Spond Ylar THR I Tides

Eular On-line Course on Rheumatic Diseases module n7 Maxime Dougados, Robert Landew
SPONDYLARTHRITIDES: PATHOGENESIS, CLINICAL ASPECTS AND DIAGNOSIS
Maxime DOUGADOS
Paris-Descartes University, Faculty of Medicine; UPRES-EA 4058; AP-HP, Cochin Hospital; Paris, France
Learning Objectives
Describe and explain the concept of spondylarthritides; Describe and explain the physiopathology of these disorders and, in particular, the respective role of genetic and environmental factors; Explain the different hypotheses explaining the role of B27 in the occurrence of the disease; Improve diagnostic approaches in this area; Improve assessment of such patients and, in particular, the evaluation of both the activity, severity, potential severity and refractory characteristics of the disease; Describe the use of the different tools permitting an optimal monitoring of these patients.
I.
THE CONCEPT OF SPONDYLARTHRITIDES I.1 Definition

The group of diseases collectively labeled spondylarthritides consists of several disorders: reactive arthritis, psoriatic arthritis, arthritis related to inflammatory bowel disease, a subgroup of juvenile chronic arthritis, and ankylosing spondylitis, with the last mentioned being the prototype of this group of interrelated disorders. It can be difficult to differentiate these disorders, because they may occur simultaneously or sequentially; in addition, some of the clinical characteristics of these diseases, such as enthesiopathy and eye involvement, are similar whatever the diagnosis. The monitoring, and to a lesser degree, the diagnosis and treatment of these diseases are related more to their clinical presentation than to the precise diagnosis [Slide 1]. The rheumatic manifestations include spinal symptoms, but also extra-spinal joint disease and enthesiopathic lesions may be seen. The extra-articular manifestations of the disease may be similar whatever the subgroup of spondylarthritides (e.g. acute anterior uveitis) or may be specific to a subgroup of spondylarthritides such as the skin lesion in psoriatic arthritis, the gut involvement in inflammatory bowel disease, and the oculo-urethro-synovial triangle in classical reactive arthritis.
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Spondylarthropathy Disease subgroups Clinical features

Ankylosing spondylitis Psoriatic arthritis Reactive arthritis IBD related arthritis Undifferentiated spondylarthropathy Rheumatological manifestations Axial involvement Peripehral arthritis Enthesiopathy Extra-articular features Acute anterior uveitis Endocarditis Genetic background Family history HLA-B27 antigen Specific manifestations Psoriasis Inflammatory bowel disease Etc.
adapted from M. Dougados et al. Best Pract Res Clin Rheum 2002;16:495-505
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Clinical presentation of spondylarthropathy
I.2 Interest
Recognition of this concept of spondylarthritides is of great importance in daily practice and has at least a fourfold effect: a) it permits earlier diagnosis, b) it facilitates patient education, c) it facilitates patient monitoring and d) it facilitates the evaluation and the indication of treatments.
I.2.1 Early diagnosis The cornerstones of treatment of all rheumatic diseases are early accurate diagnosis and effective patient education. Early diagnosis enables treatment before permanent rigidity and deformity have taken place. It also allows detection of the early changes in spinal position and therefore prevention of the abnormal postures associated with these diseases. The criteria for ankylosing spondylitis (which requires the presence of sacroiliitis on plain X-rays) may be helpful in establishing standard diagnostic levels for similar groups of patients, but they are not of much use in everyday clinical practice for diagnosis in an individual patient. This is due to two major factors: detection of radiographic evidence of sacroiliitis may sometimes take 3-7 years after disease onset and extra-spinal and/or extra-articular involvement are common features of ankylosing spondylitis at an early stage of the disease. The use of sets of spondylarthritides criteria (the Amor criteria and/or the European Spondylarthritides Study Group criteria [Slide 2, 3]) may be more helpful.
For example, the Amor criteria permit establishment of the diagnosis of spondylarthritides whatever the target symptom; for example, enthesiopathy or uveitis. Both criteria permit determination of the diagnosis of spondylarthritides even in the absence of radiographic sacroiliitis.
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Parameter A. Clinical symptoms or past history of

1. 2. 3. 4. 5. 6. 7. 8. 9.
Scoring
Lumbar or dorsal pain at night or morning stiffness of lumbar or dorsal area Asymmetrical oligoarthritis Buttock pain (if alternate buttock pain) .. Dactylitis . Heel pain or other well defined enthesiopathy .. Acute anterior uveitis Non-gonococcal urethritis or cervicitis within one month before the onset of arthritis Acute diarrhea within one month before the onset of arthritis . Psoriasis, balanitis, or inflammatory bowel disease
1 2 1 (2) 2 2 2 1 1 1
B. Radiological findings
10.
Sacroiliitis (bilateral grade 2 or unilateral grade 3) ..
C. Genetic background
11.
Presence of B27 HLA antigen and/or family history of ankylosing spondyliitis, reactive arthritis, uveitis, psoriasis or IBD .
D. Response to treatment
12.
Clearcut improvement within 48 hours after NSAID intake or rapid relapse of pain after their discontinuation .
Amor B. Rev Rhum Mal Osteoart 1990;57:85-9
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AMOR spondylarthropathy classification criteria
The European Spondylarthropathy Study Group (ESSG) criteria for spondylarthropathy Inflammatory spinal pain or Synovitis asymmetrical or predominantly in the lower limbs and One or more of the following

Family history first or second-degree relative with ankylosing spondylitis, psoriasis, acute iritis, reactive arthritis or inflammatory bowxel disease Past or present ulcerative colitis or Crohns disease, diagnosed by a physician and confirmed by radiography or endoscopy Past or present pain alternating between the two buttocks Past or present spontaneous pain or tenderness on examination of the site of insertion of the Achilles tendon or plantar fascia (enthesitis)* Episode of diarrhea occurring < 1 month before onset of arthritis Non-gonoccal urethritis or cervicitis occurring < 1 month before onset of arthritis Bilateral grade 2-4 sacroiliitis or unilateral grade 3 or 4 sacroiliitis (where grade 0 is normal, 1 possible, 2 minimal, 3 moderate and 4 completely fused [i.e., ankylosed])
*There may be inflammation of other entheses, but only Achilles and plantar fascia enthesitis from part of
the ESSG criteria
Dougados M. Arthritis Rheum 1991;34:1218-30
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ESSG spondylarthropathy classification criteria
I.2.2 Patient education Patient education is crucial for the successful management of patients with spondylarthritides, as soon as the diagnosis is made, the patient must be given a clear description of the nature of the disease, including three main points: a) explanation of the various potential clinical presentations, b) explanation of the possible progression of the target symptom and c) explanation of the possible occurrence of other clinical symptoms of spondylarthritides.
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To clarify this approach, we will take the example of a young patient presenting with inflammatory low back pain: 1. The patient has to be informed clearly about the differences between back pain due to spondylarthritides and back pain due to a mechanical problem. The physician must keep in mind that the patient has previously received or will get various information concerning back pain from different sources (such as friends or newspapers). The most frequent mistaken notions are that a) non-steroidal anti-inflammatory drugs (NSAIDs) are more toxic than efficient and b) physiotherapy has no effect on the long-term outcome of back pain. 2. Information concerning the possible occurrence of spinal ankylosis in abnormal postures will lead to better compliance with proposed treatments, such as NSAIDs, and physiotherapy and will give the patient a better understanding of the benefits of a routine annual visit. 3. The patient must be informed about the possibility of the occurrence of other clinical symptoms of spondylarthritides. For example, in this patient, the risk of the occurrence of acute anterior uveitis has to be clearly explained together with the need for an emergency visit to an ophthalmologist in such a case.
I.2.3 Patient monitoring The monitoring of patients suffering from any disease belonging to the concept of spondylarthritides is based on the clinical presentation. In other words, the monitoring is based on the following different aspects of spondylarthritides: Axial involvement Peripheral articular arthritis Enthesiopathy Extra-articular features
In practice, and to give an example, the techniques/tools/parameters evaluating the severity of axial involvement are similar whatever the subgroup of spondylarthritides (e.g. ankylosing spondylitis, psoriatic arthritis, IBD related arthritis).
I.2.4 Treatment indication/evaluation Such as for the monitoring, the indication/evaluation of therapies in this area is based on the clinical presentation rather than on the specific disease belonging to the concept of spondylarthritides. For example, methotrexate is considered as useful in patients suffering from peripheral arthritis and not from axial involvement whatever the underlying specific disorder.
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I.3 Classification/Diagnostic criteria

