Ankylosing Spondylitis, Other Spondyloarthritides, and Related Conditions

Ankylosing spondylitis is an uncommon inflammatory disease affecting joints between the vertebrae of the spine and the sacroiliac joints (the joints between the spine and the pelvis). Ankylosing spondylitis may also affect other large joints, such as those in the hips.

Causes and incidence 

The cause of ankylosing spondylitis is usually unknown, but in some cases the disease may be associated with colitis (inflammation of the colon) or psoriasis (a skin disease). Ankylosing spondylitis may run in families; and about 90 per cent of people with the condition have the genetically determined histocompatibility antigen (HLA-B27).

Symptoms 

Ankylosing spondylitis usually starts with pain and stiffness in the hips and lower back that are worse after resting and are especially noticeable in the early morning. Other, less common, symptoms include chest pain, painful heels due to additional bone formation, and redness and pain in the eyes due to iritis (inflammation of the iris). In time, inflammation in the spine can lead to ankylosis (permanent stiffness and limited movement) and kyphosis (curvature of the spine).

Diagnosis and treatment 

Ankylosing spondylitis can be diagnosed by X-rays and blood tests. There is no cure, but treatment with a programme of exercise and physiotherapy and antiinflammatory drugs can reduce the pain and limitation of movement. In some cases, DMARDs (see disease-modifying antirheumatic drugs) are also prescribed. To prevent curvature of the spine, patients are taught breathing exercises and exercises to improve posture.

Ankylosing spondylitis, other spondyloarthritides, and related conditions in detail - technical

Essentials

The spondyloarthritides are a group of inflammatory rheumatic diseases with predominant involvement of axial and peripheral joints and entheses, together with other characteristic clinical features, including inflammatory back pain, sacroiliitis, peripheral arthritis (mainly in the legs), enthesitis, dactylitis, preceding infection of the urogenital/gastrointestinal tract, psoriatic skin lesions, Crohn-like gut lesions, anterior uveitis, and a family history of Spondyloarthritis. They are the second most frequent inflammatory rheumatic diseases after rheumatoid arthritis.

Five subsets can be distinguished on clinical grounds: (1) ankylosing spondylitis; (2) reactive (spondylo)arthritis/Reiter’s syndrome (see: reactive arthritis); (3) psoriatic (spondylo)arthritis; (4) (spondylo)arthritis associated with inflammatory bowel diseases; and (5) undifferentiated spondyloarthritis. Prevalence in any population correlates roughly with that of HLA B27, but the relevance of this to pathogenesis is not known. Another more recent approach is to differentiate the SpA on the basis of the predominant clinical manifestation: predominant axial and/or peripheral SpA.

Ankylosing spondylitis

Diagnosis requires one of three clinical criteria—(1) inflammatory back pain; (2) limitation of spinal movement in three planes; or (3) deterioration of chest expansion—and radiological sacroiliac joint changes (bilateral grade 2 or unilateral grade 3/4). Sacroiliac radiographs may be normal in early disease when dynamic MRI of the sacroiliac joints can be helpful in providing objective evidence of sacroiliitis in clinically suspicious cases.

Age of onset is commonly in the twenties, with male:female ratio of 2:1. Early in the course of disease there may be no limitation of spinal movement or chest expansion, but as it progresses there is restriction of lateral flexion, forward flexion, and extension.

Treatment options include acute anti-inflammatory therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) and local corticosteroids, disease-modifying drugs (DMARDs: sulfasalazine and methotrexate) and biologicals (anti-tumour necrosis factor), together with physiotherapy. There is no cure.

Psoriatic arthritis

Psoriasis precedes joint disease in most cases, but there is poor correlation between onset, severity and activity of psoriatic skin lesions and arthritis. More than 80% of patients with psoriatic arthritis have nail dystrophy.

The most characteristic features are dactylitis and osteoproliferative changes in radiographs of peripheral joints. The CASPAR criteria, which are both sensitive and specific, require established inflammatory articular disease with at least three points from the following features: (1) current psoriasis (score 2); (2) a history of psoriasis (unless current psoriasis); (3) a family history of psoriasis (unless current psoriasis or history of psoriasis); (4) dactylitis; (5) juxta-articular new bone formation; (6) rheumatoid factor negativity; and (7) nail dystrophy.

Many patients improve with the use of NSAIDs and intra-articular steroids, especially in the case of large joint involvement or flexor tenosynovitis. Those who do not improve need to be treated with DMARDs (sulfasalazine, methotrexate).

Arthritis associated with inflammatory bowel disease

Similar to the other spondyloarthritides, the arthritis is mostly asymmetric and predominantly affects the legs. Flaring of gut symptoms is often associated with arthritis. Treatment with NSAIDs may be effective for arthritis and spondylitis but can exacerbate bowel disease: there are few data on the use of DMARDs.

Undifferentiated spondyloarthritis

Diagnosis requires inflammatory back pain and/or peripheral arthritis of the legs (usually asymmetrical) and at least one other of the following characteristic features in addition: (1) enthesitis; (2) a positive family history for spondyloarthritis; (3) psoriasis; or (4) inflammatory bowel disease. Dactylitis, anterior uveitis, and HLA B27 may also be used for making a diagnosis of undifferentiated spondyloarthritis. Nonspecific therapy is as for other arthritides. Sulfasalazine may be useful for peripheral and axial symptoms, but very few therapeutic trials with DMARDs have been performed.

SAPHO syndrome

There are no evaluated diagnostic criteria for SAPHO syndrome (synovitis, acne, pustulosis palmaris et plantaris, hyperostosis, and osteitis): most convincing clinically is the combination of a classical skin symptom—such as pustolosis or significant acne—with a characteristic joint or bone lesion—such as arthritis of the sternoclavicular joint, osteitis, or hyperostosis in the anterior chest wall. Analgesics, NSAIDs, and intra-articular steroids are usually effective.

Introduction and definitions

The spondyloarthritides are a heterogenous group of inflammatory rheumatic diseases with predominant involvement of axial and peripheral joints and entheses. In addition to these, the spondyloarthritides share other characteristic clinical features, e.g. anterior uveitis, psoriasis and colitis with Crohn-like gut lesions. Clinical symptoms in subsets of spondyloarthritides can overlap, e.g. psoriatic skin lesions in reactive arthritis, especially the subform Reiter’s syndrome, and patients can move from one subset to another, for example from undifferentiated spondyloarthritis to ankylosing spondylitis.

The various names that have been and are still used for the spondyloarthritides include seronegative spondarthropathies, spondarthritis, spondylarthropathy, and Spondyloarthritis. Importantly, the term spondyloarthritis means a category of interrelated rheumatic disease, it does not only mean axial involvement, as the asymmetric pattern of involvement of mainly the legs by oligoarthritis and enthesitis is also typical. The prefix seronegative, referring to the general absence of rheumatoid factors in the spondyloarthritides, is historical and redundant. The term spondyloarthritis is now generally preferred.

The spondyloarthritides are not ‘modern’ diseases, with ankylosing spondylitis first having been described in 1649 (Table 1).

Epidemiology

The mean age at onset is 20 to 30 years, with just a slight preponderance of men in most subsets of spondyloarthritis. Next to rheumatoid arthritis, the spondyloarthritides are the most frequent inflammatory rheumatic diseases (Table 2), with ankylosing spondylitis, psoriatic spondyloarthritis, and undifferentiated spondyloarthritis being the most common subsets. The overall prevalence of spondyloarthritides in patients presenting with back pain to general practitioners’ surgeries in the United Kingdom has been estimated at 5%.

Table 1 First historical descriptions of spondyloarthritis
Spondyloarthritis Moll/Wright 1974, ESSG 1991
Ankylosing spondylitis Connors 1649, Brodie 1888
Reactive arthritis/Reiter’s syndrome Reiter 1916, Ahonen 1973
Psoriatic arthritis Wright 1959
Arthritis associated with inflammatory bowel diseases Bargen 1930
Enthesitis Niepel 1961
HLA B27 association Brewerton, Schlosstein 1973
Undifferentiated Spondyloarthritis Khan/van der Linden 1990

ESSG, European Spondylarthropathy Study Group.

