Etiology

There is a strong genetic component in the risk of developing ankylosing spondylitis (AS), with heritability of 97%. Condition severity is also largely genetically determined, with heritability of disease activity, functional impairment, and radiographic disease extent estimated at 51%, 76%, and 62%.[38][39]

HLA-B27 is present in about 90% of patients who have AS.[18] HLA-B27 contribution to the total genetic risk for AS is, however, relatively modest (approximately 20%).[20][21]

The role of HLA-B27 in the pathogenesis of AS remains largely unclear. HLA-B27 is a heterotrimeric complex with beta2 microglobulin and presents peptides from intracellular pathogens for recognition by the T-cell receptor of CD8 T cells. HLA-B27 can also be expressed as cell surface beta2-microglobulin (beta2m)-free homodimers (B27[2]).[40]

In addition to the T-cell receptor, major histocompatibility complex class I molecules bind to natural killer receptors, including members of the killer immunoglobulin-like receptor family. HLA-B27(2) preferentially binds to certain natural killer receptors, and may have a role in the pathogenesis of AS.[41][42]

Genetic studies of AS by the Wellcome Trust Case Control Consortium have identified two other major susceptibility genes for the disease: interleukin-23 receptor and endoplasmic reticulum aminopeptidase 1 (ERAP1), also known as aminopeptidase regulator of tumor necrosis factor (TNF) receptor 1 shedding (ARTS1). The association with ERAP1, which encodes a peptidase potentially influencing the repertoire of peptides available for binding to HLA-B27, has informed a novel area of research in AS.[43][44][45]

The risk conferred by ERAP1 is entirely restricted to HLA-B27-positive individuals. The mechanism of the interaction between ERAP1 and HLA-B27 may hold the key to determining the role of HLA-B27 in the pathogenesis of AS.[46] These latest genetic discoveries, together with HLA-B27, are thought to account for approximately 70% of the overall genetic susceptibility for AS.[43]

Other genes and genetic polymorphisms have been identified and many more are undergoing confirmation.​​​[47][48][49][50][51][52][53][54]​​[55]​​​​​​​​​​​​​​​​​​

Some evidence suggests there is a negative correlation between serum vitamin D levels and the main monitoring indices of disease activity in patients with AS, and that increased levels of red cell distribution width may be associated with AS diagnosis.[56][57]​​

Antibodies directed against an epitope of a Klebsiella pneumoniae-derived protein are present in the majority of patients with AS.[58]​ One meta-analysis of case-control studies found a higher rate of serum IgA and IgG against K pneumoniae in patients with AS, compared with healthy controls.[59]​ Studies have yet to clarify the potential role of K pneumoniae in AS pathogenesis.

Pathophysiology

Overall, knowledge of the pathophysiology of AS is limited due to the difficulty of obtaining tissue from key sites, such as the sacroiliac joints, and the slowly progressive nature of the disease. However, some pivotal studies have helped to shed light on the pathogenesis of the disease.[44][60][61][62][63]

In contrast to rheumatoid arthritis, where inflammation and erosion are the only pathologic processes present, AS involves inflammation, cartilage erosion, and an additional process, which is subsequent repair (ossification). Inflammation in the axial skeleton in patients with AS is initially dominated by mononuclear cell infiltrates and by increased number of osteoclasts.[64][65][66][67] Bone resorption markers have been found to be elevated in patients with AS, particularly those with active disease, and this is a likely cause of the noted trabecular bone loss.[68][69][70] Inflammation commences at the bone cartilage interface, and this is eloquently demonstrated by magnetic resonance imaging (MRI) studies.

Immunohistochemical studies have found T cells and macrophages to be abundant in inflamed sacroiliac joints.[71] In addition, sacroiliac joint biopsies from patients with active disease revealed large amounts of protein and mRNA for TNF-alpha.[72] Subsequent studies based on MRI and tissue biopsy specimens have revealed evidence of ongoing inflammation in the facet joints, which correlates with MRI findings of bone edema.[73] This inflammation has been noted to persist subclinically despite treatment with a TNF-alpha inhibitor.[74][75] It has been hypothesized that inflammation itself may inhibit osteoproliferation, but is also a necessary precursor to new bone formation. This paradoxical situation is important, as it has an impact on choice of treatment in AS and expectations of available agents such as the TNF-alpha inhibitors that powerfully inhibit inflammation but do not appear to affect bone formation.[76][77]

