Current Diagnostic Pathology (2002) 8, 1^10

c 2002 Elsevier Science Ltd

doi:10.1054/cdip.2001.0089, available online at http://www.idealibrary.com on

MINI-SYMPOSIUM: NON-NEOPLASTIC OSTEOARTICULAR

PATHOLOGY

Enthesopathies
A. J. Freemont
Musculoskeletal Research Group, Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK

KEYWORDS
enthesis, enthesopathy,
seronegative,
spondylarthropathy

Summary Enthesis is a term used to describe the insertion of ligaments and tendons
into bone.Thisis a hybrid tissue in which what would be an abruptinterface betweenthe
bone and the brous component is made less so by the presence of collagen bres that
penetrate the bone from the ligament and frequently the presence of cartilage at the
interface. The enthesis is the subject of trauma leading to the development of a noninammatory enthesopathy and of inammation (inammatory enthesopathy). Inammatory enthesopathies are found predominantly in rheumatoid disease and the
group of disorders known as the seronegative spondylarthropathies.This paper will discuss both types of enthesopathies but will focus mainly on the seronegative spondylarthropathies and their pathology at the entheses and associated structures, as it is this
aspectofthe enthesopathies thatis of mostimportance tothe diagnostic histopathologist.

c 2002 Elsevier Science Ltd

THE ENTHESIS
Structure
Enthesis is a term used to describe the insertion of ligaments and tendons into bone. Biomechanically, this is a
potentially vulnerable region of the body and common
experience indicates that the enthesis can be the source
of considerable pain and disability. It is, however, a testament to their structure that despite there being thousands of entheses within the body a normal individual is
troubled so little with disorders of this structure.
The brous tissue component (tendon or ligament) of
the enthesis consists of parallel fascicles of collagen bres
and broblasts surrounded by bromyxoid interfascicular tissue.The tendon/ligament is encased in a similar tissue. At the insertion into bone, the interfascicular and
peristructural tissue merges with the periosteum. Many
of the collagen bres of the ligament/tendon pass
through into the bone as the perforating bres of Sharpey.These have two functions. First, they give a solid anchor to the brous structure and second they bond the
subperiosteal bone lamellae (which run at right angles to
the brous tissue insertion and are at risk of lamination)
together, making the whole structure stronger. The

strength of this insertion is evidenced in avulsion injuries

where, under heavy shock loading, bone prominences
are torn from surrounding bone rather than the tendon
or ligament being ripped from the bone.
Frequently, at the bone/brous tissue interface there
is a thin layer of cartilage (through which the Sharpeys
bres pass). The biomechanical advantage of having a
brous tissue/cartilage/bone sandwich and the mechanism leading to this pattern of connective tissue dierentiation are not fully understood.
The enthesis is highly vascular and it is one of the sites
where blood vessels and nerves enter the bone from
outside.

THE SPECTRUM OF
ENTHESOPATHIES
An enthesopathy is a disorder aecting the enthesis. Enthesopathies may be non-inammatory or inammatory.
The major causes of non-inammatory enthesopathies
can be categorized as traumatic, degenerative and metabolic. Very simply, the inammatory arthropathies are
part of the syndromes of rheumatoid disease or the seronegative spondylarthropathies.

Trauma and degeneration

Corresondence to: AJF.Tel: +44 (0)161275 5269; Fax: +44 (0)161275
5268; E-mail: tony.freemont@man.ac.uk

Although it is extremely strong, the enthesis may be damaged by single episodes of excessive load (e.g. sporting

2
injury). Degeneration is almost certainly very similar1
but the tissue damage results from chronic, repetitive
and relatively painless loading. Typical sites for the development of degenerative enthesopathies are the calcaneum (calcaneal spurs at the insertion of the plantar
aponeurosis are seen in 25% of the population), the patella and iliac crest.There is an increased incidence in obese
and diabetic patients.

Metabolic
The deposition of crystals such as calcium
pyrophosphate and hydroxyapatite in the ligament or
tendon can lead to an enthesopathy, usually through
disruption and weakening of the brous structure. A
similar appearance is seen in alkaptonuria. The bony
component can be weakened or disrupted by hypervitaminosis A, uoride intoxication, osteomalacia and
acromegaly.

Rheumatoid enthesopathy and the

seronegative spondylarthropathies
Rheumatoid enthesopathy
Although rheumatoid disease characteristically aects
synovial joints it may also cause an enthesopathy. This
may be due either to erosion of entheses in close proximity to synovial joints by pannus, or to a primary enthesopathy indistinguishable from that of the seronegative
spondylarthropathies2 (see below).

