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Eular On-line Course on Rheumatic Diseases module n7Maxime Dougados, Robert Landew

eular

SpondylarthropathyDisease subgroups Clinical features

Ankylo sin g s pon dyl it isPsoriatic arthritisReactive arthr itisIBD related arthrit isUndifferentiated spondylarthropathy

Rheumatologi cal manifestations Axial inv olv ementPeripehral arthriti sEnthesiopathy

Extra-articular features Acute an ter ior uveit isEndocarditis

Genetic backgro undFamily historyHLA-B27 antigen

Specific manifestationsPsoriasisInflammatory bowel diseaseEtc.

Clinical presentation of spondylarthropathy

adapted from M. Dougados et al . Best Pract Res Clin Rheum 2002;16:495-505

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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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eular AMOR spondyl art hropathy classifi cat ion crit eri a Amor B. Rev Rhum Mal Osteoart 1990;57:85-9

Parameter Scoring

A. Clini cal s ymptoms or p ast history of

1. Lumbar or dorsal pain at night or morning stiffness of lumbar or dorsal area 2. Asym metr ical oli goar thr iti s 3. Buttock pain (if alternate buttock pain) ..4. Dactylitis .5. Heel pain or other well defined enthesiopathy ..6. Acut e anter ior uveit is 7. Non-gonococcal urethritis or cervicitis wit hin one month before the onset of arthritis 8. Acut e diar rhea with in one m onth bef ore the onset of ar thr iti s .9. Psoriasis, balanitis, or inflammatory bowel disease

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1 (2)2

22111

B. Radiological find ings

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

C. Genetic backgrou nd

11. Presence of B27 HLA antigen and/or family his tory of ankylosing spondyliitis , reactive arthritis,uveitis, psoriasis or IBD . 2

D. Response to treatment

12. Clearcut improvement within 48 hours after NSAID intake or rapid relapse of pain after theirdiscontinuation . 2

2

eular

The European Spondyl arthropathy Study Group (ESSG) crit eria for spondyl arthropath yInflammatory spinal pain

or Synovitisasymmetrical or predominantly in the low er limbs

andOne or more of the follow ing

Family history first or second-degree relative with ankylosing spondylitis, psoriasis, acute iritis, reactivearthritis or inflammatory bowxel disease

Past or present ulcerative colitis or Crohns disease, diagnosed by a physician and confirmed byradiography 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 ofthe ESSG criteria

ESSG spondylarthropathy classification criteria

Dougados M. Arthritis Rheum 1991;34:1218-30

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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 backpain 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 ofacute 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 Classif ication crit eria

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. Allthese 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 mayawaken 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

eular

Inflammatory back pain

CALIN Criteria *

* Calin A et al . JAMA 1977;237:2613-4

At leat 4 ou t o f t he 5 fo ll ow in g:

Insidious onset

Onset before t he age of 40 years

At leas t 3 mon th s durat io n

Improvement with exercise

Morning stiffness > 30 minutes

Calin inflammatory back pain criteria4

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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eular

Inflammatory back pain

BERLIN Criteria *

* Rudwaleit M et al . Arthritis Rheum 2006;54:569-78

At leat 2 o ut of th e 4 fo ll ow in g:

Morning stiffness > 30 minutes

Improvement wit h exercise but no t wi th rest

Awaken in g b ecau se o f b ack pain d ur in g t hesecond part of the night

Alter nat in g bu tt ock p ain

Berlin inflammatory back pain criteria5

At a later stage, spondylitis may involve the thoracic or cervical spine; neck pain and stiffnessare 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.

eular Clinical spinal ankylosis6

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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.

eular Radiological thoracic spinal ankylosis7

eular Radiological lumbar spinal ankylosis (left)8

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eular Radiological cervical spinal ankylosis9

eular Radiological vertebral squarring10

eular Radiological vertebral squarring11

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eular Radiological syndesmophytes (left)12

eular Syndesmophytes13

eular Radiological bamboo column (left)14

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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 aspossible, so that physiotherapy or other appropriate treatments can be considered.

