The spondyloarthropathies refer to a diverse group of conditions associated with the HLA-B27 gene.

The spondyloarthropathies (SpAs) refer to a diverse group of conditions associated with the HLA-B27 gene. They are characterised by chronic inflammation affecting the axial skeleton (i.e. spine and sacroiliac joints) and/or peripheral joints. Due to the predominant axial skeletal involvement, they may be collectively termed ‘axial spondyloarthropathies’ (AxSpA).

These conditions include:

The SpAs are characterised by pain, stiffness, and loss of mobility. They can present with numerous musculoskeletal features:

  • Spinal & sacroiliac joint inflammation
  • Peripheral arthritis
  • Dactylitis: inflammation of an entire digit
  • Enthesitis: inflammation at a tendon insertion point
  • Extra-articular manifestations: uveitis, psoriasis, bowel symptoms

As these disorders often follow a similar pattern of symptoms and management, it is helpful to think of the various causes under the umbrella of SpA or AxSpA. The exact underlying subtype can then try to be delineated.


A variety of terms have been used for the SpAs that that can lead to confusion.

The concept of SpA or AxSpA is quite new, having first been proposed in 1974, and is still the subject of much debate. This has resulted in some extremely confusing terminology as new and old ideas mix together.


The prefix 'spondylo-' means vertebral or spinal and 'arthropathy' refers to a disease of the joints (with or without active inflammation). The group of diseases encompassed under the umbrella term SpA are also referred to as the seronegative spondyloarthritides (referring to both the lack of rheumatoid factor positivity and referring to the absence of specific antibodies for each disease). Given not all disease is axial, some clinicians refer to the syndrome just as spondyloarthropathy (SpA) rather than axial spondyloarthropathy (AxSpA).


Each condition may be sub-classified according to the location of the main symptom burden.

  • AxSpA: predominant axial involvement (spine & sacroiliac joints)
  • PSpA: predominant peripheral joint involvement

Axial spondyloarthropathies may be further subclassified according to imaging.

  • R-AxSpA: radiographic features present
  • NR-AxSpA: no radiological evidence on conventional x-ray. Diagnosis based on clinical assessment and/or MRI

Underlying disease process

The overarching umbrella term AxSpA or SpA may be used interchangeably with the underlying disease process (e.g. psoriatic arthritis).


The prevalence of spondyloarthropathy varies widely according to the population.

Among European populations, the estimated prevalence of all-cause AxSpA is around 0.54%. The highest estimated risk is in the Northern Arctic and North American population, at around 1.6% and 1.35% respectively. The male to female ratio is approximately 2:1, although this varies considerably according to the underlying cause.

Aetiology & pathophysiology

The cause of the SpA disease pattern is not yet fully clear, but it is known to have a strong genetic element.

SpAs are currently considered an inflammatory disorder rather than an autoimmune disorder (e.g. not antibody-directed). The development of any one of the diseases under this umbrella term is due to a complex interaction between an individual's genetic make-up, the gut microbiome (i.e. population of bacteria living in the gut), immune response, and mechanical stress at typical anatomical sites (e.g. axial skeleton).

The aetiology of SpA is strongly linked to underlying genetic predisposition. The strongest genetic contribution is linked to HLA-B27, which is one of the major histocompatibility complex (MHC) class I molecules.

Genetic factors

The MHC are a group of genes that encode proteins found on the surface of cells that help the immune system recognise foreign antigens. In humans, these are referred to as ‘human leucocyte antigens' (HLA). They are differentiated into two groups:

  • MHC class I (HLA-A, B, C): expressed on all nucleated cells. Important in the recognition of ‘self-antigens’. Further divided into multiple subtypes.
  • MHC class II (HLA-DR, DQ, DP): expressed on antigen-presenting cells (e.g. T-helper cells, dendritic cells). Important for activation of the adaptive immune response. Further divided into multiple subtypes.

The MHC class I subtypes are partly responsible for regulating the adaptive immune system and present intracellular peptides to receptors on a range of cells, such as CD8+ T cells, natural killer cells, and monocytes. This allows inflammation to occur in tissues without an external stimulus that typically occurs in association with HLA-B27. The allele HLA-B27 is particularly common in Caucasians (5-6% prevalence). Other factors must be important in the development of SpA because only 1-5% of patients with HLA-B27 develop the subtype ankylosing spondylitis.

Other genetic factors have been implicated in SpA including several non-HLA genes (e.g. interleukin 23 receptor variants).

Environmental factors

Environmental factors are also implicated to a modest degree and general advice on exercise and smoking cessation is vital in the overall disease course. Smokers are noted to have much higher rates of pain and disability overall and exercise therapy is a cornerstone of management regardless of disease activity.

Ankylosing spondylitis

Ankylosing spondylitis is a chronic, multi-system inflammatory disorder characterised by inflammation of the sacroiliac joints and axial skeleton.