I.3.1 Classification criteria Two sets of criteria have been proposed: the Amor criteria (Slide 2) and the European
Spondylarthritides Study Group (ESSG) criteria (Slide 3). Both sets of criteria have been validated in different countries, by different investigators. All these studies concluded at similar relevant metrological properties (e.g. sensitivity, specificity) with a trend in favor of a better sensitivity and specificity for the Amor criteria. In fact, the main difference between the two sets of criteria is based on their format: ESSG criteria are able to recognize only patients suffering from either an axial disease and/or a peripheral articular involvement; at variance, the Amor criteria are able to recognize patients without axial and/or articular peripheral articular involvement. Such difference explains why the Amor criteria are more widely used in non-rheumatological situations (for example, to evaluate the prevalence of spondylarthritides in patients suffering from uveitis). Moreover, in case of axial involvement alone, such set of criteria are able to recognize patients even in the absence of radiographic sacroiliitis.
I.3.2 Diagnostic criteria To our knowledge, there are no formal diagnostic criteria for spondylarthritides. However, because of the format and the items of such sets of criteria, one could consider that such criteria could be of interest in daily practice in order to recognize a patient at an early stage of the disease. We have seen the advantages of the Amor criteria. Currently, in order to improve their performances, and in order to take into account the role of MRI imaging in the recognition of sacroiliitis at an early stage, a study is evaluating such performances by switching the item 10 (radiological sacroiliitis bilateral grade 2 or unilateral grade 3) to the following item sacroiliitis defined either on plain X-rays or MRI.
II.
THE CLINICAL FEATURES OF SPONDYLARTHRITIDES II.1 Rheumatological manifestations

II.1.1 Axial features II.1.1.1 Inflammatory spinal pain Symptoms of ankylosing spondylitis usually first appear in late adolescence or early adulthood. The key symptom is inflammatory back pain, often associated with sacroiliac involvement. Classically, pain starts in the lumbar region or at the lumbo-dorsal junction. It is typically a dull pain of insidious onset, becoming persistent after a few months. It is inflammatory in nature the pain worsens with inactivity, morning stiffness is often prolonged and nocturnal pain may awaken the patients.
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A combination of these above symptoms are very suggestive of ankylosing spondylitis. Two different sets of criteria with both a good sensitivity and specificity have been proposed to help the physician in daily practice. Calin criteria [slide 4] are defining inflammatory spinal pain in case a patient is fulfilling at least both the 5 following: Insidious onset Onset before the age of 40 years Duration of at least 3 months Morning stiffness 30 minutes Improvement with exercises
Inflammatory back pain

CALIN Criteria * At leat 4 out of the 5 following: Insidious onset Onset before the age of 40 years At least 3 months duration Morning stiffness > 30 minutes Improvement with exercise
* Calin A et al. JAMA 1977;237:2613-4
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Calin inflammatory back pain criteria
Berlin criteria [slide 5] are defining inflammatory spinal pain in case a patient is fulfilling at least 2 of the 4 following: Morning stiffness 30 minutes Improvement with exercises and no improvement at rest Nocturnal awakening in the second part of the night Alternate buttock pain
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Inflammatory back pain

BERLIN Criteria * At leat 2 out of the 4 following: Morning stiffness > 30 minutes Improvement with exercise but not with rest Awakening because of back pain during the second part of the night Alternating buttock pain
* Rudwaleit M et al. Arthritis Rheum 2006;54:569-78
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Berlin inflammatory back pain criteria
At a later stage, spondylitis may involve the thoracic or cervical spine; neck pain and stiffness are characteristics of advanced disease. About 5% of patients presenting with chronic inflammatory back pain have ankylosing spondylitis. If there is progression to ankylosis, the inflammatory pain usually lessens but there is important functional impairment.
II.1.1.2 Ankylosis The principal concern in patients with spondylitis is progression towards ankylosis. The ankylosis is a consequence of ossification of the ligaments and also, at the thoracic level, the vertebro-costal and sterno-costal joints. Physical examination reveals impaired spinal mobility, with restricted flexion and extension of the lumbar spine or limited chest expansion [slide 6]. The restriction in motion is not proportional to the degree of ankylosis, because of secondary muscle spasms.
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Clinical spinal ankylosis
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In patients with restricted chest wall motion, airflow measurements are normal, but vital capacity is decreased and functional residual capacity is increased. Respiratory failure can occur in severe cases. However, ankylosis in the thoracic and lumbar spine [slide 7, 8,] is not necessarily linked to severe physical limitations. By contrast, ankylosis at the cervical level has major physical consequences, as the patient is unable to turn the head [slide 9]. Spine radiographs and CR scans show the following characteristic changes in the later stages of ankylosing spondylitis: squaring of the vertebrae [slide 10, 11], presence of syndesmophytes [slide 12, 13] and, finally the classic ankylosed bamboo column [slide 14]. Overall plain radiography findings do not correlate well with disease activity.
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Radiological thoracic spinal ankylosis
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Radiological lumbar spinal ankylosis (left)
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Radiological cervical spinal ankylosis
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Radiological vertebral squarring
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Radiological vertebral squarring
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Radiological syndesmophytes (left)
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Syndesmophytes
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Radiological bamboo column (left)
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II.1.1.3 Abnormal postures Ankylosis of the spine in an abnormal position is more debilitating than ankylosis in an upright position, as it can have a major impact on functioning. The first sign of abnormal posture is loss of lumbar lordosis, this is followed by thoracic kyphosis and, in severe cases, by forward stooping of the neck [slide 15]. it is important to detect these abnormal features as early as possible, so that physiotherapy or other appropriate treatments can be considered.
Normal position
(a)
(b)
(c)
(d)
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Natural history of spinal abnormal attitudes
II.1.1.4 Fracture Spinal osteoporosis is often observed, especially in patients who have had severe ankylosing spondylitis for a long duration. This contributes to the high prevalence of fractures; these fractures often occur after very minimal trauma to the rigid, ankylosed spine [slide 16, 17]. The spinal osteoporosis is partly due to the lack of mobility that is a consequence of the disease, perhaps as a result of pro-inflammatory cytokines. Assessment of biochemical markers of bone metabolism has shown that diminished bone formation and enhanced bone resorption are involved. It is thought that osteoporotic fractures of the thoracic spine contribute to thoracic kyphosis and increased occiput-to-wall distance.
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Vertebral fracture in ankylosing spondylitis
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Vertebral fracture in ankylosing spondylitis
II.1.1.5 Sacroiliitis Sacroiliac pain is typical of ankylosing spondylitis. Pain is described as occurring in the buttock, sometimes radiating to the posterior thigh. Pain in the sacroiliac joints is reproduced by applying direct pressure to the buttock over the site of sacroiliac joint when the patient is lying prone with their legs extended. Other possible sacroiliac tests include mobilizing the sacrum by direct pressure on the higher median part of the buttocks when the patient is lying prone; hopping, which reactivates pain in the homo-lateral sacroiliac joint; and mobilization of the sacroiliac joint by bending the knee and hip to 90 and bringing the thigh into maximal abduction, with the patient supine. None of these tests is entirely specific or sensitive hence most physicians practice several successively on the same patient before reaching a diagnosis of sacroiliac pain. Sacroiliitis leads to functional impairment that affects walking. In addition, it often results in ankylosis; at this stage, the pain usually disappears.
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The clinical diagnosis is supported by radiological evidence of sacroiliitis, which is still considered to be the radiographic hallmark of ankylosing spondylitis. Antero-posterior radiography of the pelvis is usually sufficient. However, unequivocal sacroiliac changes may not be evident on the radiographs until the disease had been present for many years. The earliest visible changes in the sacroiliac joints are blurring of the cortical margins of the subchondral bone, erosions and sclerosis. As erosion progresses, the joint space appears wider, then fibrous and bony ankylosing obliterates the joint. Joint changes usually become symmetrical during the course of the disease. The New York grading system for sacroiliac joint status is as follows: grade I, suspicious; grade II, evidence of erosion and sclerosis; grade III, erosions, sclerosis and early ankylosis [slide 18-22] and, finally grade IV, total ankylosis [slide 23]. Despite the common use of this description, it has to be emphasized that the term sacroiliitis is in fact inappropriate. Sacroiliitis suggests that the X-rays are able to demonstrate an inflammatory aspect of the sacroiliac joints; in fact, the observed features are the result of a destructive process (probably secondary to the inflammatory one). At variance, MRI is able to detect both the inflammatory and the destructive aspects of the sacroiliac joint involvement.
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Radiological sacroiliitis in ankylosing spondylitis
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Fusion of the sacroiliac joints
When clinical suspicion of early ankylosing spondylitis is high but standard radiography of the sacroiliac joints is normal or shows only equivocal changes, magnetic resonance imaging (MRI), especially with gadolinium enhancement, produces excellent radiation-free evidence of sacroiliitis [slide 24-26] and enthesitis. CT also can detect sacroiliitis [slide 27-29]. Bone scintigraphy [slide 30] is much more difficult to interpret and has no role in this indication. A prospective evaluation has been carried out of the relative sensitivities of MRI, quantitative sacroiliac scintigraphy and plain radiography in detecting active sacroiliitis in 44 patients with clinical symptoms of inflammatory low back pain plus additional features of spondylarthritides (mostly ankylosing spondylitis patients). MRI was found to be the most sensitive imaging technique (95% sensitivity, compared with 19% for plain radiography and 48% for quantitative sacroiliac scintigraphy). These findings indicate that MRI can detect an additional 76% of early sacroiliitis cases, compared with plain radiography. However, MRI and quantitative sacroiliac scintigraphy are expensive, can be difficult to obtain and are not always necessary; therefore, they are not routinely used.
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Sacroiliitis [MRI findings]
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Sacroiliitis [MRI findings]
* Courtesy of V Weber, Zurich
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Sacroiliitis (whole body MRI findings) *
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Sacroiliitis [CT scan findings]
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Sacroiliitis [bone scintigraphy findings]
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II.1.1.6 Anterior chest wall pain and root joints The term axial involvement is often considered to include inflammation of the anterior chest wall and root joints (shoulders and hips). Anterior chest wall pain occurs in about 15% of patients and is usually the result of sterno-clavicular, manubrio-sternal or sternocostal arthritis. As stated above, this can lead to reduced chest expansion. Arthritis occurs in the hips and shoulders in some patients, often early in the course of the disease. It is important to check for root joint involvement, as it can cause major disability. Hip involvement often leads to severe destruction, necessitating total hip replacement.
II.1.2 Peripheral arthritis Peripheral arthritis is less common than axial involvement in ankylosing spondylitis. It is mostly oligo-articular, asymmetrical, transient and migratory, with involvement of both small and large joints, predominantly of the lower limbs. A bilateral symmetrical poly-articular presentation is possible, which differs from rheumatoid arthritis in that the distal inter-phalangeal joints are often involved. Inflammation of the peripheral joints may be apparent on physical examination. A typical feature is dactylitis (sausage-like digit) [slide 31, 32], in which metacarpo-phalangeal and proximal inter-phalangeal arthritis is associated with tenosynovitis. Radiographs of the peripheral joints do not generally reveal erosion.
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Saussage like digit [dactylitis]
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Saussage like digit [dactylitis]
II.1.3 Enthesitis Painful inflammation of entheses, the sites of bony insertion of ligaments and tendons, is a classic and frequent feature of ankylosing spondylitis. The most typical enthesitis is heel pain (posterior or inferior) related to inflammation of the Achilles tendon or the plantar fascia insertion. Pain appears in the morning, as soon as the patient sets his or her foot on the floor, then disappears after a few hours. Heel enthesitis is not painful during sleep. Other clinical indicators are tenderness of the iliac crest, anterior tibial tuberosity or anterior chest wall. Enthesitis is best visualized by ultrasonography [slide 33] or MRI [slide 34] and is only detected on radiography after the ossification process has been achieved [slide 35, 36]. In case of a patient presenting with generalized pain and a suspicion of poly-enthesiopathy, bone scintigraphy has to be considered since enthesiopathy occurring in the context of spondylarthritides is more related to osteitis than tendonitis resulting in hot fixation at bone scintigraphy [slide 37].
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Heel enthesitis [MRI findings]
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Heel enthesitis [MRI findings]
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Heel enthesitis [X-rays]
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Heel enthesitis [ossification]
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Heel enthesitis [bone scintigraphy findings]
II.2 Extra-articular features