The spondyloarthritides are associated with the major histocompatability complex class I antigen HLA B27, and the prevalence of spondyloarthritides in any population correlates roughly with that of HLA B27. The magnitude of association differs between the subsets (Table 3): it has been mainly shown for ankylosing spondylitis, but in Inuit populations Reiter’s syndrome is more frequent.

Pathogenesis

The overall influence of genes in the pathogenesis of ankylosing spondylitis has been estimated to be 80 to 90%, leaving only 10 to 20% to other causative factors, such as environmental influences. HLA B27 is responsible for about one-third of the total genetic load: 32 subtypes are now recognized by polymerase chain reaction technology, three of which are not associated with ankylosing spondylitis, or are associated less strongly. There is weaker association of ankylosing spondylitis with HLA B60 and HLA DR1, the interleukin 1 (IL1) gene cluster, and possibly also tumour necrosis factor α (TNFα) polymorphisms. Recently, ERAP-1, IL-23R and IL-1 polymorphism have also been genetically associated with ankylosing spondylitis.

The relevance of HLA B27 to disease pathogenesis is not known: several models have been proposed to explain tissue tropism, the aberrant immune response to certain bacteria, and the HLA B27 association of the spondyloarthritides (Table 4).

The classical arthritogenic peptide model is backed by the demonstration of HLA B27-restricted CD8+ T-cell clones in the synovial fluid of patients with reactive arthritis. Immunodominant peptide motifs and peptides have been described, but their pathogenetic relevance is not yet clear. Lipopolysaccharide and RNA of bacteria associated with reactive arthritis and a CD4+ T-cell response directed against bacterial antigens have been detected in reactive arthritis, but it is not clear whether this immune response is beneficial or arthritogenic. At the humoral and the cellular level, molecular mimicry (partial sequence homologies at the protein and DNA level) between bacterial antigens and self structures has been described, mainly of the HLA B27 molecule. It also seems possible that patients with HLA B27+ spondyloarthritis have deficient immune reactivity, e.g. diminished ability to secrete TNFα, or a synovial Th2 response (secretion of too little interferon-γ, too much IL-4, IL-10), making elimination of bacteria difficult. Presentation of HLA B27-derived peptides themselves by HLA class II molecules, or even by HLA class I molecules, has been proposed as an explanation of the association of HLA B27 with disease.

Table 2 Prevalence of spondyloarthritis
Disease Prevalence
Spondyloarthritis 0.6–2.0%
Ankylosing spondylitis 0.2–1.4%
Undifferentiated Spondyloarthritis 0.2–0.7%
Reactive arthritis 0.01%
Psoriasis 1.0–3.0%
Psoriatic arthritis 0.3%
Arthritis associated with inflammatory bowel disease 0.001%

 

Table 19.6.3 HLA B27 association of the spondyloarthritis. Note that the prevalence of spondyloarthritis (mainly of the first four listed above) relates to the prevalence of HLA B27 in different populations, which is as shown in the second table
Spondyloarthritis HLA B27 prevalence
Ankylosing spondylitis 85–95%
Reactive arthritis 30–80%
Reiter’s syndrome 60–90%
Psoriatic arthritis:
Peripheral arthritis 10–30%
Axial involvement 40–60%
Arthritis associated with inflammatory bowel diseases
Peripheral arthritis 10–30%
Axial involvement 40–60%
Undifferentiated Spondyloarthritis 50–70%
Population HLA B27 prevalence
Native Americans 6–50%
Inuit 15–25%
North Europeans 10–25%
Middle Europeans 6–9%
North Americans 6–8%
South Europeans 4–6%
Africans 1–5%

The ‘HLA-B27 misfolding hypothesis’ suggests that HLA B27 has a tendency to misfold in the endoplasmic reticulum, it being a particular feature of HLA B27 that newly synthesized HLA B*2705 molecules fold and associate with β2-microglobulin (β(2)m) more slowly than other MHC class I molecules. As a consequence of this misfolding, free HLA B27 heavy chains (HC) can form abnormal HC homodimers, which, as β(2)m-free HLA B27 homodimers and multimers, are expressed at the cell surface of leucocytes, dendritic, and other cells with the possible function of antigen presentation.

 

Table 19.6.4 Spondyloarthritis—pathogenetic models
Model Mechanism
Arthritogenic peptide model Bacterial protein processed/ presented by B27 to CD8+ T cells
Deficient immune response Failure of B27+ cells to properly present and eliminate bacteria
Molecular mimicry Similarity of bacterial and self structures, possibly resulting in autoimmunity
Autoimmunity Self structures such as B27-derived peptides presented by class I or II molecules

 

The characteristic clinical features of the spondyloarthritides are listed in Table 5.

Diagnosis

Five subsets of spondyloarthritis can be distinguished on clinical grounds: ankylosing spondylitis; reactive (spondylo)arthritis/Reiter’s syndrome; psoriatic (spondylo)arthritis; (spondylo)arthritis associated with inflammatory bowel diseases; and undifferentiated spondyloarthritis (Bullet list 1).

Diagnostic criteria for spondyloarthritides are shown in Table 6. Inflammatory back pain is one of the main clinical criteria used to make a diagnosis. To classify a patient younger than 45 with chronic back pain (defined as being present for more than 3 months) requires two of the following four criteria to be present: morning stiffness; relief by exercise but not by rest; waking up in the second half of the night because of pain; and alternating buttock pain. Other features of possible relevance include the initially deep localization, a good response to nonsteroidal anti-inflammatory drugs (NSAIDs), other clinical signs of spondyloarthritis (enthesitis, arthritis, anterior uveitis, family history), elevated acute phase reactants (C-reactive protein, ESR), and the presence of HLA B27. To make a diagnosis of ankylosing spondylitis, HLA B27 contributes most, whereas elevated acute phase reactants contribute relatively little. Note, however, that HLA B27 alone can never make a diagnosis, but it does increase the probability of an underlying spondyloarthritis by about tenfold. Likelihood ratios have also been calculated for the other items. In combination with the leading symptom of chronic or inflammatory back pain, HLA B27 is of value to screen for patients with spondyloarthritis in a primary care setting.

Differential diagnosis

The most important, because most frequent, differential diagnosis is nonspecific low back pain, especially if it exceeds 3 months duration in a patient younger than 45 years. The leading clinical symptom of inflammatory back pain may be associated with pain radiating from the lower back to the thighs. Hence an important initial differential diagnosis is sciatica, but this usually has an acute onset.In inflammatory back pain, radiation is more often bilateral than unilateral, rarely extends below the knees, almost never into the foot, and is not associated with paraesthesia, although cough impulse pain may be present. Diagnostic procedures for the detection of disc herniation by MRI or CT can be misleading, as disc prolapses are found in as many as 30% of normal individuals.

Table 19.6.5 Characteristic clinical features of spondyloarthritis
Clinical feature Details
Inflammatory back pain  
Sacroiliitis  
Peripheral arthritis Affects predominantly but not exclusively the lower limbs; it is often asymmetric but may also involve both knees or ankles
Enthesitis Inflammation at the insertion sites of tendons and ligaments to bone (Figs. 19.6.1 and 19.6.2).
Dactylitis Inflammatory involvement of a whole finger or toe (Fig. 19.6.3) with tendovaginitis and arthritis (sausage digit).
Preceding infection in the urogenital/enteral tract  
Psoriatic skin lesions  
Crohn-like gut lesions  
Anterior uveitis  
Family history of Spondyloarthritis  

Bullet list 1 ASAS Classification Criteria for axial SpA

  • In patients with ≥3 months back pain and age at onset <45 years
  • Sacroiliitis on imaging plus ≥1 SpA feature, or HLA-B27 plus ≥2 other SpA features
  • SpA features
  • IBP
  • arthritis
  • enthesitis heel
  • uveitis
  • dactylitis
  • psoriasis
  • Crohn’s/colitis
  • good response to NSAIDs
  • family history for SpA
  • HLA-B27
  • elevated CRP

Diffuse idiopathic skeletal hyperostosis (DISH) or Forestier’s disease, an often-severe radiographic spondylosis, can be difficult to distinguish from longstanding ankylosing spondylitis. The appearance and localization of the spondylophytes helps to differentiate DISH from syndesmophytes and ankylosing spondylitis. Scoliosis is not usually a marked feature of ankylosing spondylitis.