Ankylosing spondylitis (AS) is often considered the ‘original’ form of AxSpA. It is the first to be described and is by far the most heavily studied subtype of AxSpA. It is a chronic inflammatory disorder characterised by inflammation of the sacroiliac joints and axial skeleton that presents as chronic back pain, morning stiffness, and eventually spinal deformity in long-standing cases.

For more information see ankylosing spondylitis notes.

Psoriatic arthritis

Psoriatic arthritis is a chronic inflammatory musculoskeletal disorder that is associated with psoriasis.

Psoriatic arthritis is a chronic inflammatory musculoskeletal disorder that is seen in up to 20% of patients with psoriasis. It is classically divided into five subtypes:

  • AxSpA: characterised by involvement of the sacroiliac joints and axial skeleton
  • Distal arthritis: characterised by distal interphalangeal (DIP) joint involvement
  • Symmetrical polyarthritis: very similar presentation to rheumatoid arthritis
  • Asymmetrical polyarthritis: asymmetrical distribution of joint involvement (typically < 5 small and/or large joints)
  • Arthritis mutilans: a deforming and destructive arthritis

In reality, there is a lot of overlap between these different forms, and many patients with axial disease may have some element of peripheral joint disease.

Reactive arthritis

Reactive arthritis is a type of spondyloarthropathy that is defined as arthritis occurring after an infection.

Reactive arthritis (ReA) causes sterile inflammation in joints following an infection. This is typically, but not necessarily, bacterial in nature and thus distinguishing the inflammation from septic arthritis is essential.

ReA commonly occurs several weeks following infection by a variety of organisms that usually infect the urogenital or gastrointestinal tract. ReA was historically referred to as ‘Reiter’s syndrome’, which describes a clinical triad of arthritis, urethritis, and conjunctivitis. However, only a small proportion of patients present with this classical triad.

For more information see reactive arthritis notes.

IBD-associated spondyloarthropathy

IBD-associated spondyloarthropathy is an inflammatory arthropathy associated with Crohn’s and ulcerative colitis.

IBD-associated spondyloarthropathy is also known as enteropathic arthritis. Traditionally, this form of SpA was divided into type 1 and type 2 depending on the time course and extent of joint involvement.

  • Type 1: acute and oligoarthritis (i.e. < 5 joints). Usually self-limiting and responds to treatment of underlying IBD
  • Type 2: typically more chronic and polyarticular. Commonly involves MCPs. Usually independent of gut inflammation

However, this terminology is now less common and IBD-associated spondyloarthropathy can be considered by the clinical manifestations that include features of AxSpA (spondylitis and sacroiliitis), peripheral joint involvement (arthritis, enthesitis), or a combination.

The condition should be suspected in any patient with IBD who develops joint pain, stiffness, or inflammatory back pain. HLA-B27 is found in up to 75% of patients with axial involvement.


SpA can be very difficult syndromes to diagnose.

Both the British Society of Rheumatology (BSR) and the European League Against Rheumatism (EULAR) guidelines require a diagnosis from a rheumatologist prior to commencing treatment. The NICE CG 65: Spondyloarthritis in over 16s (2017 update) outlines specific referral criteria for patients with suspected axial or peripheral SpA.

Diagnostic criteria

A variety of diagnostic criteria can be used for the SpAs based on whether the features are predominantly axial or peripheral

  • Axial
    • Assessment of Spondyloarthritis International Society (ASAS)
    • Berlin
    • Rome
    • Modified New York
  • Peripheral
    • Assessment of Spondyloarthritis International Society (peripheral)
    • Classification of Psoriatic Arthritis (CASPAR)

Modified New York Criteria

The most commonly used supportive tool for patients with suspected AxSpA is the 1984 Modified New York Criteria (validated in ankylosing spondylitis but now used in all AxSpAs):

Clinical criteria

  • Low back pain ≥ 3 months, improved by exercise and not relieved by rest
  • Limitation of the lumbar spine in sagittal and frontal planes
  • Limitation of chest expansion (relative to normal values corrected for age and sex)

Radiological criterion

  • Bilateral grade 2-4 sacroiliitis OR unilateral grade 3-4 sacroiliitis


  • Definite ankylosing spondylitis: radiological criterion is present plus at least 1 clinical criterion
  • Probable ankylosing spondylitis: if EITHER radiological criterion OR 3 clinical criteria are present alone

Other tools used include the European Spondyloarthropathy Study Group (ESSG) criteria.


Imaging in SpA is important to assess for the presence of inflammatory joint disease.

Investigations should be guided towards the underlying symptoms. Imaging is critical in the investigation of joint pain, but other tests including bloods (e.g. CRP, ESR), clinical tests (e.g. Schöber test), and special tests (e.g. HLA-B27 testing) help to determine the diagnosis.