All of the extra-articular features of spondylarthritides may be seen in ankylosing spondylitis. Only the most common and/or severe features are detailed here. II.2.1. Acute anterior uveitis The most common extra-articular manifestation of ankylosing spondylitis is acute anterior uveitis, with 25-40% of patients experiencing one or more episodes. These episodes are more likely to occur in patients who are positive for HLA-B27. It is important to detect and treat acute anterior uveitis rapidly, in order to protect the patients eyesight. The condition typically presents with unilateral eye pain and redness, photophobia and increased lachrymation [slide 38]. Patients with these signs require urgent examination by an ophthalmologist, who will provide specialized treatment (e.g. retro-orbital injections of corticosteroids in severe cases). Uveitis tends to recur, sometimes in the contra-lateral eye. The main complication is the occurrence of synechiae [slide 39].
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Acute Anterior Uveitis
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Synechia occurring after acute anterio uveitis
II.2.2 Diarrhea Inflammatory lesions in the gut are common in ankylosing spondylitis and can result in diarrhea, which is usually accompanied by blood and glairy mucus. Loss of weight is common. Inflammatory bowel disease may or may not have already been diagnosed in these patients. Colonoscopic mucosal biopsy reveals that sub-clinical inflammatory lesions are seen in 20-70% of patients with ankylosing spondylitis who have no gastrointestinal symptoms or clinically obvious inflammatory bowel disease. Follow-up studies of such patients indicate that 6% will develop inflammatory bowel disease. About 28-35% of patients with enteropathic arthritis have axial disease: 10-20% have sacroiliitis alone, 7-12% have spondylitis and 10% have the classic features of ankylosing spondylitis. The axial radiology is indistinguishable from that of uncomplicated ankylosing spondylitis, although the frequency of asymmetrical sacroiliitis is probably higher. The clinical picture may also be indistinguishable from classic ankylosing spondylitis. The onset of axial involvement often precedes activity. that of bowel disease, and axial symptoms do not fluctuate with bowel disease
II.2.3 Dermatologic manifestations Dermatologic manifestations are frequent in spondylarthritides and are usually related to a specific disorder such as psoriasis or reactive arthritis. Psoriasis is observed in 20 to 40% of patients suffering from spondylarthritides. Nail lesions are a common feature observed in patients suffering from rheumatological manifestations [slide 40, 41]. Palmo-plantar pustulosis [slide 42] can also be observed in particular in association with acute aseptic synovitis, hyper-ostosis and aseptic osteitis.
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Mucosal lesions such as balanitis are rarely observed except in cases of reactive arthritis [slide 43].
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Nail lesion of psoriasis
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Nail lesion of psoriasis
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Palmo-plantar pustulosis
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Balanitis
II.3 Genetic background

II.3.1 Family history In a patient complaining of at least one of the symptoms described above, the recognition of a family history of spondylarthritides e.g. ankylosing spondylitis, psoriasis is of great interest. Such family history is observed in 30 to 35% of patients suffering from spondylarthritides.
II.3.2 HLA B27 antigen HLA B27 is observed in 8 to 12% of a normal Caucasian population and in 80 to 90% of patients with spondylarthritides. This prevalence range from 30% (peripheral psoriatic arthritis) to 85% (ankylosing spondylitis) and to 98% in patients with a family history of spondylarthritides.
II.4 Other biological markers

Only 40% of patients with active disease exhibit biological markers of inflammation, with elevated erythrocyte sedimentation rates (ESR) and C-reactive-protein (CRP) levels; blood cell count is normal and rheumatoid factor is negative. Mild normo-chronic anemia may be detected. A raised alkaline phosphatase level may be present in severe disease.
III.
THE DIFFERENT DISEASES BELONGING TO THE CONCEPT OF SPONDYLARTHRITIDES

Spondylarthritides can present with a wide spectrum of clinical features. Certain features occur more commonly in some types of spondylarthritides than others. Typical patterns are shown in [slide 44]. However, it is possible for any of the principal clinical features to be present in any of the distinct diseases.
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Ankylosing spondylitis Axial symptoms Peripheral arthritis Enthesitis Extra-articular features: Uveitis Psoriasis Diarrhea Conjunctivitis, urethritis Aortic insufficiency
Psoriatic arthritis
Enteropathic arthritis
Reactive arthritis
Juvenile onset spondylarthropathy
Undifferentiated spondylarthropathy
+++ + + ++
++ +
++ +
++ +
+ +
+ +
+ +++ +++ +++
NB: This table represents the clinical patterns of the different spondylarthropathies. There is, however, some overlap of symptoms and so it is possible for any of the principal clinical features to be present in any of the distinct diseases. The more plus signs, the higher the frequency of the clinical feature (qualitative, non validated parameter).
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Frequency of clinical features/disease in SpA
III.1 Ankylosing spondylitis

