung function test | Restrictive pattern possible (↓ FVC with normal FEV1:FVC ratio) |
| Echocardiography | Aortic root dilatation, aortic valve thickening, aortic regurgitation possible |
| DEXA | Osteoporosis is common
However, syndesmophytes can cause a falsely elevated bone mineral density |
Management
Non-Pharmacological Management
Refer all patients to a specialist physiotherapist for an individualised structured exercise programme, which should include:
- Stretching, strengthening, and postural exercises
- Deep breathing
- Spinal extension
- Range of motion exercises
- Aerobic exercises
Consider hydrotherapy as an adjunctive therapy
NICE recommends considering regular osteoporosis assessment every 2 years (with DEXA scan)
Pharmacological Management
| Step 1 | Oral NSAIDs
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| Step 2 (if NSAIDs are ineffective) | TNF-alpha inhibitor, such as:
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| Step 3 (if TNF-alpha inhibitors are inappropriate or ineffective) |
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Surgical Management
Only consider surgery if there is spinal deformity that is:
- Significantly affecting QoL, and
- Severe or progressing despite optimal non-surgical management
Reactive Arthritis
Causes
Reactive arthritis is a sterile joint inflammation triggered by a preceding mucosal infection, most commonly:
- Genitourinary infections (→ sexually acquired reactive arthritis)
- Chlamydia trachomatis – most common
- Neisseria gonorrhoea
- Ureaplasma urealyticum
- Gastrointestinal infections (→ post-enteric reactive arthritis)
- Salmonella
- Shigella
- Campylobacter
- Yersinia
Risk Factors
- History of genitourinary or gastrointestinal infection 1-6 weeks prior to the onset of arthritis
- Young adults (18-40 y/o)
- Males (for sexually acquired reactive arthritis)
- Post-enteric reactive arthritis affects males and females equally
- HLA-B27
Clinical Features
Reactive arthritis is classically considered a peripheral spondyloarthropathy with axial involvement being less common.
| Articular manifestation |
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| Extra-articular manifestation |
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The classic triad of reactive arthritis:
- Conjunctivitis (“can’t see”)
- Urethritis (“can’t pee”)
- Arthritis (“can’t limb a tree)
The term “Reiter syndrome” was historically used to describe the specific triad of symptoms, but it has fallen out of favour as it does not capture the full clinical spectrum and is tied to ethical concerns regarding Hans Reiter.
Referral Criteria (For Peripheral Spondyloarthritides)
Refer patients with dactylitis to rheumatology
Refer the following patients with enthesitis without apparent mechanical cause to rheumatology if:
- Persistent, or
- In multiple joints, or
- ANY of the following are also present
- Back pain without apparent mechanical cause
- Current or past uveitis
- Current or past psoriasis
- Gastrointestinal or genitourinary infection
- IBD (Crohn’s disease or UC)
- 1st degree relative with spondyloarthritis or psoriasis
Investigation and Diagnosis
Reactive arthritis is primarily a clinical diagnosis
Supporting investigations include:
| Investigation | Description |
|---|---|
| Blood tests |
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| Imaging |
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| Synovial fluid analysis | Characterised by sterile inflammation
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| Microbiology testing |
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Do not routinely test for infective antibody status to diagnose reactive arthritis in people with a history of gastrointestinal infection
Management
| Treat any underlying infections | For example, manage the underlying chlamydia with doxycycline (see the Chlamydia article for more information)
While the active underlying genitourinary or gastrointestinal infection should be treated, do NOT offer long-term antibiotics (≥4 weeks) solely to manage the resulting reactive arthritis |
| Management of arthritis | Acute management:
The acute phase is usually self-resolving Long-term DMARD therapy is NOT always needed, only indicated if symptoms become chronic (>6 months) or if the disease is refractory Chronic management (DMARDs):
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| Management of extra-articular manifestation |
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Psoriatic Arthritis
Causes and Risk Factors
The exact cause of psoriatic arthritis is not fully understood.
| Genetic risk factors |
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| Environmental triggers |
Smoking appears to be protective against the development of psoriatic arthritis (NB this contrasts with smoking being the strongest environmental risk factor for RA) |
| Associations and comorbidities |
Psoriatic arthritis is a distinct inflammatory arthritis associated with psoriasis, rather than psoriasis itself.
~15% of patients develop both psoriasis and psoriatic arthritis from the onset, and another ~15% develop psoriatic arthritis, then psoriasis.
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Clinical Features
Psoriatic arthritis is classically a peripheral spondyloarthropathy, but may also have axial involvement.
