TNF-alpha inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis

Ankylosing spondylitis and non‑radiographic axial spondyloarthritis are part of a group of clinically heterogeneous inflammatory rheumatologic diseases known as spondyloarthritis. Spondyloarthritis can be categorised as having either predominantly axial (sacroiliac joints or spine) or peripheral involvement. In people with axial spondyloarthritis, the predominant symptom is back pain with inflammation of the sacroiliac joints (sacroiliitis) or the spine, or both. The onset of symptoms typically occurs in the third decade of life. Damage is progressive and irreversible and there is increased risk of spinal fracture later in life. There may also be peripheral joint involvement or extra‑articular manifestations such as uveitis, inflammatory bowel disease and psoriasis.

Disease is classified as ankylosing spondylitis if changes to the sacroiliac joints or the spine, or both, can be seen on X‑ray. These include erosions, sclerosis (thickening of the bone), and partial or total ankylosis (fusion of joints). The prevalence of ankylosing spondylitis is thought to range from 0.05% to 0.23% and it is about 3 times more common in men than in women.

Not everyone with symptoms of axial spondyloarthritis will have changes that can be seen on X‑ray. Disease is then classified as axial spondyloarthritis without radiographic evidence of ankylosing spondylitis (non‑radiographic axial spondyloarthritis). Sacroiliitis or inflammation of the spine may be visible on MRI. Limited epidemiological data are available for non‑radiographic axial spondyloarthritis, but it affects about equal numbers of men and women.

Conventional therapy for ankylosing spondylitis and non‑radiographic axial spondyloarthritis includes non‑steroidal anti‑inflammatory drugs and physiotherapy. Tumour necrosis factor (TNF) ‑alpha inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab and infliximab) are typically used when the disease has not responded adequately to conventional therapy.

In clinical trials of ankylosing spondylitis and non‑radiographic axial spondyloarthritis, 3 key disease components are assessed: disease activity, physical function and structural damage. Several assessment tools have been developed to measure these:

• Disease activity is most commonly assessed using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). BASDAI is a validated, composite index that records patients' responses to 6 questions relating to 5 major symptoms: fatigue, axial pain, peripheral pain, stiffness and enthesitis. Responses are recorded on 10 cm visual analogue scales (VAS). An instrument commonly used to assess spinal mobility is the Bath Ankylosing Spondylitis Metrology Index (BASMI). This uses clinical measurements such as the amount of movement achieved when the patient rotates their head (cervical rotation) or reaches towards the floor (lumbar side flexion).

• Physical function is often assessed using the Bath Ankylosing Spondylitis Functional Index (BASFI). BASFI is a patient‑assessed, validated, composite index made up of 10 questions that address function and the patient's ability to manage their disease. As with BASDAI, responses are recorded on a 10 cm VAS.

• Structural damage and disease progression in ankylosing spondylitis are usually evaluated by radiography, using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS).

Studies of the natural history of ankylosing spondylitis and non‑radiographic axial spondyloarthritis show that disease activity (measured by BASDAI) is fairly stable over time and does not change. Physical function (assessed by BASFI) does deteriorate ('progress') over time, but the rate of progression is not constant or predictable. Changes in BASFI scores over time may be partially driven by progression of spinal damage as assessed by mSASSS.

The Assessment of Spondyloarthritis International Society (ASAS) has developed a set of response criteria that are commonly used in ankylosing spondylitis clinical trials. The ASAS criteria relate to improvement across a set of 4 domains:

• patient global assessment (measured on a 10 cm VAS)

• physical function (measured using BASFI)

• inflammation (using the mean of 2 questions from BASDAI relating to severity and duration of morning stiffness)

• spinal pain (measured on a 10 cm VAS).
  
  An ASAS 20 response (a common primary efficacy outcome in clinical trials) is defined as an improvement of more than 20% and an absolute change of 1 or more points on the 0 to 10 cm VAS in at least 3 of the 4 domains. In the fourth domain, there must be no worsening by a similar amount. Other definitions of ASAS response (ASAS 40, 50 and 70, based on improvements of 40%, 50% and 70% respectively) and an improvement of 50% or more in BASDAI score (BASDAI 50) are also used to measure outcomes in clinical studies.