III.1.1 Clinical features Ankylosing spondylitis is the prototype of the disease belonging to the concept of spondylarthritides. It is defined by the presence of axial symptoms resulting in both spinal mobility limitation and radiological evidence of sacroiliitis. Nevertheless, other manifestations can obviously be observed, in particular in enthesiopathy (40 to 60%) and/or acute anterior uveitis (30 to 50%).
III.1.2 Classification/Diagnostic criteria III.1.2.1 Classification criteria In 1984, the modified New York criteria were elaborated based on the comparison of the existing sets of criteria in relatives of ankylosing spondylitis patients and in population control subjects. The modified New York Criteria are similar to the New York Criteria, but the New York pain criterion (which was not specific enough) was replaced by a slightly modified Rome pain criterion [slide 45]. Clinical criteria are: Low back pain and stiffness for more than 3 months which improves with exercise, but is not relieved by rest. Limitation of motion of the lumbar spine in both the sagittal and the frontal planes. Limitation of chest expansion relative to normal values corrected for age and sex.
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A. Diagnosis
1) Clinical criteria a) Low back pain and stiffness for more than 3 months which improves with exercise, but is not relieved by rest b) Limitation of motion of the lumbar spine in both the sagittal and the frontal planes c) Limitation of chest expansion relative to normal value corrected for age and sex 2) Radiological criterion Sacroiliitis grade > 2 bilaterally or sacroiliitis grade 3-4 unilaterally
B. Grading
1) Definite ankylosing spondylitis if the radiological criterion is present with at least one clinical criterion 2) Probable ankylosing spondylitis if: a) Three clinical criteria are present
b) The radiological criterion is present without any signs or symptoms fulfilling the criteria
van der Linden J et al. Arthritis Rheum 1984;27:361-8
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Modified New York criteria for ankylosing spondylitis
The radiological criterion is: sacroiliitis grade 2 bilaterally or sacroiliitis grade 3-4 unilaterally. Ankylosing spondylitis is considered as definite if the radiological criterion is associated with at least one clinical criterion and probable if three clinical criteria are present or if the radiological criterion is present without any signs or symptoms corresponding to the clinical criteria. In 2008, the modified New York criteria are widely used both in clinical practice and in clinical trials to classify ankylosing spondylitis patients. They have shown their superiority over the New York and Rome criteria, which are now used infrequently. The modified New York criteria are also often used as an aid for diagnosis even though they were not designed as such and do not perform well in early disease. A prospective study indicated that the sensitivity of the modified New York criteria increased with disease duration (sensitivity of 0% for a disease duration of two years versus 60.2% for a disease duration of more than 10 years). The delay before detecting radiological sacroiliitis might explain these results. Although the modified New York criteria are sensitive, they are unable to select mild, undifferentiated or early forms of the disease. For these purposes, spondyloarthritis classification criteria can be used, and there is an ongoing study to create diagnostic criteria for early disease.
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III.1.2.2 Diagnostic criteria Despite the fact that there are currently no formal diagnostic criteria for ankylosing spondylitis, three aspects have to be re-emphasized. a) In case of a patient consulting because of axial symptoms, the Berlin and Calin criteria can be used to recognize an inflammatory back pain. b) In such a patient, the use of the modified Amor criteria could be of interest. c) Recently, based on preliminary data, a tree decision format set of diagnostic criteria has been proposed [slide 46].
From Rudwaleit M et al., Ann Rheum Dis 2004;63:535-43
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Diagnostic criteria for ankylosing spondylitis (tree decision)
III.2 Psoriatic arthritis

III.21 Clinical features Moll and Wright defined psoriatic arthritis as an inflammatory arthritis associated with psoriasis, which is usually negative for rheumatoid factor. Psoriasis is a common skin disease among Caucasian (1-3% prevalence), but uncommon in some other ethnic groups, such as Afro-Caribbeans and Native Americans (0-0.3%). It affects men and women equally. Approximately 10% of patients have associated psoriatic arthritis. Psoriasis usually antedates the appearance of arthritis, but the onset is simultaneous in 20% of patients, and in up to 15% the arthritis may precede the onset or diagnosis of psoriasis. The arthritis usually starts between the ages of 30 and 50 years, but can also begin in childhood. In the majority of patients, exacerbations and remissions of skin and joint involvement occur with little or no apparent relationship.
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There is a poly-articular or oligo-articular pattern of joint involvement in 90% of patients. Approximately 5% present with predominant spondylitis. A few patients present with predominant distal inter-phalangeal disease, a mutilating type of disease known as osteomyelitis (SAPHO) syndrome usually called arthritis mutilans. The typical pattern of joint involvement is an asymmetrical distribution with distal inter-phalangeal involvement and dactylitis. Psoriatic arthritis is a chronic erosive disease and treatments resemble those of rheumatoid arthritis.
III.2.2 Clinical features A group of experts under the acronym of CASPAR has recently proposed a set of criteria. Such criteria include the presence of inflammatory articular disease (joint, spine, enthesis) within 3 or more joints and the following: current psoriasis (score 2), personal history or family history of psoriasis (if current psoriasis is absent), current psoriatic nail dystrophy, negative rheumatoid factor, and/or current/history of dactylitis, juxta-articular new bone formation. The criteria were developed in patients attending rheumatology clinics with a sensitivity of 91.4% and a specificity of 98%.
III.3 Entheropathic arthritis

Entheropathic arthritis describes the occurrence of inflammatory arthritis in patients with ulcerative colitis or Crohns disease. The frequency of arthritis in inflammatory bowel disease ranges from 17 to 20%, with a higher prevalence in patients with Crohns disease. The most common manifestation of enteropathic arthritis is inflammation of the peripheral (limb) joints. Axial involvement and enthesitis may also be encountered. The peripheral arthritis is usually transient, migratory and non-deforming. The inflammatory episodes are generally selflimiting, often subsiding within 6 weeks, but recurrences are common. In some cases, the arthritis may become chronic and destructive. Intestinal symptoms usually antedate or coincide with joint manifestations, but arthritis may precede the intestinal symptoms by years.
III.4 Reactive arthritis

Reactive arthritis describes an episode of aseptic peripheral arthritis that occurs within 1 month of a primary infection elsewhere in the body, usually a genito-urinary infection with Chlamydia trachomatis or enteritis due to Gram-negative enterobacteria such as Shigella, Salmonella, Yersinia or Campylobacter species (slide 47)
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Chlamydia trachomatis Shigella flexneri Salmonella spp Yersinia enterolytica Yersinia pseudotuberculosis Campylobacter fetus jejuni Clostridium difficile Intravesical injection of bacilli Calmette-Gurin to treat bladder cancer Chlamydia pneumoniae unconfirmed
Adapted from Smith JA et al. Best Pract Res Clin Rheum 2006;20:571-92
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Bacteria that trigger reactive arthritis
It can also follow local injection of bacille Calmette-Gurin (BCG) into the site of bladder cancer, but not BCG inoculation as used in some countries to decrease the risk of tuberculosis. Genitourinary tract infection with Chlamydia trachomatis is the most commonly recognized initiator of reactive arthritis in developed countries, whereas infections with entero-bacteria are the most common triggers in developing parts of the world. In about 25% of cases, however, the triggering organism is unknown. Reactive arthritis is classified as a spondylarthritides because it is linked to HLA-B27 and shares clinical features with other spondylarthritides. Reactive arthritis is typically an acute, asymmetric oligo-arthritis and is frequently associated with one or more characteristic extra-articular features such as ocular inflammation (conjunctivitis or acute iritis), enthesitis, muscocutaneous lesions, urethritis and, on rare occasions, carditis. Conjunctivitis occurs in one-third of patients with reactive arthritis, usually at the same time as flares of arthritis, and acute anterior uveitis may occur at some time in about 5% of patients. The triad of arthritis, conjunctivitis and urethritis is called classical reactive arthritis; most patients with reactive arthritis do not present with this triad. The average duration of arthritis is 4-5 months, but two-thirds of patients have mild musculoskeletal symptoms that persist for more than 1 year. Recurrent attacks are more common in patients with Chlamydia-induced reactive arthritis. Approximately 15-30% of patients develop chronic or recurrent peripheral arthritis, sacroiliitis or spondylitis. Most patients with reactive arthritis have a positive family history for spondylarthritides or are positive for HLA-B27.
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III.5 Juvenile onset spondylarthritides

Juvenile-onset spondylarthritides usually manifest initially as peripheral arthritis or enthesitis in children aged 8-12 years, but onset at younger or older ages also occurs. There is a striking predominance of males, particularly in the pre-pubertal stage. Juvenile-onset spondylarthritides resemble their adult counterparts, with diverse associations of peripheral arthritis, enthesitis and axial involvement. The disease pattern often changes throughout childhood, adolescence and adulthood (e.g. from mono-arthritis to a more complex form of disease leading to axial, peripheral and extra-articular manifestations). Oligo-arthritis affecting the knee, ankle and/or mid-foot is the typical initial presentation. There are undifferentiated and differentiated forms of juvenile-onset spondylarthritides, which can be classified according to the International Association for Rheumatology criteria in the enthesitis-related-arthritis (ERA) subgroup. The adult ESSG criteria, which have been validated in children, may also be used. Prognosis seems to be less favorable in juvenile-onset spondylarthritides than in adult spondylarthritides. There is the potential for structural damage at some sites (particularly the feet, hips and, sometimes, the spine), leading to functional impairment at long-term follow-up. Nearly 60% of patients have moderate-to-severe limitations 10 years after disease onset. The probability of remission is only 17% after a disease duration of 5 years.
III.6 Undifferentiated spondylarthritides

Undifferentiated spondylarthritides are frequently under-diagnosed and include isolated clinical syndromes, such as HLA-B27-associated sero-negative oligo-arthritis or poly-arthritis, mostly of the lower limbs. This arthritis has no recognizable preceding bacterial infectious trigger, nor associated inflammatory bowel disease or psoriasis. Patients with undifferentiated
spondylarthritides may have dactylitis with a sausage-like appearance to the affected finger or toe. They may also experience enthesitis, especially at the heel. Some patients may present with an episode of acute anterior uveitis (acute iritis) or have a syndrome of aortic insufficiency plus heart block. The cardiac syndrome or the acute iritis may occur in patients who never develop signs of arthritis, and may sometimes accompany or precede the onset of spondylarthritides.
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IV.
PATHOGENESIS
For several decades, it has been recognized that several factors could interfere with the occurrence or the severity of the disease (e.g. genetic factors, environmental factors and, in particular, infection and immunological disorders). The still remaining question is how to make the link between these 2 or 3 different factors.
IV.1 Genetic aspects of spondylarthritides