Psoriatic arthritis is classically classified into 5 clinical subtypes:
| Asymmetric oligoarthritis |
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| Symmetrical polyarthritis |
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| Distal arthritis |
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| Arthritis mutilans | A severe, highly destructive form characterised by osteolysis, leading to:
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| Spondyloarthritis (axial disease) |
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Other hallmark features:
- Nail disease (pitting, onycholysis, splinter haemorrhages)
- Present in 80-90% of patients
- Strongly associated with distal arthritis
- Other MSK features
- Enthesitis (e.g. Achilles tendon, plantar fascia)
- Dactylitis (“sausage digits”) (diffuse swelling of the fingers and toes)
- Uveitis
- Often chronic, bilateral uveitis (posterior uveitis possible)
- Differs from the typical acute, anterior uveitis seen in ankylosing spondylitis
Ocular disease in the form of uveitis differs from that associated with ankylosing spondylosis because it is often chronic, bilateral, and can involve the posterior elements
Referral Criteria (For Peripheral Spondyloarthritides)
Refer patients with dactylitis to rheumatology
Refer the following patients with enthesitis without apparent mechanical cause to rheumatology if:
- Persistent, or
- In multiple joints, or
- ANY of the following are also present
- Back pain without apparent mechanical cause
- Current or past uveitis
- Current or past psoriasis
- Gastrointestinal or genitourinary infection
- IBD (Crohn’s disease or UC)
- 1st degree relative with spondyloarthritis or psoriasis
Investigation and Diagnosis
| Investigation | Findings in psoriatic arthritis |
|---|---|
| X-rays | Changes in peripheral joints:
Axial disease may show bulky, asymmetric, and discontinuous syndesmophytes (on spine X-rays) |
| Ultrasound and MRI | Highly sensitive for detecting early subclinical joint inflammation, enthesitis, and dactylitis before X-ray changes occur |
| Blood tests |
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Management
Note the following management principles apply to the peripheral forms of psoriatic arthritis (i.e. non-axial disease).
Unlike most other spondyloarthropathies, psoriatic arthritis is commonly managed with DMARDs as part of first-line long-term treatment, making its management more similar to RA.
1st line: conventional DMARDs (e.g. methotrexate, sulfasalazine, leflunomide)
- If there is inadequate response to conventional DMARD monotherapy at the maximum tolerated dose for at least 3 months, consider switching or adding another conventional DMARD
- Adjuncts to manage symptoms (in addition to DMARD)
- 1st line: consider NSAIDs
- 2nd line: corticosteroids
If psoriatic arthritis failed to respond adequately to at least 2 conventional DMARDs → escalate to biological DMARDs
- TNF-alpha inhibitors (e.g. adalimumab, etanercept, infliximab)
- IL-17 inhibitors (e.g. secukinumab, ixekizumab)
- IL-23 inhibitors (e.g. guselkumab)
- IL12/23 inhibitors (e.g. ustekinumab)
Exception: if the patient has non-progressive monoarthritis, consider intraarticular corticosteroid injections
Enteropathic Arthritis
Causes and Risk Factors
Enteropathic arthritis is strongly associated with IBD (Crohn’s disease and UC)
Genetic risk factors:
- HLA-B27 is strongly associated with axial involvement
- Other HLAs are associated with peripheral involvement (e.g. HLA-DRB1*0103, HLA-B27, and HLA-B35, HLA-B44)
Clinical Manifestation
Enteropathic arthritis may present as axial and/or peripheral spondyloarthropathy
| Axial enteropathic arthritis |
Axial enteropathic arthritis presents very similarly to ankylosing spondylitis Gradual onset of inflammatory lower back pain and buttock pain (from the sacroiliitis)
Sacroiliitis can be demonstrated by:
Imaging findings:
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| Peripheral enteropathic arthritis | Peripheral enteropathic arthritis is typically non-erosive and non-deforming, with 2 types:
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Referral Criteria (For Peripheral Spondyloarthritides)
Refer patients with dactylitis to rheumatology
Refer the following patients with enthesitis without apparent mechanical cause to rheumatology if:
- Persistent, or
- In multiple joints, or
- ANY of the following are also present
- Back pain without apparent mechanical cause
- Current or past uveitis
- Current or past psoriasis
- Gastrointestinal or genitourinary infection
- IBD (Crohn’s disease or UC)
- 1st degree relative with spondyloarthritis or psoriasis
Management
Management of enteropathic arthritis requires an MDT approach involving both rheumatology and gastroenterology
- Optimise management of underlying IBD (see the Crohn’s Disease and Ulcerative Colitis (UC) article)
- Manage arthritis as below
| Peripheral arthritis | 1st line: conventional DMARDs (e.g. methotrexate, sulfasalazine, leflunomide) +/- NSAIDs as an adjunct |
| Axial arthritis | Management similarly as ankylosing spondylitis:
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