Table 19.6.6 Diagnostic criteria for spondyloarthritis (1991 European Spondylarthropathy Study Group criteria)
Major criteria
Inflammatory back pain
Oligoarthritis (asymmetric) of the lower limbs
Minor criteria
Enthesitis
Alternating buttock pain
Preceding symptomatic infection
Psoriasis
Crohn-like gut lesions
Family history
Radiographic sacroiliitis

To make the diagnosis requires the presence of one major and one minor criterion. Note that dactylitis, uveitis and HLA B27 are not included in these criteria. The peripheral arthritis does not have to be asymmetric, although it often is; both knees or ankles might well be involved. Inflammatory back pain is mostly due to sacroiliitis but can also be caused by enthesitis.

 

Table 19.6.7 Differential diagnosis of sacroiliitis
Spondyloarthritis
Reactive arthritis
Psoriatic arthritis
Arthritis associated with inflammatory bowel disease
Undifferentiated Spondyloarthritis
SAPHO syndrome
Other rheumatic diseases
Rheumatoid arthritis
Systemic lupus erythematosus
Sjögren’s syndrome
Gout
Osteoarthritis
Paget’s disease
Hyper/hypoparathyroidism
Non-rheumatic diseases
Septic sacroiliitis
Acute (staphylococci, steptococci, others)
Chronic (tuberculosis, brucellosis)
Malignancies (lymphoma, metastasis)

Sacroiliitis occurs in a number of other rheumatic and infectious diseases, as shown in Table 19.6.7. The differential diagnosis of peripheral arthritis of the legs includes Lyme disease, sarcoidosis (Löfgren’s syndrome), gout, and undifferentiated oligoarthritis. The differential diagnosis of enthesitis includes epicondylitis and fibromyalgia, and that of dactylitis is erysipela and infection.

Prognosis

There are no good studies, but the following seem to be poor prognostic factors: hip arthritis, limitation of lumbar spine movements, dactylitis, oligoarthritis, young age at onset (<16 years), poor efficacy of NSAIDs, an ESR of more than 30 mm in the first hour, and already the presence of syndesmophytes.

Ankyolosing spondylitis

Ankylosing spondylitis is a chronic inflammatory rheumatic disease that mainly affects the axial skeleton, starting in the sacroiliac joints and often progressing to the spine, but peripheral joints, enthesial structures, the anterior uvea, and the aorta can also become affected.

The diagnosis is made on the basis of significant radiological changes in the sacroiliac joints and the spine, the typical clinical history of inflammatory back pain and stiffness, and evidence of limited spinal movement and/or chest expansion on physical examination.

Epidemiology

The age of onset is commonly in the twenties, but ankylosing spondylitis can begin in childhood, or considerably later (at age >50). The men:female ratio is about 2:1. About 90% of white patients with ankylosing spondylitis are positive for HLA B27, the risk of developing this condition being increased tenfold in HLA B27-positive individuals. If a first-degree relative or dizygotic twin is affected, the risk is 25 to 30%, rising to 50 to 60% in monozygotic twins. Reactive arthritis, psoriasis, and inflammatory bowel disease are additional, partly independent, risk factors.

Immunopathology and pathogenesis

The leading features of ankylosing spondylitis are spinal inflammation and ankylosis, but their cause is unknown. The association of ankylosing spondylitis with bacterial infections is a lot less clear than in reactive arthritis. Antibodies to Klebsiella pneumoniae are more frequently detected in patients with ankylosing spondylitis than in healthy controls, but similarly often in patients with Crohn’s disease and first-degree relatives of those with ankylosing spondylitis. This finding is probably explained by increased gut permeability, and its predominant clinical association is with peripheral (not axial) arthritis.

The sacroiliac joint is the structure most frequently involved in the initial phase of disease. If biopsy is performed, T cells and macrophages are seen to be the predominant infiltrating cells, with CD4+ and CD8+ T cells both present. The reason for this tropism is unclear. The fact that sacroiliac and spinal joints are affected in diseases caused by mycobacteria and other microbes may argue for a pathogen-triggered pathogenesis in ankylosing spondylitis, but bacteria associated with reactive arthritis have not been detected in the sacroiliac joints.

Clinical features

The most common initial symptom is inflammatory back pain, commonly in the lower back and the buttocks. Early in the course of disease there may be no limitation of spinal movement or chest expansion. As it progresses, there is restriction of lateral flexion, forward flexion, and extension. There is often a flattening of the lumbar lordosis, or an inability to reverse this on forward flexion. With more advanced disease a thoracic kyphosis develops, with concomitant restriction of thoracic rotation and chest expansion due to inflammation and ankylosis of the costovertebral and costotransverse joints. In severe cases movements of the cervical spine are also restricted in all planes, with dramatic limitation of lateral flexion. The combination of cervical stiffness and severe thoracic kyphosis can lead to difficulties with forward vision. An example of a young patient with severe progressive disease is shown in Fig. 19.6.4. Severe spinal disease is more frequent in men than in women. There is no evidence that pregnancy has a significant impact on the course of the disease.

Peripheral joint involvement occurs in 30 to 50% of cases at some time, with about 20 to 30% of patients having acute peripheral arthritis of the legs, often with joint effusions as the first symptom, this being especially marked in children. This situation is difficult to differentiate from reactive arthritis. Joint involvement is usually oligoarticular and often asymmetrical. The joints most often involved are the knees, ankles, hips, shoulders, wrists, temporomandibular joints, sternoclavicular joints, manubriosternal joints, costovertebral joints, zygapophyseal joints, and symphysis pubis. Small joints are rarely affected.

Enthesitis occurs at the heel at the insertion of the Achilles tendon and the plantar fascia, and at the iliac crests, the ischial tuberosities, the greater trochanters, and other sites. The diagnosis is often difficult if no swelling is apparent, in which case ultrasound can be revealing. Dactylitis of fingers and toes is uncommon in ankylosing spondylitis, being seen most often in psoriatic arthritis.

Physical examination of the spine and thoracic cage

The physical examination is important in the evaluation of patients with ankylosing spondylitis—in particular to quantitate flexibility of the spine and thoracic cage. The following measurements are useful, but it should be stressed that the values expected of normal individuals are dependent on age and physical training.

  • Anterior and lateral spinal mobility (Schober test):
    • • Ventral—with the patient standing upright, a horizontal line is drawn across the lumbar spine connecting the two posterior superior iliac spines. Marks are made in the midline over the spine 10 cm cranial (original version) and 5 cm caudal (modified version) to the horizontal line. The patient then bends with legs straight and the distance is measured again. It normally increases by more than 3 cm, and in younger people by more than 5 cm. The measure is age dependent.
    • • Lateral—the distance between the tip of the longest finger and the floor is measured in the upright position. This is repeated when the patient tries to flex laterally towards the ground as far as possible, normally moving by more than 10 cm.
  • Chest expansion—the circumference of the thorax is measured in the fourth intercostal space after maximal inspiration and expiration. It normally alters by more than 3 cm, in younger people by more than 5 cm: again the measure is age dependent. In patients with ankylosing spondylitis it indicates involvement of the costovertebral joints.
  • Occiput/wall distance—in the upright position the patient leans backwards against a wall. The distance between occiput and wall is measured: there is no gap (0 cm) in most young patients; in patients with ankylosing spondylitis it usually indicates hyperkyphosis of the thoracic spine.
  • Chin/sternum distance—the chin is maximally bent towards the sternum, and should normally be able to touch it.
  • Cervical rotation—the head is rotated to the left and right sides, with the angles of rotation measured (normally >50°).
  • Intermalleolar distance—the patient tries to stand with their feet together and also to spread their legs maximally: the malleoli should normally touch and the distance of the spread feet usually exceeds 1 m. This measure is dependent on age, training, and the degree of osteoarthritis of the hip.