The involvement of genetic factors in spondyloarthropathy susceptibility has long been suspected due to frequent familial clustering of cases. The first identified genetic factor was the tissue antigen HLA-B27. Nevertheless, further genetic epidemiological studies have suggested the existence of other predisposing genes. Recent progresses on genome sequencing will enable scientist to identify them.
IV.1.1 The first genetic factor identified: the tissue antigen HLA-B27 The hypothesis of genetic susceptibility factors involved in ankylosing spondylitis was first developed during the years 1950-1960 based on familial aggregation of cases. In 1973, Brewerton and Schlosstein both reported the association of HLA-B27 with ankylosing spondylitis: Schlosstein, from the University of California, observed B27 among 88% of ankylosing spondylitis patients compared with only 6% among healthy controls. At the same time, Brewerton from the London Westminster Hospital reported similar results, i.e., an association of B27 with ankylosing spondylitis in 95% of patients. Further investigations in the 1990s on B27-transgenic rat have confirmed the direct involvement of B27 in the disease susceptibility. Nevertheless, the precise role of B27 in the pathophysiology of the disease remains unknown. Several lines of evidence recently suggest that HLA-B27 may not behave like other class I molecules: HLA-B27 heavy chains can form homo-dimers that do not contain the 2-microglobulin light chain (a phenomenon also called HLA-B27 misfolding). Such homodimers could mediate or be the target for a pro-inflammatory response. These hypotheses are under investigation.
IV1.2 Family studies Family studies have clearly shown that the risk of developing ankylosing spondylitis in patients relatives was 20 to 40 higher than in the normal population. The observation of B27 cosegregation with the disease among the affected members of such multiplex families yielded arguments in favour of a direct involvement of this gene in disease susceptibility.
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Nevertheless, Calin and van der Linden demonstrated that B27 did not account for the whole susceptibility to the disease, suggesting that other familial factors, presumably additional genetic factors, were also involved. Indeed, the risk of developing ankylosing spondylitis in a Dutch study published in 1984 was 20 fold higher among first degree relatives B27 positive of an affected subject (21%) than among B27-carriers from the general population (1.3%).
IV1.3 Twin studies The difference of concordance between monozygotic (MZ) and dizygotic (DZ) twins has confirmed the great importance of genetic factors in disease susceptibility. Moreover, such studies have provided evidence that some genetic factors were not linked to the MHC. As monozygotic twins inherit identical genetic material, the concordance rate (i.e., the ratio between the number of pairs with both affected twins and the total number of pairs) should be 100%, if the disease determinants were purely genetic [Slide 48]. This is not the case for ankylosing spondylitis, as expected for a complex disease in which environmental and genetic factors are involved. In fact, twin studies have reported a MZ concordance rate around 70%, suggesting the involvement of environmental factors in 30% of the disease susceptibility. Interestingly, the whole genetic susceptibility was not explained by B27, as the concordance rate between dizygotic twins B27-positives (around 25%) was not equal to the concordance rate of B27positive monozygotic twins.
MZ
Concordance
E
Discordance
DZ
Concordance
Discordance
Concordance and discordance in monozygotic (MZ) and dizygotic twins (DZ). A pair is concordant if both twins are affected; a pair is discordant if only one twin is affected. Discordance between monozygotic twins is related to environmental factors (E); Discordance between dizygotic twins is of genetic origin (G).
Adapted from Miceli C et al. Fast Facts, Ankylosing Spondylitis 2004
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IV1.4 Methodology of the genetic studies The genetic dissection of complex, multifactorial diseases such as spondylarthritides is difficult: the model underlying the inheritance of the disease is unknown, several genes are likely to be involved and may be different from patient to patient (genetic heterogeneity). Moreover, the molecular variants of a gene (alleles) associated with the disease susceptibility may be present in healthy subjects suggesting that the exposure to specific environmental factors is probably required to develop the disease (incomplete penetrance). In order to identify susceptibility genes for spondylarthritides, two main strategies have been developed: the candidate gene and the genome scanning approaches.
IV.1.4.1 Candidate gene approach Proceeding that way, one hypothesizes that a gene is a good candidate related to its potential involvement in the physiopathology of the disease (e.g., cytokines, genes involved in apoptosis). Polymorphisms (molecular differences) of that gene are then studied. Some gene polymorphisms are unlikely to have a functional effect (for example, when they lead to a conservative amino-acid substitution). Others, affecting regulatory regions of the gene or leading to a truncation of the related protein (as it has been demonstrated for CARD15, a gene associated to Crohns disease susceptibility), are more likely to have a functional repercussion by affecting the structure or the regulation of the gene expression. The candidate gene approach is often based on case-control studies that compare the frequency of different alleles of a gene between a set a patients and a set of healthy controls [slide 49]. If the difference between groups is statistically significant, this allele is said to be associated with the disease. The control group needs to be carefully chosen in order to avoid frequency differences not related to disease: for example, patients and controls have to be ethnically matched. In order to overcome this bias, statistical tests have been developed as the transmission disequilibrium test (TDT) as proposed by Spielman that analyses the intra-familial transmission of alleles, but requires the genotyping of the patients parents [slide 50]. To date, numerous genes have been investigated through candidate gene approaches [slide 51]. Most of the relevant studies have produced negative results. Others have demonstrated a weak association with AS. Nevertheless, none, except HLA-B27, seems to significantly contribute to the disease susceptibility.
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Patients
Healthy controls
Association studies. The polymorphic marker tested is bi-allelic (or ). The alleles are not equally distributed among patients and healthy controls. The disease is associated with the allele .
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Genetic aspects: association studies
Transmitted Not transmitted
1 3
3 1
Transmission disequilibrium test. The number of alleles transmitted and not transmitted to the affected children by their heterozygous parents is calculated for each allele within a family set.
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Genetic aspects: transmission disequilibrium test
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Androgen receptor ANKH (Homo sapiens homolog of murine progressive ankylosis) CARD15/NOD2 (apoptosis regulator) CYPD6 (debrisoquine hydroxylase) HLA-B27 (human leukocyte antigen B27) HLA-B60 (human leukocyte antigen B60) HLA-DRB1 (human leukocyte antigen DRB1) HSP70 (heat shock protein, 70 kD) IL-1RA (interleukin-1RA) IL-10 (interleukin-10) LMP2 (proteasome subunit) LMP7 (proteasome subunit) MICA (major histocompatibility complex class I related-polypeptide sequence A) TAP (transporter associated with antigen processing) T-cell receptor TNF (tumor necrosis factor )
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Genes investigated by case-control or intra-familial association studies in SpA
IV.1.4.2 Genome-wide scanning approach The aim of genome-wide studies is to localize one or more region(s) containing a susceptibility gene on the genome. These approaches are based on either linkage studies performed in multiplex families (with multiple affected members) or association studies comparing patients and controls (case-control studies). The software used in such studies estimates the resemblance between affected members within a family for a panel of highly polymorphic markers (usually 300 to 400) called micro-satellites, evenly distributed throughout the genome. Susceptibility loci are defined by regions more often shared by affected individuals than expected according to Mendels law. The regions evidenced that way are broad and need further refinement using denser sets of markers centred on the regions of interest (called fine mapping). To date, in ankylosing spondylitis, three genome-wide scans have been published. Several regions of interest have been found on chromosome 1, 2, 6 (the MHC region), 9, 10, 16 and 19 [slide 52]. The strongest linkage observed outside the MHC was on chromosome 16q (q represents the long arm of a chromosome). Other genome-wide screens are underway in multiplex families collected in France, North America and Canada. The results from these different linkage studies will provide information to identify susceptibility loci for
spondylarthritides. The case-control genome screening requires a high technology (evaluation of thousands of genes).
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A recent publication (ref. 11) suggests that two genes might be important to consider: ART S1 which might be implicated in the peptide presentation and IL23R (receptor of the interleukin 23) which has probably a role in inflammation. Such association (IL23R and diseases) has also been observed in psoriasis and Crohns disease, data re-emphasizing the interest of the concept of spondyloarthritis.
G F E G S 2 0 0 4
1 2 3 4 5 6 7 8 9 10 11 12
O x f o r d 1 9 9 8 & 2 0 0 1
N A S C
13 14 15 16 17 18 19 20 21 22 Y X
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IV.2 Infections
The spondylarthritides-like disease seen in B27-Tg rats develops when animals are housed in a probiotic environment present in most conventional animal facilities [slide 53, 54], even when the environment is free of specific pathogens. In contrast, when raised under entirely germ-free conditions, B27-Tg rats do not develop disease. Interestingly, colonization of the gastrointestinal tract with normal gut flora , in particular Bacterodes spp., is sufficient to trigger the development of inflammation. The colitis that develops is particularly associated with increased expression of interferon- (IFN-), but also increased amounts of IL-1, IL-2, MIP2, and IL-6. Another study found increased pro-inflammatory (TNF-, IL-I, IL-8) and Th1 (IL-2, IL-12, IFN-) cytokines, with weak expression of the Th2 cytokine, TGF-. The cellular source(s) for these cytokines, and in particular those considered to be Th1, has not been established. However, it is worth noting that mesenteric lymph node (MLN) T-cells from B27-Tg rats with disease produce more IFN- in response to unfractionated MLN cells stimulated with caecal bacterial lysates than MLN T-cells from healthy non-Tg rats. It is expected that the majority of the IFN- is released from Tcells, however, other sources have not been ruled out, and further studies on the inflammatory cytokine response using cells from pre-morbid animals are needed. Several gastrointestinal or genito-urinary pathogens have been strongly implicated as triggers of HLA-B27 associated reactive arthritis in humans, including Compylobacter spp., Chlamydia spp., Salmonella spp. and Shigella spp. [slide 47].
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DNA from these organisms has been found by polymerase chain reaction in synovial cell and fluid samples; and salmonella, yersinia and shigella lipopolysaccharide have also been found in the joints of patients with reactive arthritis. The presence of bacterial products in the joints provides a potential link between gut infection and joint inflammation. However, despite being strongly implicated in reactive arthritis, the requirement for gut pathogens and gut inflammation in AS is less clear.
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B27 transgenic mice
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B27 transgenic mice
IV.3 Inflammation
The most common sites of inflammation in AS include sacroiliac joints, entheses, vertebral bodies adjacent to inter-vertebral discs, peripheral joint synovium, gastrointestinal tract and the eye. Many of these lesions are poorly accessible, thus, information on histopathology is limited. In early sacroiliitis, there is synovitis with myxoid-appearing bone marrow, and subsequent formation of pannus and granulation tissue.
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T-cells (CD4 > CD8) and CD68+ macrophages are accompanied by proliferating fibroblasts and neovascularization, and there is over-expression of TNF- and TGF- mRNA. Destroyed bone is eventually replaced, and endochondral ossification results in bony ankylosis. There is considerably more information about peripheral synovitis, although these studies are not restricted to patients with AS. The synovitis of SpA displays features of other types of inflammatory arthritis, such as increased vascularity and endothelial cell activation, with increased expression of adhesion molecules and chemotactic factors. Infiltrating cells include activated T lymphocytes, wit CD4+ T cells often predominating over CD8+ T cells, natural killer (NK) cells, B lymphocytes and CD68+ macrophages. Relevant differences include a tendency towards greater vascularity, greater CD4+ T cell and CD20+ B-cell infiltration, and few lymphoid aggregates. While total numbers of CD68+ macrophages appear to be similar or slightly lower in spondylarthritides, macrophages expressing CD163 are reportedly increased, while total numbers of CD68+ macrophages appear to be similar or slightly lower in spondylarthritides. CD163 is the hemoglobin scavenger receptor and may define a population that produces more pro-inflammatory tumor necrosis factor- (TNF)- and less interleukin (IL)-10, which could promote a Th1 response. They can also release soluble CD163 that may inhibit T-cell proliferation and activation. Lower expression of the MARCO scavenger receptor on synovial macrophages from SpA patients has also been reported. Enthesitis, a hallmark of spondylarthritides includes hyper-osteoclastic, inflammatory, erosive lesions along with infiltration of the underlying bone marrow. There are abundant lymphocytes including CD8+ and CD4+ T cells in lesions from patients with established disease, while early enthesitis (1 month-1 year of disease) reveals a predominance of CD68+ macrophages. These studies provide evidence for elements of both innate and adaptive immune responses in inflammatory lesions from patients with spondylarthritides. Although there are differences between the spondylarthritides and other inflammatory arthritides, there are perhaps more similarities. Macrophages appear to play an important role in early disease, but it is also clear that T-cells are involved. The observation that TNF- is over-expressed in sacroiliac joints provided a strong rationale for the use of TNF inhibitors, which has led to impressive improvements in the outlook for individuals of upstream pathogenic mechanisms, and important questions such as the specificity of inflammation and bone formation for the axial skeleton remain unanswered.
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V.
ASSESSMENT/MONITORING
There is frequently confusion between these two concepts (e.g. assessment/monitoring). For this section of this course, we will define assessment by the tools enabling to characterize a patient at a single point of time, we will define monitoring by the tools enabling to evaluate the changes in a patient over time. However, it is also obvious that frequently the tools permitting to assess a patient are similar to the ones permitting to monitor a patient. Moreover, for both concepts, one has to consider systematically the 4 different potential clinical presentations: axial involvement, peripheral arthritis, enthesiopathy and extra-articular features.
V.1 Assessment
The characterization of a patient necessitates to answer systematically the following 5 questions: Is the patient really suffering from the disease? Is the disease severe? Is the disease potentially severe? Is the disease refractory?
V.1.1 Disease yes/no? This concept (diagnostic/classification) has been previously discussed. Here it is important to emphasize the fact that at the individual level, such question might be difficult to answer. In other words, any set of criteria has never a 100% sensitivity and specificity performance. In daily practice, the difficult situation is the one of a patient with a very painful condition (active disease) refractory to different drugs and previously considered by other colleagues as suffering from spondylarthritides based on subjective symptoms (e.g. heel pain, inflammatory back pain, anterior chest pains, ) without objective symptoms. Before considering a potentially toxic, expensive and inadequate treatment such as anti-TNF agents, it is strongly recommended to repeat these investigations, such as plain X-rays and/or MRI, in order to objectively confirm the disease.
V.1.2 Active disease yes/no? The activity of the disease is referring to the concept of inflammation. An international society (ASAS: ASsessment of Ankylosing Spondylitis) has provided recommendations concerning the different instruments/tools to use in order to optimally evaluate specific domains (e.g. pain, function, ) [slide 55].
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Domain
Physical function Pain Spinal mobility
Instrument
BASFI or Dougados Functional Index VAS/NRS last week in spine, at night, due to ankylosing spondylitis and VAS/NRS last week, in spine due to ankylosing spondylitis Chest expansion and modified Schober and occiput-to-wall distance and lateral spinal flexion VAS/NRS last week Duration of morning stiffness in spine last week VAS/NRS last week Number of swollen joints (44 joint count) Validated enthesis indexes ESR Antero-posterior + lateral lumbar and latero cervical spine and X-ray pelvis to visualize sacroiliac joint and hips) As above
Patient global assessment Morning stiffness Fatigue Peripheral joints and entheses Acute phase reactants Spine radiographs
Hip radiographs
BASFI, Bath Ankylosing Spondylitis Functional Index; BASMI, Bath Ankylosing Spondylitis Metrology Index; CRP, C-reactive Protein; DCART, disease-controlling anti-rheumatid therapy; ESR, erythrocyte sedimentation rate; NRS, numerical rating scale; SMARD, symptom modifying anti-rheumatic drugs; VAS, visual analog scale. Included in core set to DCART, SMARD/physical tehrapy and clinical record keeping. Included in core set to DCART and clinical record keeping. Included in core set for DCART.
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ASAS recommendations (from van der Heijde D et al., 1999)
V.1.2.1 Specific clinical presentation The tools facilitating activity evaluation are summarized in slide 56.
Axial involvement
Night pain Morning stiffness CRP
Peripheral arthritis
Night pain Morning stiffness Swollen joint count CRP
Enthesiopathy
Pain Functional impairment
Extra-articular features
Acute anterior uveitis
Pain Functional impairment
Pain Tender joint count Functional impairment
Enthesiopathy index
Psoriasis IBD
MRI
US MRI
US MRI Bone Scan
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V.1.2.1.1 Axial involvement Both the level of night pain and clinical pain are important to consider using either a Visual Analogue Scale or a Numerical Analog Scale. Morning stiffness is evaluated by considering both its duration and its intensity.
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Functional impairment is evaluated in clinical trials by using the BASFI [slide 57]. All the tools are Patient Reported and could be considered as subjective. Usually, a value over 40 on a scale from 0 to 100 is considered as reflecting an active disease. The main question in daily practice is, whether it is mandatory to employ objective methods such activity before considering a new therapy such as anti-TNF. Two non-subjective instruments allow the evaluation of activity: Serum level of C reactive protein keeping in mind that an increase in CRP is only observed in 40% of patients considered as suffering from an active disease. Presence of inflammation in MRI either at the sacro-iliac of vertebral level.
Bath Ankylosing Spondylitis Functional Index (BASFI)

