The ‘enthesis’ is the region of insertion of a tendon, ligament, capsule, or fascia into bone. The enthesis is now understood to be a complex structure that extends into the bone and marrow cavity.¹³ Recent work suggests that the entheseal fibrocartilage is the major target of the immune response and the primary site of the immunopathology.¹⁴ The bone marrow demonstrates edema and contains cellular infiltrates. T lymphocytes are abundant in these areas with a preponderance of CD8+ cells.¹⁵ Pathologic studies have demonstrated inflammatory infiltration and destruction which affect the whole anulus fibrosus, not just the enthesis of the intervertebral disc.¹⁶

Synovitis

Patients with spondyloarthropathy may have peripheral arthritis, typically mono- or oligoarticular, and often affecting one or both knees. Microscopic analysis reveals fibrin, synovial cell proliferation, lymphocytes, and plasma cells in the synovium.¹⁷ A more recent hypothesis suggests that bacterial antigens and microorganisms in a susceptible HLA-B27-postitive patient may interact to produce inflammation and arthritis in ankylosing spondylitis.¹⁸ It is well established in reactive arthritis that synovial fluid demonstrates bacteria-specific T-cell responses to the bacterium that causes the arthritis.^19,²⁰

Sacroiliitis

Studies of the sacroiliac joint reveal evidence of synovitis, osteitis, and enthesitis. Biopsy and autopsy specimens demonstrate pannus formation, myxoid marrow, superficial cartilage destruction, intra-articular fibrous strands, new bone formation, and bony ankylosis. Biopsy samples demonstrate cellular infiltrates of T lymphocytes, with both CD4+ and CD8+ cells.^21,²² Contrast-enhanced magnetic resonance imaging (MRI) studies of the sacroiliac joints in inflammatory back pain can demonstrate the following: sacroiliitis is more often bilateral in AS (84%) than in undifferentiated SpA (48%); the dorsocaudal parts of the synovial joint and the bone marrow are the most frequently inflamed structures early in the disease; in contrast, the entheses and ligaments are more commonly involved in later stages.²³

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of sacroiliitis is narrow and is summarized in Table 35.1.⁷

Table 35.1 Spondyloarthropathies

SPONDYLOARTHROPATHIES
	AS Reiter’s syndrome (reactive arthritis) Psoriatic arthritis Inflammatory bowel disease Acne-associated arthritis or SAPHO syndrome Intestinal bypass arthritis
INFECTIOUS
	Pyogenic infections Tuberculosis Brucellosis Whipple’s disease
OTHER
	Hyperparathyroidism Paraplegia Sarcoidosis (rare)

Spinal pain and restriction may also be caused by diffuse idiopathic skeletal hyperostosis (DISH). In contrast to SpA, DISH usually presents with later age of onset, normal sedimentation rate, larger and more flowing ligamentous ossifications (syndesmophytes), and the absence of sacroiliitis.²⁴

DIAGNOSIS

Ankylosing spondylitis

The classification criteria for AS were reassessed in 1984 and are referred to as the ‘modified New York criteria for ankylosing spondylitis.’ The criteria include both clinical and radiographic categories.^25,²⁶ The three clinical criteria include:

• Low back pain and stiffness of longer than 3 months’ duration, improved with exercise but not relieved by rest;

• Limitation of motion of the lumbar spine in both the sagittal and frontal planes; and

• Limitation of chest expansion relative to normal values corrected for age and sex.

The two radiologic criteria include:

• Sacroiliitis with more than minimum abnormality bilaterally; and

• Sacroiliitis of unequivocal abnormality unilaterally.

‘Definite AS’ is present in the presence of one clinical criterion and one radiologic criterion. ‘Probable AS’ is diagnosed if three clinical criteria are present or one radiologic criterion.

Clinical features

Clinical features of AS are heralded by chronic low back pain and stiffness as the initial symptoms in 75% of patients.²⁷ Often, the symptoms develop spontaneously and progress insidiously. Buttock pain that radiates into the thigh may be erroneously blamed on sciatica. This pain may reflect involvement of the sacroiliac joints.^28,²⁹ A history of nocturnal back pain, diurnal variation with prolonged morning stiffness, and improvement with exercise should raise the suspicion of an inflammatory etiology to chronic back pain. A good response to nonsteroidal antiinflammatory drug (NSAID) therapy and an age younger than 40 also increase the likelihood of inflammatory back pain.³⁰ Another, less common presentation of AS may be enthesitis or peripheral arthritis, mono- or oligoarticular.³¹ The enthesitis may involve the Achilles or plantar tendon insertions. The knee is often involved in the arthritis. These findings are not unique to AS. The differential diagnosis may include Reiter’s syndrome or reactive arthritis.

Physical examination

The earliest physical examination finding is often tenderness in the region of the sacroiliac joints or pain on provocative test maneuvers such as hip hyperextension and sacral compression tests. The two most sensitive maneuvers are pressure over the anterior-superior iliac spines and pressure over the lower half of the sacrum.³² As the disease progresses, physical examination findings will reflect restricted ranges of motion. As an example, reduced chest expansion is measured from maximal exhalation to maximal inhalation at the level of the fourth intercostal space. An expansion of less than 2.5 cm is considered abnormal.²⁷ The restricted motion reflects fusion of the costovertebral joints.