Features suggestive of SpA that require investigation include:

  • Enthesitis (back pain, hip pain, pain in heels)
  • Morning stiffness > 30 minutes
  • Joint/back pain improves with exercise
  • Presentation under 40 years
  • Good response to NSAIDs
  • Extra-articular features (uveitis)


An elevated ESR and CRP are supportive of SpA but non-specific. HLA-B27 testing is also useful. While the majority of people who are HLA-B27 positive do not have SpA, the majority of people with AxSpA are HLA-B27 positive (around 50-75%, depending on the underlying cause). This will often be requested in General Practice prior to referral to a rheumatologist.


An x-ray of the pelvis and lumbar spine is a useful start, but beware that changes may occur late in the disease and that women are more likely to have disease not seen on x-ray. Nevertheless, it is a key cornerstone of diagnosis. An MRI may be able to provide more detail.

Important to look for syndesmophytes (calcification of the spinal ligaments/annulus fibrosus, seen in AS and axial involvement in psoriatic arthritis), bilateral sacroiliitis (sclerosis, joint space narrowing, and erosions seen in all forms of AxSpA as well as several other diseases) or fusion of the sacroiliac joints (very late sign).

Peripheral x-rays and/or MRI is important for peripheral joint involvement. Musculoskeletal ultrasound may also be used to look for early inflammatory arthritis.


The aim of management in SpA is to prevent disease progression that can lead to functional impairment and disability.

The management of the spondyloarthropathies depends on the extent of disease, pattern of involvement, and underlying subtype. A general approach can be applied to all conditions that include initial therapy with nonpharmacological treatments and NSAIDs. Patients with ongoing disease can be escalated to second-line agents including conventional disease-modifying anti-rheumatic agents (DMARDs) and biological DMARDs.

The choice of DMARD depends on the severity of symptoms, the pattern of disease (i.e. axial or peripheral), the subtype of SpA, and response to previous therapies.

Nonpharmacological treatment

A range of nonpharmacological management strategies should be employed for patients with SpA.

  • Patient education
  • Smoking cessation
  • Psychological support
  • Physiotherapy: exercise has been shown to improve disease activity in SpA


The use of NSAIDs (e.g. naproxen, ibuprofen, or selective COX-2 inhibitors) should be offered to all patients with symptomatic SpA if there are no major contraindications. They may be prescribed alongside proton pump inhibitors to protect the gastric mucosa. NSAIDs can also be used to treat peripheral arthritis symptoms.

NSAIDs may be the only medication required to treat AxSpA in a significant number of patients with major relief of symptoms. Following a trial of NSAID therapy, symptoms should improve in 2-4 weeks. Some patients need to continue NSAIDs daily whereas others may adopt a more ‘on demand’ administration according to symptoms. It is critical to consider long-term gastrointestinal, renal, and cardiac side-effects when prescribing long-term NSAIDs.


Generally avoided in patients with AxSpA or psoriatic arthritis. May be used in patients with reactive arthritis, particularly during the acute course if symptoms do not improve with NSAIDs.

Conventional DMARDs

Generally reserved for treatment of patients without significant spondylitis who fail to respond to NSAIDs (i.e. peripheral involvement). Conventional DMARDs are relatively ineffective for spondylitis and enthesitis.

  • Methotrexate: dihydrofolate reductase inhibitor, which interferes with DNA synthesis. Must be given with folic acid. Typically once a week dosing (oral or S/C). Teratogenic and contraindicated in liver disease. Major side-effects include myelosuppression, hepatotoxicity (e.g. fibrosis), pulmonary fibrosis, and increased infection risk.
  • Leflunomide: inhibition of pyrimidine synthesis. 10-15% get GI side-effects (diarrhoea and nausea). Teratogenic. Given as daily oral dose. Main side-effects include hepatotoxicity, hypertension, leucopaenia, rash, and alopecia.
  • Sulfasalazine: mechanism poorly characterised. Anti-inflammatory and immunosuppressive effects. Daily oral dose. Theoretical risk of neonatal haemolysis in third trimester. Classical side-effects include GI, decreased sperm count (whilst taking medication), and cutaneous reactions.

Biological DMARDs

TNF-alpha inhibitors are commonly used in patients who fail to respond to NSAIDs with AxSpA. Anti-TNF therapy is very effective against spondylitis and axial involvement. Patients with peripheral joint involvement who fail to respond to conventional DMARDs may be escalated to biologics.

  • TNF-alpha inhibitors: commonly used as first-line biologics. Options include adalimumab, golimumab, infliximab
  • IL-17A inhibitors: may be used as an alternative to anti-TNF therapy if ineffective or contraindicated. Options include secukinumab and ixekizumab
  • Other agents: some agents are licensed for use in certain subtypes (e.g. Janus kinase inhibitors in psoriatic arthritis). Many are only used as part of a clinical trial due to limited data
Author Dr. Benjamin Bennett Ben is an IMT3 in London with a passion for rheumatology.

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