1. 2. 3. 4. 5. 6. 7. 8. 9. Putting on your socks or tights without help or aid (e.g. sock aids): Bending forward from the waist to pick up a pen from the floor without an aid: Reaching up to a high shelf without help or aids (e.g. helping hand): Getting up out of an armless dining room chair without using your hands or any other help: Getting up off the floor without help from lying on your back: Standing unsupported for 10 minutes without discomfort: Climbing 12-15 steps without using a handtail or walking aid (one foot each step): Looking over your shoulder without turning your body:
Doing physically demanding activities (e.g. physiotherapy exercises, gardening or sports): 10. Doing a full days activities whether it be at home or at work:
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Evaluation of functional impairment [BASFI]
V.1.2.1.2 Peripheral arthritis Evaluation of activity is not different from that in peripheral arthritis or rheumatoid arthritis e.g. number of tender joints, number of swollen joints, CRP, ). There is no consensual definition of a peripheral active disease. However, the presence of at least 3 swollen joints is usually considered to reflect active disease, in particular when associated with an increased CRP.
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V.1.2.1.3 Enthesiopathy The evaluation of the activity of enthesiopathy is not standardized. However, by analogy with other rheumatic disorders, such evaluation requires the collection of information related to the level of pain and functional disability (such tools are different in regard to the localization of the enthesiopathy. For example, functional impairment of heel enthesitis can be adequately evaluated by using the WOMAC-function sub-scale. As with axial involvement, the remaining question in a specific situation in daily practice is whether an objective demonstration of such activity is required before considering a specific treatment such as anti-TNF. For this objective demonstration, both MRI and ultrasonography with a power Doppler evaluation can be of interest.
V.2.1.1.4 Extra-articular features It is beyond the scope of this chapter to detail the different tools permitting to evaluate the activity of all the extra-articular features of spondylarthritides. However, from a rheumatological point of view, it is of interest that some therapies such as sulfasalazine, anti-TNF may be considered in cases of active anterior uveitis defined by the number of attacks per year (usually at least 3).
V.1.2.2 General evaluation Besides the different instruments facilitating activity assessment of the different clinical presentations, a single instrument (e.g. a composite index) has been proposed to permit a general evaluation. Such an instrument (BASDAI, [slide 58]) is simple to use since it contains only 6 questions: The last 2 questions are related to morning stiffness The first one to fatigue The second one to axial involvement The third one to peripheral articular involvement And the fourth one to enthesiopathy.
Using a scale of 0 to 100, a composite score above 40 is considered as the threshold above which a disease can be considered as active.
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Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)