Physical examination for extra-articular organ involvement

Acute anterior uveitis can occur at any time in the course of disease and is seen in 20 to 30% of patients. It is typically unilateral, but either eye may be affected in separate episodes. Recurrent attacks are common. Aortic regurgitation secondary to aortitis occurs in about 1 to 2% of patients with ankylosing spondylitis, most frequently in advanced disease, and may be associated with atrioventricular block. Probably on the basis of a restrictive pulmonary defect due to limited chest expansion, apical pulmonary fibrosis occurs in no more than 1% of patients, especially those with advanced disease. Cauda equina syndrome caused by arachnoid cysts may complicate severe longstanding disease, with resultant disturbance of the bladder and bowel function. Lumbar diverticulae may be demonstrated by MRI.

Diagnosis

The 1984 modified New York criteria for ankylosing spondylitis are shown in Table 8 below. There is a significant diagnostic delay in women (8 years) and in men (5 years), the most probable reason being that back pain is a very frequent complaint, and that primary care and general physicians are often not trained to distinguish inflammatory from other causes of back pain, such that referral for specialist opinion is delayed.

Laboratory and radiological features

The ESR and the C-reactive protein are raised in 30 to 50% of patients, with moderate correlation to overall disease activity. Less commonly, serum IgA levels are raised. Mild to severe normochromic normocytic anaemia occurs in about 10 to 20% of patients.

Table 19.6.8 Diagnostic criteria for ankylosing spondylitis
Clinical parameters
Inflammatory back pain
Limitation of spinal movement in three planes
Deterioration of chest expansion
Radiological parameters
Sacroiliac joint changes of at least:
 Bilateral grade 2
Unilateral grade 3 or 4

Note that other Spondyloarthritis-like symptoms and syndesmophytes are not part of these criteria. For a definite diagnosis of ankylosing spondylitis, the radiological criterion is essential and one clinical criterion required. If only clinical symptoms and findings are present, a diagnosis of probable ankylosing spondylitis may be made.

Sacroiliac radiography

Dependent on stage, severity, and duration of disease, there are sacroiliac joint abnormalities in almost all patients. The radiological changes are graded from 0 (normal), to I (minimal changes), II (sclerosis, some erosions), III (severe erosions, pseudodilatation of joint space, limited ankylosis), and IV (ankylosis). They are crucial for the diagnosis of ankylosing spondylitis and for the differentiation from undifferentiated spondyloarthritis, but it must be noted that significant inter- and intraobserver variability has been reported—particularly concerning grades I and II—which creates diagnostic problems and confusion. Sclerosis, joint space narrowing, and even synchondrosis occur in healthy elderly individuals. Oblique and other special views are generally not significantly better than normal anteroposterior pelvic radiographs, but can be helpful in a few cases.

Sacroiliac MRI and CT

In early ankylosing spondylitis sacroiliac radiographs may be normal, and in clinically suspicious cases dynamic MRI of the sacroiliac joints can be helpful in providing objective evidence of sacroiliitis (see ‘Undifferentiated Spondyloarthritis’). Active inflammation can be demonstrated by enhancement after application of a contrast agent (gadolinium DTPA) or by special magnetic resonance sequences, such as short tau inversion recovery (STIR) or other fat saturation techniques that optimize the visualization of oedematous areas. CT of the sacroiliac joints is superior to normal radiographs for documenting bony changes such as erosions and ankylosis. The sacroiliac joint is accessible to biopsy under CT guidance.

Spinal radiography

The characteristic spinal lesion, mostly occurring in more advanced disease, is the syndesmophyte—a bony proliferation originating from an inflammatory area at the ligamentous/discal attachment to the vertebral edge. This early ankylotic structure predominantly grows cranially to fuse with the next vertebral body and has to be distinguished from the spondylophyte, which mainly grows laterally and typically indicates degenerative vertebral disease.

In ankylosing spondylitis the earliest spinal lesions are frequently in the lower thoracic and upper lumbar spine, sometimes preceded by squaring of the vertebrae seen on lateral films. The zygapophyseal joints are frequently involved at all stages. Anterior spondylitis is indicated by lateral spinal radiographs showing hypersclerotic corners (Romanus lesion). Spondylodiscitis (Anderson lesion) is revealed by erosion of the disc and vertebra with a hypersclerotic lining. In later stages new bone formation and calcification of ligaments occurs, eventually leading to bridging syndesmophytes and the characteristic ‘bamboo spine’.

Spinal MRI

Early spinal inflammation (spondylitis, spondylodiscitis) can be detected by dynamic MRI, which can be useful for localizing inflammation in the spine in the early stages when plain radiographs are normal.

Treatment

Although there is no cure for ankylosing spondylitis, several treatments are available. The main therapeutic options are:

  • Acute anti-inflammatory therapy—NSAIDs and local corticosteroids; systemic corticosteroids are not recommended
  • Disease-modifying therapy—sulfasalazine for peripheral arthritis and possibly in early disease stages; methotrexate has limited value for peripheral arthritic is clearly not useful for axial conditions. There is no evidence for the use of leflunomide, gold, or hydroxychloroquine
  • Antiresorptive therapy—bisphosphonates (disodium pamidronate) may have some value in selected patients
  • Biologicals—anti-TNF therapy (infliximab, adalimumab, etanercept, golimumab)

NSAIDs are better than analgesics and can be used in combination with them. Diclofenac (50–150 mg), meloxicam (7.5–15 mg), acemetacin and indometacin (50–150 mg) are frequently given. Thalidomide and phenylbutazone are reserved for severe cases when other agents have failed. The more novel COX-2 selective coxibs (celecoxib 100–200 mg, etoricoxib 90–120 mg) are also useful. The main risk of NSAIDs is gastrointestinal side effects: 25% of patients suffer these, ranging from dyspepsia to peptic ulceration and (rarely) bleeding, perforation, and death. It is important to identify patients at risk and to provide them with proper information about possible symptoms, and prophylactic therapy with proton pump inhibitors is indicated in those at particularly high risk (older age, history of ulcer, disability, comorbidity). As most NSAIDs may be associated with a slightly increased incidence of cardiovascular events over time, the individual risk profile of the patient also has to be taken into account. This might be of special clinical relevance, as patients with ankylosing spondylitis may have increased cardiovascular risk because of persistent inflammation.

Most patients with ankylosing spondylitis do not respond to small doses of corticosteroids. Transient high-dose steroid treatment has been tried in extreme cases with additional symptoms of inflammatory bowel disease. In our experience, women and HLA B27-negative ankylosing spondylitis patients are most likely to respond to low-dose corticosteroid therapy.

Sulfasalazine is given in a dosage of 2 to 3 g/day, when effects may be seen after 2 to 4 months. The influence on peripheral joint disease is more significant than for axial symptoms, but this may be due to the preferential study of patients with longstanding disease. Sulfasalazine is mainly indicated for patients with early, active disease.

The anti-TNFα antibodies infliximab (in a dosage of 5 mg/kg intravenously every 6 to 8 weeks after an initial induction phase at weeks 0, 2, and 6), which has also been found to be effective in Crohn’s disease and rheumatoid arthritis, and adalimumab (40 mg subcutaneously every 2 weeks) and golimumab 50 mg s.c/month have been shown in randomized placebo-controlled trials to have significant clinical efficacy in patients with persistently active ankylosing spondylitis. The TNF receptor antagonist etanercept (50 mg subcutaneously weekly, given either in one or two dosages) has similar clinical efficacy for musculoskeletal symptoms but seems to be less effective or without effect for gut, skin, and eye symptoms associated with spondyloarthritis.