eular Natural history of spinal abnormal attitudes

Normal (a) (b) (c) (d)position

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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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eular Vertebral fracture in ankylosing spondyliti s16

eular Vertebral fracture in ankylosing spondyliti s17

II.1.1.5 Sacroi lii tis

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 subchondralbone, 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 (probablysecondary to the inflammatory one). At variance, MRI is able to detect both the inflammatory

and the destructive aspects of the sacroiliac joint involvement.

eular Radiological sacroiliitis in ankylosing spondylitis18


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eular Fusion of the sacroiliac joints23

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.

eular Sacroiliit is [MRI findings]24

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eular Sacroiliiti s [CT scan findings]28

eular Sacroiliit is [CT scan findings]29

eular Sacroiliit is [bone scintigraphy findings]30

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II.1.1.6 Anterior chest wall pain and root joint s

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 ispossible, 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.

eular Saussage like digit [ dactylitis]31

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eular Heel enthesitis [MRI findings ]34

eular Heel enthesiti s [X-rays]35

eular Heel enthesitis [ ossification]36

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eular Heel enthesitis [bone scintigraphy fi ndings]37

II.2 Extra-arti cular 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 patientseyesight. 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].

eular Acute Anterior Uveit is38

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eular Synechia occurring after acute anterio uveitis39

II.2.2 DiarrheaInflammatory 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 that of bowel disease, and axial symptoms do not fluctuate with bowel disease

activity.

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].

eular Nail lesion of psoriasis40

eular Nail lesion of psoriasis41

eular Palmo-plantar pustulosis42

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eular Modified New York cr iteria for ankylosing spondylit is

A. Diagnosis

1) Clinical criteria

a) Low back pain and stiffness for m ore 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 sacroiliiti s grade 3-4 unilaterally

B. Grading

1) Definite ankylosing spond ylitis 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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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 clinicaltrials 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 thesepurposes, 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 Diagnost ic crit eria

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].

eular From Rudwaleit M et al. , Ann Rheum Dis 2004;63:535-43

Diagnostic criteria for ankylosing spon dylitis (tree decision)46

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 rheumatoidfactor, 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 diseaseranges 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 self-

limiting, 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 arthr iti s

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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eular Bacteria that tr igger reactive arthri tis

Chlamydia trachomatis

Shigella flexneri

Salmon ella spp

Yersinia enterolyti ca

Yersinia pseudotuberculosis

Campylo bacter fetus jejuni

Clostridium difficile

Intravesical injection of bacilli Calmette-Gurin t o tr eat bl adder cancer

Chlamydia pneumoni ae unconfirmed

Adapted from Smith JA et al . Best Pract Res Clin Rheum 2006;20:571-92

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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, thetriggering 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 reactivearthritis; 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 firs t genetic factor identified: the tis sue 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 ., anassociation 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 homo-

dimers 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 co-

segregation 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 ankylosingspondylitis, 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 B27-

positive monozygotic twins.

eular

Concordance

Concordance Discordance

Discordance

E

EG

Concordance and discordance in monozygotic (MZ) and dizygotic twins (DZ). A pair isconcordant i f both twins are affected; a pair is discordant i f only one twin is affected.Discordance between monozygotic twins is related to environmental factors (E); Discordancebetween dizygotic twins is of genetic origin (G).

MZ

DZ

Genetic aspects: concordance

Adapted from Miceli C et al . Fast Facts, Ankylosing Spondylitis 2004

48

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IV1.4 Methodo logy of t he genetic studi es

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 presentin 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 inapoptosis). 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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eular

Patients Healthy controls

Ass oci atio n studi es. The po lym orp hi c marker tested is bi-allelic ( or ). The alleles arenot equally distributed among patients and healthy controls. The disease is associated withthe allele .