In rheumatoid arthritis and spondyloarthropathy patients (some of whom had AS), the inflamed synovium of peripheral joints exhibits similar characteristics. The expression of the receptor activator of nuclear factor kB (RANK), RANK ligand, and osteoprotegerin (all components of a system central to resorption), leads to osteoclast activation, and the onset of erosions in both diseases.[60][61] It is the additional osteoproliferative process in AS (a healing osteitis) that leads to the ossification of the outer fibers of the annulus fibrosus and gives the typical appearance of a syndesmophyte. This suggests that this pathway may not be the critical one leading to the bone formation noted in AS, supporting the theory that inflammation and new bone formation are uncoupled. Bone studies have identified that, via TNF mediation, upregulation of Wnt (a molecule involved in osteoblast formation and a natural inhibitor of Dkk-1 signaling) is likely to be responsible for this new bone formation.[78] This may have important implications for the treatment of AS.[62]

Classification

Modified New York criteria for ankylosing spondylitis[3]

These clinical criteria require definite evidence of sacroiliitis on plain radiographs. Such x-ray changes represent established damage and take many years to develop. Definite AS if criterion 4 and any one of the other criteria are fulfilled.

  1. Low back pain of at least 3 months' duration that is improved by exercise and not relieved by rest.

  2. Limited lumbar spinal motion in sagittal and frontal planes.

  3. Chest expansion decreased relative to normal values for sex and age.

  4. Bilateral sacroiliitis grade 2 to 4, or unilateral sacroiliitis grade 3 or 4.

European Spondyloarthropathy Study Group criteria (classification of spondyloarthropathy)[4]

Inflammatory spinal pain or synovitis, which is:

  • Asymmetrical or

  • Predominantly in the lower limbs

and ≥1 of the following:

  • Alternate buttock pain

  • Sacroiliitis

  • Enthesitis (inflammation of the tendon or ligament attachments to bone)

  • Positive family history of spondyloarthropathy

  • Psoriasis

  • Inflammatory bowel disease

  • Urethritis or cervicitis or acute diarrhea occurring within 1 month before arthritis.

Amor criteria[5]

Classification of spondyloarthropathy with ≥6 points:

  • Inflammatory back pain (1 point)

  • Unilateral buttock pain (1 point)

  • Alternating buttock pain (2 points)

  • Enthesitis (inflammation of the tendon or ligament attachments to bone) (2 points)

  • Peripheral arthritis (2 points)

  • Dactylitis (2 points)

  • Acute anterior uveitis (2 points)

  • HLA-B27-positive or family history of spondyloarthropathy (2 points)

  • Good response to nonsteroidal anti-inflammatory drugs (NSAIDs) (2 points).

ASAS classification criteria of axial spondyloarthritis[6]

The Assessment of SpondyloArthritis (ASAS) International Society has developed and validated new classification criteria to encompass patients with both nonradiographic axial spondyloarthritis and established AS. The following should be applied to patients under 45 years of age, with back pain of more than 3 months' duration:

Either

  • Sacroiliitis on imaging (active inflammation on magnetic resonance imaging or definite x-ray changes as per modified New York criteria)

  • Plus at least 1 spondyloarthritis feature from:

    • Inflammatory back pain

    • Arthritis

    • Heel enthesitis

    • Uveitis

    • Dactylitis

    • Psoriasis

    • Crohn disease/colitis

    • Good response to NSAIDs

    • Family history of spondyloarthritis

    • HLA-B27

    • Elevated C-reactive protein

or

  • HLA-B27-positive

  • Plus at least 2 spondyloarthritis features.

ASAS consensus definition of early axial spondyloarthritis[7]

In patients with a diagnosis of axial spondylitis (axSpA), early axSpA should be defined as:

  • Duration of symptoms ≤2 years

  • Axial symptoms include cervical/thoracic/back/buttock pain or morning stiffness

  • In the presence or absence of radiographic damage

This definition should be adopted in research studies addressing early axSpA.

Calin criteria (inflammatory back pain)[8]

Four out of 5 must be present:

  • Age <40 years

  • Back pain >3 months

  • Insidious onset

  • Improvement with exercise

  • Early morning stiffness.

Rudwaleit criteria[9]

A positive likelihood ratio of 3.7 for the presence of inflammatory back pain (not diagnosis of AS) is achieved if 2 of 4 criteria are present and increases to 12.4 if 3 of 4 criteria are present:

  • Morning stiffness >30 minutes

  • Improvement in back pain with exercise but not with rest

  • Awakening in the second half of the night because of back pain

  • Alternating buttock pain.

ASAS International Society criteria for inflammatory low back pain[10]

Sensitivity 77.0% and specificity 91.7% if at least 4 out of 5 parameters are present. Note that sensitivity and specificity refer to the presence of inflammatory low back pain, not to the diagnosis of AS:

  • Age at onset <40 years

  • Insidious onset

  • Improvement with exercise

  • No improvement with rest

  • Pain at night (with improvement on getting up).

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