Schober’s test and finger-to-floor test will also become abnormal. The Schober’s test is performed by marking the fifth lumbar vertebra and a point in the midline 10 cm above. The patient is then asked to flex forward maximally while maintaining the knees straight. The distance between the two points exceeds 15 cm in normal individuals.¹

Laboratory studies

Laboratory studies in AS are often non-specific. Acute-phase reactants such as erythrocyte sedimentation rate and C-reactive protein are often elevated, but are not specific for AS and do not necessarily reflect disease activity.^33,³⁴ A mild normochromic normocytic anemia may be present. Serologic tests for lupus and rheumatoid arthritis should be negative.

HLA-B27 is present in approximately 90% of Caucasian patients and 50–60% of African-American patients with AS.³ It is present in only 6% of the general population.

Undifferentiated spondyloarthropathy, Reiter’s syndrome, and reactive arthritis

The spondyloarthropathy family of diseases share common features. As a spine specialist, it is most important to diagnose the presence of a spondyloarthropathy, rather than the specific type.

The classification criteria for SpA is based on clinical features, as there are no specific confirmatory blood tests. There are two sets of clinical criteria that have been developed and validated in Europe and are used widely. These are the European Spondyloarthropathy Study Group (ESSG) and the multiple-entry criteria by Bernard Amor.¹

The European Spondyloarthropathy Study Group criteria

To consider the diagnosis of spondyloarthropathy according to the ESSG criteria, a patient must demonstrate one of two entry criteria:

• Inflammatory spinal pain; or

• Synovitis, either asymmetric or predominantly in the lower limbs.

Indications for the designation of spinal pain as ‘inflammatory’ are:

• Onset before 40 years of age;

• Insidious onset;

• Duration longer than 3 months;

• Morning stiffness; and

• Improvement with exercise.

Indications for the designation of synovitis are:

• Soft tissue swelling;

• Warmth over a joint;

• Joint effusion;

• Decreased active and passive range of motion; and

• Symptoms are worse after rest.

There are other features which can be considered if a patient has one or two of the entry criteria. These include:

• Positive family history;

• Psoriasis;

• Inflammatory bowel disease;

• Urethritis, cervicitis, acute diarrhea;

• Alternating buttock pain;

• Enthesopathy; and

• Sacroiliitis.

The ESSG criteria have been evaluated in many studies, including those in Europe, Brazil, and Alaska.³⁵^–³⁸

The Amor criteria

The Amor criteria are a series of items which are weighted with a point scoring system.^1,^39,⁴⁰

In order to qualify for a diagnosis of spondyloarthropathy, a patient must score a total of at least six from among the list of features detailed in Table 35.2.

Table 35.2 Clinical features scored in the Amor classification

	Feature	Score
CLINICAL
	Night pain or morning stiffness of the thoracic or lumbar spine	1
	Asymmetrical oligoarthritis	2
	Buttock pain (uni- or bilateral)	1 or 2
	Sausage-like toe or digit	2
	Heel pain	2
	Iritis	2
	Nongonococcal urethritis or cervicitis within 1 month prior to arthritis	1
	Acute diarrhea within 1 month prior to arthritis	1
	Presence or h/o psoriasis, balanitis, inflammatory bowel disease	2
RADIOLOGIC
	Sacroiliitis (grade >2 if bilateral; grade >3 if unilateral)	2 or 3
GENETIC
	HLA-B27 present and/or family h/o spondyloarthropathy	2
RESPONSE TO TREATMENT
	Clear-cut response to NSAIDs	2

Specific diagnoses

The Amor and ESSG criteria are for the diagnosis of spondyloarthropathy in general. The criteria for the subtypes of spondyloarthropathy are less well defined.

Reactive arthritis

Inflammatory arthritides developing after a distant infection are labeled reactive.⁴¹ Inciting organisms may be: Chlamydia, Yersinia, Salmonella, Shigella, Campylobacter, Clostridium difficile, Brucella, and Giardia.⁴² The infection should have occurred within 6 weeks of clinical presentation of the arthritis. The presence of HLA-B27 renders the host susceptible; however, there is an interplay between HLA-B27 and environmental/infectious triggers in the development of reactive arthritis.⁴³

Reiter’s syndrome

Reiter’s syndrome represents one example of reactive arthritis. The classic triad of uveitis, urethritis, and arthritis defines Reiter’s syndrome. The pathogenesis is similar to reactive arthritis since both are triggered by an infectious agent and are more common in those patients with the HLA-B27 gene.⁴⁴

Not all patients present with all three features of the triad. The American College of Rheumatology requires peripheral arthritis (longer than 1 month’s duration) in association with urethritis or cervicitis.⁴⁵

Undifferentiated spondyloarthropathy

Among patients who meet ESSG or Amor criteria for spondyloarthropathy, there is a large group that does not fit into the above discrete categories. These patients are labeled as undifferentiated spondyloarthropathy.¹ In a recent study from Spain,⁴⁶ 68 patients with the diagnosis of undifferentiated spondyloarthropathy (uSpA) were followed for 2 years. At the end of this period, 75% retained the diagnosis of uSpA; disease remission occurred in 13%; ankylosing spondylitis 10%; and psoriatic arthritis 2%. In addition, a subset of patients with uSpA may be found to have reactive arthritis.⁴⁷