1. How would you describe the overall level of fatigue/tiredness you have experienced? 2. How would you describe the overall level of AS neck, back or hip pain you have had? 3. How would you describe the overall level of pain/swelling in joints other than neck, back or hips you had? 4. How would you describe the overall level of discomfort you have had from any areas tender to touch or pressure? 5. How would you describe the overall level of morning stiffness you have had from the time you wake up? 6. How long does your morning stiffness last from the time you wake up?
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Evaluation of the disease activity[BASDAI]
V.1.3 Severe disease yes/no? The severity of the disease is referring to the concept of irreversible structural damage. Such severity can be defined using different approaches. For clinical studies, the following definition have been proposed: death, job loss, functional impairment, range of motion, hip involvement, radiological score. Here, we will focus on the last 4 proposals.
V.1.3.1 Functional impairment Functional impairment can be related to both the activity and the severity of the disease. The available instruments (BASFI, HAQ, WOMAC, ) can be used depending of the clinical presentation of spondylarthritides. A value of at least 30 on a 0-100 scale is usually considered as reflecting a severe disease.
V.1.3.2 Range of motion These domains can be evaluated differently in clinical research studies and in clinical practice.
V.1.3.3 Evaluation of range of motion in clinical trials The most frequently used instrument in clinical trials is currently a composite index combining the information from 5 different tools: cervical rotation [slide59], tragus to wall distance [slide 60), spinal lateral flexion [slide 61], lumbar flexion (modified Schober test) [slide62], intermalleolar distance [slide 63]. This composite index termed BASMI is detailed in [slide 64].
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Spinal mobility: cervical rotation
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Spinal mobility: tragus to wall distance
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Spinal mobility: spinal lateral flexion
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Spinal mobility: lumbar flexion [modified Schobers test]
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Spinal mobility: inter-malleolar distance
Bath Ankylosing Spondylitis Mobility Index (BASMI)

Score Variable Cervical rotation (*) Tragus to wall distance (cm) Spinal lateral flexion Lumbar flexion Inter-malleolar distance 0 >70 <15 >10 >4 >120 1 20-70 15-30 5-10 2-4 70-100 2 <20 30 <5 <2 <70
Jenkinson JR et al. J Rheumatol 1994;21:1964-98
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Evaluation of spinal mobility [BASMI]
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V.1.3.4 Evaluation of range of motion in daily practice In order to understand the usefulness of the physical examination, the natural history of the disease has to be kept in mind [slide 15]. Moreover, the different instruments have to be split into 2 categories: The ones evaluating the loss of motion (stiffness) such as lumbar flexion, chest expansion; The ones evaluating the abnormal postures such as the L3 wall distance or the tragus to wall distance. Apart from the decrease in chest expansion, it is evident that abnormal postures have to be carefully checked in order to optimally adapt the physical therapy. Once the loss of lumbar lordosis [slide 15] appears to be the first abnormal posture to occur, the loss of lumbar lordosis has appeared, a thoracic kyphosis and a fixed flexed posture of the cervical spine are the next risks of such abnormal postures. The most disabling abnormal posture is the loss of the horizontal view, for which a surgical spinal intervention (vertebral osteotomy) can be considered.
V.1.3.5 Hip involvement Coxitis is closely related to the severity of spinal ossification and by itself responsible for functional impairment. The frequency after 10 years of disease duration is around 10 to 15% in Western European countries, but up to 40 to 50% in other parts of the world such as North Africa.
V.1.3.6 Spinal radiographic severity scoring system Such a system has been proposed using a 1-5 Likert scale [slide 65]. This scoring system is rarely used, but may be of interest when conducting clinical studies.
V1.4 Potential severe disease yes/no? This information is and will be more and more important in the future, since as in rheumatoid arthritis, there is a trend to treat the patients with efficiently as early as possible and, preferably, before irreversible structural damage has occurred. Several studies including cohorts of early inflammatory back pain are currently addressing this issue. At present, a scoring system based on a retrospective study is available [slide 66]. The negative predictive value is of highest value than the positive predictive value. In other words, the absence of any of the parameters listed in the [slide 66] is highly predictive of a good prognosis.
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Staging severity scoring system* Radiographic grading

Stage I: Stage II: Grade II or higher bilateral radiographic sacroiliitis Minor radiographic evidence of spinal involvement in <1 spinal segment (<3 vertebrae which equals <15% of the spine) Moderate radiographic evidence involvement in <2 spinal segments which equals15-<50% of the spine) Radiographic evidence of >2 spinal segments (13-19 50-<80% of the spine) of (4-12 spinal vertebrae
Stage III:
Stage IV:
spinal involvement in vertebrae which equals
Stage V:
Widespread (>80%) fusion of the spine (>20 vertebrae)

*Braun J et al. Ann Rheum Dis 2002;61suppl3:9-23
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Spinal radiographic severity in AS
Presence of the following parameters during the first 2 years*: Hip involvement ESR > 30 mm 1st H Refractory to NSAIDs Reduction in lumbar spine motion Dactylitis Mono/oligo arthritis Age at onset < 16 years Diarrhea Urethritis Psoriasis IBD
*Amor B et al. J Rheumatol 1994;21:1883-7
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Criteria for potential severe disease
V.1.5 Refractory disease yes/no? This question is of great importance, when considering the potential indication of therapies such as anti-TNF. Therefore, the most frequent situation is when defining a patient as refractory to NSAIDs. Because of the individual variability in the response to NSAIDs, the current recommendation is to define a patient as refractory to NSAIDs only in case of persistence of an active disease despite the intake of at least 2 courses of NSAIDs taken at an optimal dosage during at least 2 to 3 weeks.
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V.2 Monitoring
Two main domains have to be monitored both in daily practice and in clinical trials: activity and severity.
V.2.1 Monitoring of the activity of the disease The tools described in section V.1.2 are obviously used for such monitoring A change of at least 50% in the BASDAI score is usually considered as reflecting a clinically relevant improvement. The international society (ASAS) has proposed 2 composite indices in order to monitor the activity of the disease in clinical trials: o o One set of responder criteria (ASAS20 [slide 67]); One set of remission criteria [slide 68].
Such sets of criteria have been developed via databases evaluating symptomatic drugs (e.g. NSAIDs); recently, ASAS has proposed a new set of criteria for evaluating potential disease modifying drugs including 2 other domains (spinal mobility and biological inflammation [slide 69]).
V.2.2 Monitoring of the severity of the disease Actually, the main parameter is the radiological evaluation of the spine. For this purpose, several scoring systems not evaluating the destructive process, but the constructive one (syndesmophyte count) have been proposed. The mSASSS [slide 70] is most frequently used in clinical trials.
ASAS Response Criteria

Improvement of at least 20% and absolute improvement of at least 10 on a 0-100 scale in at least 3 of the following domains*: patient global pain function inflammation Absence of deterioration (of at least 20% and absolute deterioration of at least 10 or a 0-100 scale) in the potential remaining domain.
*Definition of the domain: Patient global = Pain = Function = Inflammation = VAS (0-100) VAS global, last 2 days (0-100) BASFI (0-100) 1st choice: 2nd choice: 2 last questions of the BASDAI morning stiffness duration with a maximum of 120 mm or a 0-100 scale Anderson J et al. Arthritis Rheum 2001;44:1876-86
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ASAS20 responder criteria set
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ASAS Remission Criteria