The aim of physiotherapy is to maintain and enhance function by improving mobility and muscle strength. Patients affected by spinal stiffness should have physiotherapy on a regular daily basis. Hip replacement is indicated for those with severe hip involvement, and osteotomy can be indicated in cases where visual problems are due to severe kyphosis.

Prognosis

The established myth is that ‘patients with ankylosing spondylitis generally do well’. However, one-third are severely disabled and experience intense pain and impairment of health comparable to those with rheumatoid arthritis. Ankylosing spondylitis does not burn out: disease activity and pain are independent of its duration. As the disease usually starts in the second or third decade of life, patients with ankylosing spondylitis typically suffer its effects for many years. Mortality may be slightly increased, possible causes of premature death being amyloidosis, NSAID gastropathy (ulcers, bleeding), vertebral fractures, and cardiac or respiratory complications.

Reactive arthritis/Reiter's syndrome

For further information see: reactive arthritis.

Undifferentiated spondyloarthritis

Definition

The term undifferentiated spondyloarthritis (uSpA) was introduced and defined by the European Spondylarthropathy Study Group (ESSG) in 1991. Terms such as incomplete Reiter’s syndrome, syndrome of enthesopathy and arthritis, HLA B27-positive oligoarthritis (and others) had been used previously. Patients with uSpA have the typical clinical features of spondyloarthritides but do not fit into any of the other defined categories. The fact that patients with a clinical picture of peripheral oligoarthritis but without spinal symptoms are also classified/diagnosed with uSpA by the ESSG criteria can be confusing in some cases, and uSpA may represent an early form of another spondyloarthritis subset (most often ankylosing spondylitis), or be a genuine spondyloarthritis subset of its own. The new ASAS criteria for SpA cover axial and peripheral SpA, especially axial SpA is a possible predecessor of ankylosing spondylitis, since at least 50% of the patients develop ankylosing spondylitis.

Epidemiology

The prevalence of uSpA is not known precisely, but the frequency is not much less than that of psoriatic arthritis, and it is commoner in men. About 70% of patients are HLA B27-positive. In some contrast to other spondyloarthritides, late-onset disease has been reported.

Clinical features

The main clinical features are inflammatory back pain, asymmetric peripheral arthritis, predominantly of the lower limbs, enthesitis, dactylitis, and anterior uveitis.

Diagnosis

The diagnosis of uSpA requires inflammatory back pain and/or peripheral arthritis of the lower limbs and at least one other characteristic feature in addition—enthesitis, a positive family history for spondyloarthritis, psoriasis, or inflammatory bowel disease. Dactylitis, anterior uveitis, and HLA B27 are not part of the ESSG Group criteria, but are part of Amor’s criteria, and may also be used for making a diagnosis of uSpA. It has recently been argued that at least three to four of these parameters should be positive before a diagnosis can be made. Radiographs are not essential for a diagnosis, but in clinically suspicious cases MRI of the sacroiliac joints can be helpful in providing objective evidence of sacroiliitis.

The differential diagnosis of asymmetric peripheral arthritis of the lower limbs in spondyloarthritis comprises Lyme disease, sarcoidosis, gout, osteoarthritis, atypical rheumatoid arthritis, and connective tissue diseases and other rarer conditions.

Treatment

Nonspecific therapy with NSAIDs, intra-articular steroid injections, transient immobilization, ice packs, and physiotherapy is similar to that of other arthritides. Sulfasalazine may have some efficacy for peripheral and axial symptoms, but very few therapeutic trials with disease-modifying agents have been performed in uSpA. TNF blockers are probably as effective as in established ankylosing spondylitis.

Prognosis

The long-term prognosis in uSpA is uncertain: in about 50% of cases a transition to ankylosing spondylitis has been reported, which may occur over several years.

Psoriatic arthritis

Definition

All kinds of arthritis occurring in association with psoriasis can be regarded as psoriatic arthritis, but it is clear that there can be considerable variability in arthritic manifestation. Many patients can be classified as having a spondyloarthritis, but some are affected in a manner more closely resembling rheumatoid arthritis, and there are other unique forms such as arthritis mutilans. Different forms of psoriasis may be associated with a somewhat different form of arthritis.

Epidemiology

Psoriasis is common, with prevalence between 1 and 3% of the population. Arthritic symptoms occur in 20 to 40% of these patients, with the axial skeleton affected in 15 to 25%, such that the overall prevalence of psoriatic arthritis is somewhere around 0.1 to 0.3%. The peak age of onset of psoriatic arthritis is between 20 and 40 years: juvenile disease is rare. Both sexes are equally affected, but women more frequently get polyarthritis and men more often have spinal involvement.

Pathogenesis

Familial aggregation and high concordance rates in monozygotic (70%) compared with dizygotic twins (20%) suggest that there are important genetic factors in psoriasis and psoriatic arthritis. About 30% of patients give a clear history of affected first-degree relatives. The genetic impact is thought to be multifactorial. Psoriasis is associated with HLA B13, B17, B37, and HLA DR7, the strongest association being with Cw6 (RR = 24). HLA associations of psoriatic arthritis are with HLA B38 and B39 (peripheral arthritis), with HLA DR4 (symmetric polyarthritis) and HLA B27 (spondylitis).

The importance of HLA genetic linkage may lie in determination of the immunological response to particular antigens, and there has been much interest in the possible role of streptococcal infection. A proliferative response of skin and synovial T cells to streptococcal antigens has been detected in psoriatic arthritis, but also in rheumatoid arthritis, and the (immuno)histology is similar in the two conditions, although some differences have been described.

Koebner’s phenomenon is described in psoriasis, when plaques arise at sites of skin injury, scratches, and scars, but the role of trauma in psoriatic arthritis is not clear. Drugs can exacerbate and trigger psoriasis: most well known are β-blockers, antimalarials, and lithium, and withdrawal of corticosteroids can induce a skin flare, but the relevance of these factors to psoriatic arthritis is uncertain.

Clinical features

The most characteristic features of psoriatic arthritis are dactylitis and osteoproliferative changes in radiographs of peripheral joints. The pattern of axial involvement is somewhat different from that in ankylosing spondylitis, and in contrast to rheumatoid arthritis, patients with psoriatic arthritis may have involvement of the distal interphalangeal joints. It is possible that psoriatic arthritis can occur without skin involvement.

Psoriatic arthritis has been divided into five subgroups: distal interphalangeal (overlapping, most common); asymmetrical (Spondyloarthritis-like); symmetrical (rheumatoid arthritis-like); mutilans (unique, rare); and spinal (ankylosing spondylitis-like). It must be stressed, however, that these subgroups are not clearcut. In one study the initial classification pattern changed when patients were evaluated over a period of 8 years: finally only two categories remained—peripheral disease without axial involvement (70%), and axial involvement with or without peripheral arthritis (30%). The latter was correlated with duration of the disease and magnitude of joint involvement. Erosions were found in 70% of the patients.

Psoriasis precedes joint disease in most cases (70–80%); both occur simultaneously in 15%; and in about 10% arthritis comes first. There is poor correlation between onset, severity, and activity of psoriatic skin lesions and arthritis. More than 80% of patients with psoriatic arthritis have nail dystrophy, whereas this is the case in only 20% of those with uncomplicated skin disease. Nail dystrophy, ranging from some to many nail pits and horizontal (not longitudinal) ridging to onycholysis, occurs most often in those with distal interphalangeal involvement. In some patients the involvement of interphalangeal joints and nails is closely correlated, with both appearing on the same finger(s). Acute anterior uveitis occurs mainly in those with radiological sacroiliitis and ankylosing spondylitis.

Different types of psoriatic skin involvement lead to different types of arthropathy. Most frequent is the common psoriasis vulgaris, but a type of skin disease that frequently affects the palms of the hands and soles of the feet with many psoriatic plaques is also seen: pustolosis palmaris et plantaris. This type is associated with the SAPHO syndrome (see below), which is related to the spondyloarthritis but has unique features that justify the designation as a separate subset of these disorders.