Genetic aspects: association studies


49

eular

Transmitted 1 3

Not transmitted 3 1

Tr ansmiss ion d isequi li br ium tes t. The number o f al lel es t ransmi tt ed and nott ransmit ted to the affected children by their heterozygous parents is calculatedfor each al lele within a family set .

Genetic aspects: tr ansmission di sequilibr ium test


50

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eular

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 )

Genes investigated by case-control or intra-familial association studies in SpA


51

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 theresemblance 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.

eular

Oxf or d

1998

&

2001

N ASC

1 2 3 4 5 6 7 8 9 10 11 12

13 14 15 16 17 18 19 20 21 22 Y X

GFEGS

2004

Genome-wide scanning approach [results of 3 different studies ]52

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 theenvironment 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 worthnoting 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 T-

cells, 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 inflammationin AS is less clear.

eular B27 transgenic mice53

eular B27 transgenic mice54

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 ofinflammatory 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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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.

eular Evaluation of functi onal impairment [BASFI]

Bath Ankylosing Spondylitis Functional Index (BASFI)

1. Put ti ng on your s ocks or t ight s w it hout hel p or ai d ( e.g . sock aids):

2. Ben ding f or war d f ro m the wai st t o p ic k u p a p en f ro m the f lo or withou t an aid:

3. Reachi ng up t o a hi gh s hel f w it hou t hel p or ai ds ( e.g. helping hand):

4. Get ti ng u p o ut o f an ar mless d in in g r oom c hai r w itho ut us in g you r han ds o r an yother help:

5. Get ti ng u p o ff the f lo or witho ut h elp f rom lying on yo ur b ac k:

6. Standing unsupported for 10 minutes without discomfort:

7. Cl imb ing 12-15 st eps w it hout us ing a handt ai l or w alki ng ai d (one f oot eachstep):

8. Looking over your shoulder wi thou t turning your body:

9. Doing physical ly demanding ac tivi ties ( e.g. physiotherapy exercises, gardeningor sports):

10. Doing a ful l days ac tivi ties whether i t be at home or at work:

57

V.1.2.1.2 Peripheral arthri tis

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 ofa 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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eular Evaluation of the di sease activity [BASDAI]

Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)

1. How w ou ld yo u des cribe t he o ver all lev el o f fatig ue/t ir edn es s yo u hav e

experienced?2. How would you describe the overall level of AS neck, back or hip pain

you have had?

3. Ho w wou ld yo u d es cr ib e t he o ver al l l ev el o f p ai n/s wel li ng i n j oi nt s o th er t han n eck , b ack o r h ip s yo u h ad ?

4. How would you describe the overall level of discomfort you have hadf rom any areas tender to touch or p ressu re?

5. How w ou ld you d esc rib e th e o verall lev el o f m orn ing st iff ness yo u h av eh ad f ro m t he t ime yo u wak e u p?

6. Ho w l on g d oes yo ur mor ni ng s tif fn es s l as t f ro m t he t ime yo u wak e u p?

58

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 mot ion

These domains can be evaluated differently in clinical research studies and in clinical practice.

V.1.3.3 Evaluation o f range of mo tion in cl inical tr ials

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], inter-

malleolar distance [slide 63]. This composite index termed BASMI is detailed in [slide 64].