A value below 20 on a 0-100 scale in each of the 4 domains*:
patient global pain function inflammation * Definition of the domain
Patient global: Pain: Inflammation: VAS (0-100) VAS global, last 2 days (0-100) 1st choice: 2nd choice: 2 last questions of the BASDAI morning stiffness duration with a maximum of 120 mm or a 0-100 scale
Function: BASFI (0-100)
Anderson J et al. Arthritis Rheum 2001;44:1876-86
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ASAS remission criteria set
ASAS DMARD - Responder criteria

Improvement of at least 20% and absolute improvement of at least 10 on a 0-100 scale in at least 4 (or 5) of the following domains: Patient global Pain Function Morning stiffness Spinal mobility CRP
*Braun J et al. Ann Rheum Dis 2004;63:1438-44
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ASAS DMARD responder criteria set
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Radiological evaluation of AS Modified Stoke Ankylosing Spondylitis Spine Score (M SASSS) M SASSS
Anterior site of the vertebra C2 to T1, T12 to S1 Score = 0 = normal
1 = erosion, sclerosis 2 = syndesmophyte 3 = bridging syndesmophytes
Range 0 - 72
Wanders A et al. Arthritis Rheum 2004;50:2612-32 Wanders A et al. Ann Rheum Dis 2004;63:1601-4
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Radiological spinal scoring system in AS [mSASSS]
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Summary
Spondylarthritides are a heterogeneous family of disorders characterized by the association of: axial inflammatory pain and sometimes ankylosis; variable inflammatory peripheral arthritis, predominantly asymmetrical and affecting the lower limbs; enthesitis (e.g. heel pain). They may be associated with extra-articular features such as chronic inflammatory bowel disease, psoriasis, urethritis and a tendency to anterior ocular inflammation. Individuals with the HLA-B27 tissue antigen have an increased risk of developing ankylosing spondylitis. Genetic epidemiological studies suggest the existence of other predisposing genes, such as the IL23R Genome scanning studies reveal that the strongest linkage, other than the MHC region, is to be found on chromosome 16q. The prevalence of ankylosing spondylitis is 0.1-1.4% in Caucasians and 0.04-6% in non-Caucasian populations. The rate of withdrawal from the labor force is three times higher in patients with ankylosing spondylitis than in the general population. Ankylosing spondylitis is 2-3 times more common in men than women. The initial symptom of ankylosing spondylitis is typically a dull inflammatory lower back pain of insidious onset, becoming persistent after a few months. The radiographic hallmarks of ankylosing spondylitis are signs of sacroiliitis starting with blooming of the cortical margins of the subchondral bone, erosions and sclerosis. Arthritis of the peripheral joints is mostly oligo-articular, asymmetrical, transient and migratory, with involvement of both small and large joints, predominantly of the lower limbs. Painful inflammation of entheses, the sites of bony insertions of ligaments and tendons, is a classic feature of ankylosing spondylitis. Acute anterior uveitis is the most common extra-articular manifestation, with 25-40% of patients experiencing one or more episodes. The most serious complication of ankylosing spondylitis is functional impairment due to abnormal posture. The ASsessment in Ankylosing Spondylitis (ASAS) working group has proposed several core sets of overlapping domains to facilitate evaluation of therapy and enhance record keeping. The domains of pain, patient global assessment of disease activity, morning stiffness, fatigue, spinal mobility and physical function are included in all the core sets. Apart from the genetic factors, environmental factors and, in particular, infections can interfere with the occurrence or the severity of the disease.
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REFERENCES
1. van der Linden S, Pascual E. Spondylarthropathies. Best Pract Clin Res Clin Rheum 2002;6(4):495-705. 2. Braun J, van der Heijde D. Spondylarthropathies. Best Pract Clin Res Clin Rheum 2006;20(3):399-620. 3. Dougados M, van der Linden S, Juhlin R, Huitfeldt B, Amor B, Calin A, Cats A et al. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 1991;34:1218-27. 4. Amor B, Dougados M, Mijiyawa M. Critres de classification des spondylarthropathies. Rev Rhum Mal Osteoartic 1990;57:85-9. 5. Rudwaleit M, Metter A, Listing J, Sieper J, Braun J. Inflammatory back pain in ankylosing spondylitis: a reassessment of the clinical history for application as classification and diagnostic criteria. Arthritis Rheum 2006;54:569-78. 6. Rudwaleit M, van der Heijde D, Khan MA, Braun J, Sieper J. How to diagnose axial spondyloarthritis early. Ann Rheum Dis 2004;63:535-43. 7. Dougados M, van der Heijde D. Ankylosing spondylitis. Fast Facts, Health Press, Oxford, 2004 84 pages. 8. Anderson JJ, Baron G, van der Heijde D, Felson DT, Dougados M. Ankylosing spondylitis assessment group preliminary definition of short-term improvement in ankylosing spondylitis. Arthritis Rheum 2001;44:1876-86. 9. van der Heijde D, Bellamy N, Calin A, Dougados M, Khan A, van der Linden S, on behalf the ASAS working group. Preliminary core sets for efficacy endpoints in ankylosing spondylitis. Br J Rheumatol 1997;24:2225-9. 10. Wanders AJ, Landew RB, Spoorenberg A, Dougados M, van der Linden S, Mielants H, van der Tempel H, van der Heijde DM. What is the most appropriate radiologic scoring method for ankylosing spondylitis? A comparison of the available methods based on the Outcome Measures in Rheumatology Clinical Trial filter. Arthritis Rheum 2004;50:2622-32. 11. Wellcome Trust Case Control Consortium; Australo-Anglo-American Spondylitis Consortium TASC), et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 2007;39:1329-37. 12. Sidiropoulos PI, Hatemi G, Song IH, Avouac J, Collantes E, Hamuryudan V, Herold M et al. Evidence-based recommendations for the management of ankylosing spondylitis: systematic literature search of the 3E Initiative in Rheumatology involving a broad panel of experts and practicing rheumatologists. Rheumatology (Oxford) 2008;47:355-61. 13. Combe B, Landew R, Lukas C, Bolosiu HD, Breedveld F, Dougados M, Emery P et al. EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2007;66:34-45.
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Eular On-line Course on Rheumatic Diseases module n7 Maxime Dougados, Robert Landew

SPONDYLARTHRITIDES: PATHOGENESIS, CLINICAL ASPECTS AND DIAGNOSIS

THE CONCEPT OF SPONDYLARTHRITIDES I.1 Definition

Spondylarthropathy Disease subgroups Clinical features

Clinical presentation of spondylarthropathy

Parameter A. Clinical symptoms or past history of

Sacroiliitis (bilateral grade 2 or unilateral grade 3) ..

Amor B. Rev Rhum Mal Osteoart 1990;57:85-9

AMOR spondylarthropathy classification criteria

ESSG spondylarthropathy classification criteria

I.3 Classification/Diagnostic criteria

THE CLINICAL FEATURES OF SPONDYLARTHRITIDES II.1 Rheumatological manifestations

Inflammatory back pain

Calin inflammatory back pain criteria

Inflammatory back pain

Berlin inflammatory back pain criteria

Clinical spinal ankylosis

Radiological thoracic spinal ankylosis

Radiological lumbar spinal ankylosis (left)

Radiological cervical spinal ankylosis

Radiological vertebral squarring

Radiological vertebral squarring

Radiological syndesmophytes (left)

Radiological bamboo column (left)

Natural history of spinal abnormal attitudes

Vertebral fracture in ankylosing spondylitis

Vertebral fracture in ankylosing spondylitis

Radiological sacroiliitis in ankylosing spondylitis

Radiological sacroiliitis in ankylosing spondylitis

Radiological sacroiliitis in ankylosing spondylitis

Radiological sacroiliitis in ankylosing spondylitis

Radiological sacroiliitis in ankylosing spondylitis

Fusion of the sacroiliac joints

Sacroiliitis [MRI findings]

Sacroiliitis [MRI findings]

* Courtesy of V Weber, Zurich

Sacroiliitis (whole body MRI findings) *

Sacroiliitis [CT scan findings]

Sacroiliitis [CT scan findings]

Sacroiliitis [CT scan findings]

Sacroiliitis [bone scintigraphy findings]

Saussage like digit [dactylitis]

Saussage like digit [dactylitis]

Heel enthesitis [MRI findings]

Heel enthesitis [MRI findings]

Heel enthesitis [X-rays]

Heel enthesitis [ossification]

Heel enthesitis [bone scintigraphy findings]

II.2 Extra-articular features

Acute Anterior Uveitis

Synechia occurring after acute anterio uveitis

Nail lesion of psoriasis

Nail lesion of psoriasis

II.3 Genetic background

II.4 Other biological markers

THE DIFFERENT DISEASES BELONGING TO THE CONCEPT OF SPONDYLARTHRITIDES

Juvenile onset spondylarthropathy

+ +++ +++ +++

Frequency of clinical features/disease in SpA

III.1 Ankylosing spondylitis

van der Linden J et al. Arthritis Rheum 1984;27:361-8

Modified New York criteria for ankylosing spondylitis