A severe form of psoriatic arthritis can occur in HIV-infected patients, although is not clear whether HIV increases the overall prevalence of psoriatic arthritis. Severe peripheral enthesitis (predominantly of the heel) and dactylitis are characteristic. Knee arthritis can be rapidly destructive. Axial inflammation is less frequent.

There is an overlap between psoriatic arthritis and reactive arthritis in the form of keratoderma blennorrhagica—a desquamating psoriasis-like lesion mostly occurring on the soles of the feet in patients with Reiter’s syndrome.

Psoriatic arthritis often improves during pregnancy. There is no adverse effect of the disease on mother or child.

Diagnosis

Scaling erythematous papules and plaques on the scalp and extensor aspects of the extremities, often surmounted by a silvery white micaceous scale that is easily removed, are suggestive of psoriasis. Elbows and knees are often affected. The diagnosis of psoriatic arthritis is based on the presence of these characteristic skin lesions, which are not always obvious. Less accessible areas such as the navel, perineum, and scalp need to be examined carefully. The patient should be asked whether they have a family history of psoriasis or psoriatic arthritis.

As psoriasis is a frequent disease, it must be remembered that a patient with psoriasis can have an attack of gout or another form of arthritis. The diagnosis of psoriatic arthritis should be considered in those without skin lesions if there is distal interphalangeal joint involvement, dactylitis, the involvement of a whole finger or toe, tendon sheaths and bone of an affected limb, and/or typical radiographic changes.

The CASPAR (Classification criteria for psoriatic arthritis) criteria consisted of established inflammatory articular disease with at least three points from the following features: current psoriasis (assigned a score of 2; all other features are assigned a score of 1), a history of psoriasis (unless current psoriasis is present), a family history of psoriasis (unless current psoriasis is present or there is a history of psoriasis), dactylitis, juxta-articular new bone formation, rheumatoid factor negativity, and nail dystrophy. These criteria are sensitive (0.914) and specific (0.987).

Laboratory and radiological features

Acute phase reactants are often raised. HLA determinations including HLA B27 do not provide diagnostic help in those with psoriatic arthritis, but in HLA B27-negative patients who appear to have ankylosing spondylitis, psoriasis (and inflammatory bowel disease) should always be sought. The presence of rheumatoid factor does not formally exclude a diagnosis of psoriatic arthritis, there being a background prevalence of rheumatoid factor positivity, but a positive result should always make the physician consider the diagnosis carefully.

The distribution of radiological changes reflects clinical involvement, with the interphalangeal joints involved earlier than larger joints. A characteristic lesion in advanced cases is the so-called pencil-in-cup deformity, which evolves by resorption of the distal end of a phalanx or metacarpal with uniform deep erosion of the end of the corresponding distal phalanx. In some cases the joints can be completely destroyed and invisible on the radiograph.

Radiological grounds for thinking the diagnosis more likely to be psoriatic arthritis than rheumatoid arthritis are distal interphalangeal joint involvement, asymmetric joint involvement, marginal erosions with adjacent bone proliferation (whiskering), osteolysis, periostitis, proliferative new bone formation, and ankylosis. Radiological sacroiliitis is a finding in 20 to 40% of patients. The axial disease in psoriatic arthritis can be indistinguishable from that in primary ankylosing spondylitis, but in psoriatic arthritis the following are more likely: asymmetrical sacroiliitis; less zygapophyseal joint involvement; fewer, coarser, and asymmetric syndesmophytes; and bony bridging that is more often than not asymmetrical. Psoriatic arthritis syndesmophytes can be indistinguishable from spondylophytes typical of DISH (Forestier’s disease).

When scintigraphy is used to detect the extent and localization of arthritis, an increased uptake of the isotope technetium-99 can frequently be detected in the sternoclavicular and manubriosternal joints, but this is not necessarily associated with clinical symptoms.

Treatment

Many patients improve with the use of NSAIDs and intra-articular steroids, especially in the case of large joint involvement or flexor tenosynovitis. However, 20 to 40% of patients will not improve and need to be treated with disease-modifying antirheumatic drugs (DMARDs). Sulfasalazine 2 to 3 g daily is often effective against arthritis. Methotrexate 7.5 to 25 mg orally or subcutaneously weekly is also good for arthritis, and even better for the skin. Intramuscular gold and azathioprine can be tried. Antimalarials and penicillamine are not used; the former may exacerbate psoriasis. Ciclosporin is given in severe cases. There is limited information on the use of combination therapy. Systemic corticosteroids are limited to extreme cases of arthritis: psoriasis usually flares when they are withdrawn.

Local skin therapy has no effect on joint symptoms. Etretinate is not clearly beneficial for arthritis and may cause arthralgias and many other adverse reactions. The role of physiotherapy is similar to that in other spondyloarthritides, and there are no special considerations for surgical intervention in psoriatic arthritis, apart from the fact that the presence of florid skin lesions close to a joint is a relative contraindication to surgery.

Prognosis

Severe psoriasis can lead to significant disability. There are only limited data from long-term studies in psoriatic arthritis, but in cross-sectional studies 10 to 20% of patients with psoriatic arthritis are in a poor functional class, and the HLA antigens HLA B27, HLA B39, and DQw3 have been associated with such an outcome.

Arthritis associated with inflammatory bowel disease

Definition

An arthropathy with various clinical symptoms occurring in association with Crohn’s disease and ulcerative colitis is termed arthritis associated with inflammatory bowel disease. Other forms of arthropathy occurring in association with enteropathy are Whipple’s disease, and arthritis after intestinal bypass surgery.

Epidemiology

A relationship between gut and joint disease was postulated in 1922 when Smith treated arthritis patients with segmental bowel surgery. Bargen and Hench in 1929 and 1935 described arthritis in association with ulcerative colitis and Crohn’s disease. Moll and Wright included arthritis associated with inflammatory bowel disease in the concept of spondyloarthritis in 1973. Mielants and Veys described Crohn’s-like gut lesions in all subsets of spondyloarthritis in 1984.

The prevalence of Crohn’s disease and ulcerative colitis is between 0.05 and 0.1% of the population, generally higher in white and Jewish people. The peak occurrence of both diseases is between 15 and 35 years, but it may appear in every decade of life; both sexes are equally involved. Arthritis associated with inflammatory bowel disease occurs in 10 to 30% of patients with inflammatory bowel disease, in general more frequently in Crohn’s disease than in ulcerative colitis, and more often in patients with colonic involvement and in those with extensive bowel disease.

There is a genetic predisposition for inflammatory bowel disease with documented familial aggregation for both Crohn’s disease and ulcerative colitis. The association with HLA B16, HLA B18, and HLA B62 is not strong. The peripheral arthritis of inflammatory bowel disease is only weakly associated with HLA B27, but axial inflammation is more strongly associated with it (50%). The patient with inflammatory bowel disease who is HLA B27-positive is at high risk of developing spondylitis. The relative frequency of sacroiliitis and ankylosing spondylitis in inflammatory bowel diseases varies between 2 and 20% or more, partly depending on the sensitivity of the diagnostic imaging procedure. Only 4% of patients with ankylosing spondylitis develop overt inflammatory bowel disease, whereas 60% have microscopically detectable Crohn-like gut lesions.

Pathogenesis

The pathogenesis of inflammatory bowel disease and arthritis associated with inflammatory bowel disease is not known. One hypothesis is of an aberrant immune response to gut bacteria, with gut inflammation leading to increased permeability, allowing bacteria to cross the mucosal border and get access to joints. There is some evidence from the HLA B27 transgenic rat model that gut and joints are closely linked: susceptible rats get both colitis and arthritis once they have left a germ-free environment.

Clinical features

Patients with ulcerative colitis and Crohn’s disease typically present with bloody diarrhoea and abdominal pain, and in severe cases with fever, weight loss, and fatigue. 