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eular Spinal mobili ty: cervical rotation59

eular Spinal mobility: tragus to wall dist ance60

eular Spinal mobili ty: spi nal lateral fl exion61

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eular Spinal mobili ty: l umbar flexion [modified Schobers test]62

eular Spinal mobility: inter-malleolar distance63

eular

Bath Ankylosing Spondylitis Mobility Index (BASMI)

VariableScore

0 1 2

Cervical rotation (*) >70 20-70


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eular Spinal radiographic severity in AS

Staging severity scoring system*Radiographic grading

*Braun J et al . Ann Rheum Dis 2002;61suppl3:9-23

Stage I: Grade II or higher bilateral radiographic sacroilii t is

Stage II: Minor radiographic evidence of spinal involvementin


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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 Monito ring o f the activ ity o f 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 One set of responder criteria (ASAS20 [slide 67]);

o 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 t he 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.

eular

ASAS Response Criter iaImprovemen t o f at l eas t 20% and abso lu te improvemen t o f at l eas t 10 on a 0-100scale in at l eas t 3 o f the fol lowing domains*:

patient globalpain

functioninflammation Absen ce of deteri or ati on (of at leas t 20% and absolu te det erioration of at leas t10 or a 0-100 scale) in the potent ial remaining domain.

*Definition of the domain:

Patient global = VAS (0-100)

Pain = VAS global, last 2 days (0-100)

Function = BASFI (0-100)

Inflammation = 1 st choice: 2 last questions of the BASDAI2nd choice: morning stiffness duration with a maximum

of 120 mm or a 0-100 scale

Anderson J et al . Arthritis Rheum 2001;44:1876-86

ASAS20 responder c rit eria set67

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eular

ASAS Remission Criteria

A value below 20 on a 0-100 scale in each of the 4 domains*:

patient globalpainfunctioninflammation

* Definition of the domainPat ient global : VAS (0-100)

Pain: VAS global, last 2 days (0-100)

Function: BASFI (0-100)

Inflammation: 1 st choice: 2 last questions of the BASDAI2nd choice: morning stiffness duration with a maximum

of 120 mm or a 0-100 scale

Anderson J et al . Arthritis Rheum 2001;44:1876-86

ASAS remission cr it eri a set68

eular

ASAS DMARD - Responder cr iteria

Improvement of at least 20% and absolute improvement of atleast 10 on a 0-100 scale in at least 4 (or 5) of the followingdomains:

Patient global

Pain

Function

Morning stiffness

Spinal mobility

CRP

*Braun J et al . Ann Rheum Dis 2004;63:1438-44

ASAS DMARD responder c rit eria set69

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eular

Radiological evaluation o f AS

Modified Stoke Ankylosing Spondylitis

Spine Score (M SASSS)M SASSS

Anterior s it e of the vert ebraC2 to T1, T12 to S1Score = 0 = normal

1 = erosion, sclerosis2 = syndesmophyte3 = bridging syndesmophytes

Range 0 - 72

Wanders A et al . Arthritis Rheum 2004;50:2612-32Wanders A et al. Ann Rheum Dis 2004;63:1601-4

Radiological spinal scoring system in AS [mSASSS]70

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SummarySpondylarthritides 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 lowerlimbs;

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 ankylosingspondylitis.

Genetic epidemiological studies suggest the existence of other predisposing genes, such as theIL23R

Genome scanning studies reveal that the strongest linkage, other than the MHC region, is to befound on chromosome 16q.

The prevalence of ankylosing spondylitis is 0.1-1.4% in Caucasians and 0.04-6% in non-Caucasianpopulations.

The rate of withdrawal from the labor force is three times higher in patients with ankylosingspondylitis 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 ofinsidious onset, becoming persistent after a few months.

The radiographic hallmarks of ankylosing spondylitis are signs of sacroiliitis starting with bloomingof the cortical margins of the subchondral bone, erosions and sclerosis.

Arthritis of the peripheral joints is mostly oligo-articular, asymmetrical, transient and migratory, withinvolvement 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 classicfeature of ankylosing spondylitis.

Acute anterior uveitis is the most common extra-articular manifestation, with 25-40% of patientsexperiencing one or more episodes.

The most serious complication of ankylosing spondylitis is functional impairment due to abnormalposture.

The ASsessment in Ankylosing Spondylitis (ASAS) working group has proposed several core setsof 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 interferewith the occurrence or the severity of the disease.

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Spond Ylar Thr i Tides