As with the other spondyloarthritides, the arthritis is mostly asymmetric and predominantly affects the legs. The arthritis is migratory, often transient, but tends to recur. It does not frequently become chronic but may be associated with erosive disease in some patients. Flaring of gut symptoms is often associated with arthritis, especially in ulcerative colitis. Patients experience significantly fewer joint symptoms after colectomy.

Two types of arthropathy were distinguished in a study of almost 1500 patients with inflammatory bowel disease, essentially on the basis of the number of joints involved and (importantly) without knowledge of spinal radiographs. Pauciarticular disease (type I, fewer than five joints involved) affected 3.6% of patients with ulcerative colitis and 6% of those with Crohn’s disease and was acute and self-limiting, with episodes lasting 4 to 5 weeks, in 83 and 79% of the cases. Polyarticular disease (type II, five or more joints) affected 2.5% of patients with ulcerative colitis and 4% of those with Crohn’s disease and was associated with persistent symptoms in 87 and 89% of the cases.

The onset of peripheral arthritis is associated with exacerbations of colitis, but there is no link between enteric and spinal symptoms. Acute anterior uveitis occurs in 10% of patients with inflammatory bowel disease. It is associated with axial involvement and with HLA B27. The type of uveitis is somewhat different in inflammatory bowel diseases to that in other spondyloarthritides: posterior uveitis and scleritis may occur. The most common skin lesion in arthritis associated with inflammatory bowel disease is erythema nodosum, occurring in association with exacerbation of enteritis.

Diagnosis

Most arthritic symptoms occurring in patients with inflammatory bowel disease can generally be attributed to spondyloarthritides. However, as in psoriasis, patients can have more than one disease (osteoarthritis, etc.). As many as 50 to 60% of all patients with ankylosing spondylitis have gut lesions resembling those in Crohn’s disease, but most are asymptomatic. Clinically apparent ankylosing spondylitis often precedes Crohn-like symptoms. This spectrum of diseases clearly and typically belongs to the spectrum of spondyloarthritides. The differentiation (if needed) will rarely cause problems, as one disease is usually predominant. Along with psoriasis, inflammatory bowel disease should always be looked for in HLA B27-negative patients who appear to have ankylosing spondylitis.

Treatment

Treatment of inflammatory bowel disease is always the first consideration and will probably influence peripheral arthritis. Treatment with NSAIDs may be effective for arthritis and spondylitis but can exacerbate bowel disease. There are few data on the use of DMARDs. Sulfasalazine is effective in ulcerative colitis and other spondyloarthritides and may accordingly be used in arthritis associated with inflammatory bowel disease. Azathioprine is effective in Crohn’s disease and can be tried to treat severe and chronic joint disease. Corticosteroids are the therapy of choice in acute inflammatory bowel disease and will generally help arthritis, but they should not be used for mild and transient joint symptoms. As stated above, NSAIDs tend to exacerbate gut symptoms, but etoricoxib did not cause more flares than placebo (both c.10%) in one controlled study.

Prognosis

The prognosis of arthritis associated with inflammatory bowel disease is generally good. Joint destruction is a rare event. Patients may have ankylosing spondylitis at presentation of inflammatory bowel disease, or develop this later.

SAPHO syndrome

Definition

French workers proposed SAPHO (synovitis, acne, pustolosis palmaris et plantaris, hyperostosis, and osteitis) as a unifying diagnosis for several idiopathic bone and skin diseases, thereby combining over 50 different terms published in the literature (including pustulotic arthro-osteitis, chronic multifocal osteomyelitis, Tietze syndrome (German), and acquired hyperostosis syndrome). Their description of the common symptoms and overlapping features of this heterogenous group of rheumatic joint, bone, and skin diseases has led to better recognition of the relatively rare condition.

There is an argument that SAPHO simply represents a subset of psoriatic arthropathy; also that it might not really belong to the spondyloarthritides at all, because only 43% of patients with SAPHO fulfilled the European Spondylarthropathy Study Group criteria, and only 1 in 19 was HLA B27-positive in one follow-up study. However, there are some clear similarities.

Pathogenesis

The pathogenesis of SAPHO syndrome is unclear. Some authors think that it is similar to that of reactive arthritis. Propionibacterium acnes, which can induce arthritis in animals, has been detected in acne lesions and grown from osteitic lesions in some cases. However, cultures are negative in the vast majority of cases, and antibiotics are ineffective.

Diagnosis

There are no evaluated diagnostic criteria for SAPHO. Most convincing clinically is the combination of a classical skin symptom—such as pustolosis or significant acne (acne conglobata and acne fulminans or hidradenitis suppurativa)—with a characteristic joint or bone lesion such as arthritis of the sternoclavicular joint, osteitis, or hyperostosis in the anterior chest wall.

Diagnosis is important to avoid unnecessary biopsy procedures, but can be very difficult, especially in those without typical skin lesions. The most important differential diagnoses are bacterial osteomyelitis and malignancy. The pattern of joints affected differs from other rheumatic diseases: the sternoclavicular joint (Figs. 19.6.11 and 19.6.12), the clavicle, the ribs, and the mandible are frequently involved by arthritis, osteitis, and/or hyperostosis. Sacroiliitis, mostly unilateral, occurs in one-third of patients.

Treatment

Analgesics, NSAIDs, and intra-articular steroids are usually effective. In severe cases systemic corticosteroids should be considered. Immunosuppressive agents can be added if the steroid dose cannot be tapered to less than 10 mg/day (of prednisolone, or equivalent). Sulfasalzine, azathioprine, and methotrexate have been tried successfully in some cases. Radiation therapy can also be effective in refractory cases. No controlled studies have been performed. Patients with refractory disease might also respond to treatment with TNF blockers.

Prognosis

The course of disease is very variable. Initially, occurrence of several flares per year is common. Further progress is usually favourable, but complications such as axillary vein and C8 compression can occur. Some patients may develop ankylosis and a few progress into ankylosing spondylitis.

Other enteric arthropathies

Whipple’s disease

Whipple’s disease is a rare systemic disease that usually involves the small intestine. The associated arthritis is often symmetric and polyarticular, and may antedate the intestinal complaints by years. It is not usually destructive. Axial involvement occurs but is not typical.

Arthritis associated with coeliac disease

For a description of coeliac disease (gluten-sensitive enteropathy) see: coeliac disease. The joint manifestations show a striking response to a gluten-free diet, which strongly suggests a causal relationship. The pattern of arthritis is very variable, and overt bowel symptoms are absent in half of cases, making diagnosis difficult. The lumbar spine, hips, knees, shoulders, elbows, wrists, and ankles are most frequently affected, often symmetrically. The arthritis is not destructive. HLA B8 and DR3 are frequently found. The pathogenesis is unclear.

Arthropathies associated with collagenous colitis

Collagenous colitis is a chronic diarrhoeal disease characterized by a normal or near-normal mucosa endoscopically and a thick subepithelial collagen layer. More than half of patients with this disorder have some form of arthritis and use NSAIDs regularly.

Arthropathies associated with intestinal bypass surgery

Arthritis has been reported in 5 to 50% of patients in the first 3 years after jejunoileal bypass surgery. A symmetric peripheral polyarthritis involves the knees, wrists, metacarpophalangeal and metatarsophalangeal joints, elbows, proximal interphalangeal joints, and ankles and is usually nondestructive. Almost half of those affected also have vesicopustular skin lesions. No specific HLA association has been found, but two previously healthy HLA B27-positive patients developed spondylitis. Bacterial overgrowth of the blind loop is critical for pathogenesis.

Further reading

 
 
General
 
Amor B, et al. (1994). Predictive factors for the long-term outcome of spondyloarthropathies. J Rheumatol, 21, 1883–7. 
Braun J, et al. (1998). Prevalence of spondylarthropathies in HLA-B27 positive and negative blood donors. Arthritis Rheum, 41, 58–67.[CrossRef] [Web of Science] [Medline] 
 
Braun J, Bollow M, Sieper J (1998). Radiologic diagnosis and pathology of the spondyloarthropathies. Rheum Dis Clin North Am, 24, 697–735.[CrossRef] [Web of Science] [Medline] 
 
Brebam M, Hacquard-Bouder C, Falgarone G (2004). Animal models of HLA-B27-associated diseases. Curr Mol Med, 4, 31–40.[CrossRef] [Web of Science] [Medline] 
 
Calin A, et al. (1977). Clinical history as a screening test for ankylosing spondylitis. J Am Med Assoc, 237, 2613–14.
 
Dougados M, et al. (1991). The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum, 34, 1218–27. [Web of Science] [Medline] 
 
Khan MA, van der Linden SM (1990). A wider spectrum of spondyloarthropathies. Semin Arthritis Rheum, 20, 107–13.[CrossRef] [Web of Science] [Medline] 
 
Moll JM, et al. (1974). Associations between ankylosing spondylitis, psoriatic arthritis, Reiter’s disease, the intestinal arthropathies, and Behcet’s syndrome. Medicine (Baltimore), 53, 343–64.
 
Sieper J, Braun J (1995). Pathogenesis of spondylarthropathies. Persistent bacterial antigen, autoimmunity, or both? Arthritis Rheum, 38, 1547–54. [Web of Science] [Medline] 
 
Ankylosing spondylitis
 
Bollow M, et al. (2000). Quantitative analysis of sacroiliac biopsies in spondyloarthopathies: T cells and macrophages predominate in early and active sacroiliitis–cellularity correlates with the degree of enhancement detected by magnetic resonance imaging. Ann Rheum Dis, 59, 135–40.[Abstract/Full Text]
 
Braun J, Seiper J (2007). Ankylosing spondylitis. Lancet, 369, 1379–90.[CrossRef] [Web of Science] [Medline] 
 
Brophy S, et al. (2002). The natural history of ankylosing spondylitis as defined by radiological progression. J Rheumatol, 29, 1236–43.
 
Gorman JD, Sack KE, Davis JC Jr (2002). Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. N Engl J Med, 346, 1349–56.[CrossRef] [Web of Science] [Medline] 
 
Gran JT, Skomsvoll JF (1997). The outcome of ankylosing spondylitis: a study of 100 patients. Br J Rheumatol, 36, 766–71.
 
McGonagle D, et al. (1998). Characteristic magnetic resonance imaging entheseal changes of knee synovitis in spondylarthropathy. Arthritis Rheum, 41, 694–700.[CrossRef] [Web of Science] [Medline] 
 
McLeod C, et al. (2007). Adalimumab, etanercept and infliximab for the treatment of anklosing spondylitis: a systematic review and economic evaluation. Health Technol Assess 11, 1–158, iii–iv.
 
Rudwaleit M, Metter A, Listing J, et al. (2006). Inflammatory back pain in ankylosing spondylitis: a reassessment of the clinical history for application as classification and diagnostic criteria. Arthritis Rheum, 54, 569–78.[CrossRef] [Web of Science] [Medline] 
 
Zink A, et al. (2000). Disability and handicap in rheumatoid arthritis and ankylosing spondylitis—results from the German rheumatological database. J Rheumatol, 27, 613–22.
 
Undifferentiated spondyloarthritis
 
Gomariz EM, et al. (2002). The potential of ESSG Spondyloarthritis classification criteria as a diagnostic aid in rheumatological practice. J Rheumatol, 29, 326–30.
 
Olivieri I, et al. (2001). Ankylosing spondylitis and undifferentiated spondyloarthropathies: a clinical review and description of a disease subset with older age at onset. Curr Opin Rheumatol, 13, 280–4.[CrossRef] [Web of Science] [Medline] 
 
Zeidler H, Mau W, Khan A (1992). Undifferentiated spondyloarthropathies. Rheum Dis Clin North Am, 18, 187–202.
 
Psoriatic arthritis
 
Gladman DD (1998). Psoriatic arthritis. Rheum Dis Clin North Am, 24, 829–44.[CrossRef] [Web of Science] [Medline] 
 
Helliwell P, et al. (1991). A re-evaluation of the osteoarticular manifestations of psoriasis. Br J Rheumatol, 30, 339–45.
 
Helliwell PS (2004). Relationship of psoriatic arthritis with the other spondyloarthropathies. Curr Opin Rheumatol, 16, 344–9.[CrossRef] [Web of Science] [Medline] 
 
Marsal S, et al. (1999). Clinical, radiographic and HLA associations as markers for different patterns of psoriatic arthritis. Rheumatology, 38, 332–7.
 
Reece RJ, et al. (1999). Distinct vascular patterns of early synovitis in psoriatic, reactive and rheumatoid arthritis. Arthritis Rheum, 42, 1481–4.[CrossRef] [Web of Science] [Medline] 
 
Richter Cohen M, et al. (1999). Baseline relationships between psoriasis and psoriatic arthritis: analysis of 221 patients with active psoriatic arthritis. J Rheumatol, 26, 1752–6. [Web of Science] [Medline] 
 
Taylor W, et al. (2006). Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum, 54, 2665–73.
 
Arthritis associated with inflammatory bowel disease
 
Leirisalo-Repo M, et al. (1994). High frequency of silent inflammatory bowel disease in spondyloarthropathy. Arthritis Rheum, 37, 23–35. [Web of Science] [Medline] 
 
Mielants H, et al. (1996). Course of gut inflammation in spondylarthropathies and therapeutic consequences. Baillière’s Best Pract Res Clin Rheumatol, 10, 147–64.
 
Orchard TR, Jewell DP (1999). The importance of ileocaecal integrity in the arthritic complications of Crohn’s disease. Inflamm Bowel Dis, 5, 92–7. [Web of Science] [Medline] 
 
Orchard TR, Wordsworth BP, Jewell DP (1998). Peripheral arthropathies in inflammatory bowel disease: their articular distribution and natural history. Gut, 42, 387–91.[Abstract/Full Text]
 
Taurog J, et al. (1994). The germfree state prevents the development of gut and joint inflammatory disease in HLA B27 transgenic rats. J Exp Med, 180, 2359–64.
 
SAPHO syndrome
 
Boutin RD, Resnick D (1998). The SAPHO syndrome: an evolving concept for unifying several idiopathic disorders of bone and skin. Am J Rheumatol, 170, 585–91.
 
Kahn MF, Khan MA (1994). The SAPHO syndrome. Baillière’s Best Pract Res Clin Rheumatol, 8, 333–62.
 
Koehler H, et al. (1975). Sterno-kosto-klavikuläre Hyperostose. Deutsche Medizinische Wochenschrift, 100, 1519–23. [Medline] 
 
Maugars Y, et al. (1995). SAPHO syndrome: a followup study of 19 cases with special emphasis on enthesis involvement. J Rheumatol, 22, 2135–41. [Web of Science] [Medline] 
 
Moll C, et al. (2008). Ilium osteitis as the main manifestation of the SAPHO syndrome: response to infliximab therapy and review of the literature. Semin Arthritis Rheum, 37, 299–306.
 
Sonozaki H, et al. (1981). Clinical features of 39 patients with pustolotic arthroosteitis. Ann Rheum Dis, 40, 547–53.
 
Other enteric arthropathies
 
Fleming JL, Wiesner RH, Shorter RG (1988). Whipple’s disease: clinical, biochemical and histopathological features and assessment of treatment in 29 patients. Mayo Clin Proc, 63, 539–51. 
 
Goff JS, et al. (1997). Collagenous colitis: histopathology and clinical course. Am J Gastroenterol, 92, 57–60. 
 
Pinals RS (1986). Arthritis associated with gluten-sensitive arthropathy. J Rheumatol, 13, 201–4. 
 
Stein HE, et al. (1981). The intestinal bypass arthritis-dermatitis syndrome. Arthritis Rheum, 24, 684–90.