The seronegative spondylarthropathies

These are a group of clinically related inammatory disorders. The disorders now included in the seronegative
spondylarthropathies (SS) are as follows:
(1) Primary (uncomplicated) ankylosing spondylitis.
(2) Reactive arthritis and Reiters disease.
(3) The arthritides associated with psoriasis, ulcerative
colitis, Crohns and Whipples disease.
(4) Juvenile spondylarthropathy.
Criteria for inclusion in this group are:
(1) Absence of rheumatoid factor in the serumFhence
the name seronegative.
(2) Absence of subcutaneous (rheumatoid) nodules.
(3) Inammatory peripheral arthropathy (may be asymmetrical).
(4) Radiological sacro-iliitis with or without radiological
erosion and/or new bone formation at the margins of
vertebral bodies. This is essentially the radiology of
the most common enthesopathies and gives the
group the name spondylarthropathies.

CURRENT DIAGNOSTIC PATHOLOGY

(5) Evidence of clinical overlap between members of the

groupFthe clinical syndromes of each of the disorders in the group share characteristics with one or
more of the others.
(6) Tendency to familial aggregationFthese disorders
have a tendency to run in families and some families
contain related individuals aected by dierent members of the group.
(7) Signicant association with HLA-B27 allotype.
The enthesopathy in this condition is an enthesitis, a primary inammation of the enthesis. The cause for this is
unknown, but in many types of SS actual or presumed
infection has been implicated. This association requires
further study but direct (sometimes subclinical) infection of the enthesis, epitope sharing between entheses
and bacterial cell walls and immune complex deposition
in the walls of the penetrating vasculature have all been
implicated.

Others
Two disorders, one inammatory (SAPHO syndrome)
and one non-inammatory (DISH) require special
mention.
Acne-associated arthritis (SAPHO syndrome)
SAPHO is an acronym for synovitis, acne, pustulosis,
hyperostosis and osteitis.3 In SAPHO, palmoplantar
pustulosis is associated with bone and joint disorders.
The initial descriptions localized these disorders to the
anterior chest wall, but latterly more peripheral
bones and joints have been associated with severe
acne. Typically, these patients present with pustulotic
acne and sternoclavicular bone involvement. Other
bones may be involved. The bone lesion combines a
sterile, active chronic inammatory cell inltrate with
hyperostosis, which may resemble Pagets disease. The
aetiology is unknown although there are reports of
the organism Propionibacterium acnes being isolated from
the bone and there is a suggestion that there may be a
genetic basis for the disorder.4 The most favoured
explanation for SAPHO syndrome is that it represents a
form of seronegative spondylarthropathy with an
enthesitis and inammatory involvement of the adjacent
marrow.
DISH
The acronym DISH stands for diuse idiopathic skeletal
hyperostosis.5 It is also known as Forrestiers disease.
Although it may have a metabolic or degenerative origin,
the cause of DISH is unknown.There is both a spinal and
peripheral enthesopathy with massive ligamentous ossication and periarticular bridging.

ENTHESOPATHIES

PATHOLOGYAT THE ENTHESIS

(ENTHESOPATHIES)
Principles behind the pathology
There are two fundamental principles that underpin the
pathology of this site:
(a) Tissue damage heals by bone formation.
(b) There are peculiarities of the tissue, probably at the
molecular level, that make it prone to lymphocytemediated inammatory damage in susceptible individuals in association with, or following on from inammation in other tissues, most commonly the
bowel, genitourinary and respiratory systems and
the skin.

Healing by bone formation

A characteristic of healing at the enthesis following traumatic or inammatory damage is the formation of excess
bone, usually in the line of pre-existing ligament or
tendon. As in all reactive bone formation, the initial
event is the formation of new, woven osteoid from
either brous tissue or by endochondral ossication.
This then rapidly undergoes remodelling and replacement by lamellar bone. This process explains the
characteristic lesion of traumatic enthesopathy, the traction spur; and that of the inammatory enthesopathy,
the syndesmophyte. In traumatic enthesopathies healing
does not always occur. Persistent pain following injury
is characterized at the tissue level by vascular invasion
of the ligament/tendon. The invading vessels have a
characteristic appearance with a leash of microvessels
arising from a single feeding vessel (Fig. 1). Once these
congeries of vessels form, spontaneous healing never
takes place.

Inammation at the enthesis

It was the work of Ball2,6,7 that elucidated the pathology
of the inammatory enthesopathy. While investigating
the pathology of ankylosing spondylitis (AS), he showed
that bony ankylosis of the spine was preceded by a lymphocyte-mediated, destructive, inammatory enthesopathy. This was best illustrated in the spine at the
entheses where the spinal ligaments and outer bres of
the annulus brosus insert into the bone of the vertebral
rim. He also showed that the same inammatory enthesopathy was seen in the other seronegative spondylarthropathies and in rheumatoid disease.
It was the development, in the other seronegative
spondylarthropathies, of a condition in the spine identical to ankylosing spondylitis that paved the way for a
whole new way of looking at the pathogenesis of disease.
Many diseases were known to be due to environmental

Figure 1 Two images of the congeries of blood vessels that

characterize irreversible tissue damage within the ligament/tendon immediately adjacent to the enthesis. In (A) (H&E 150) a
single feeding vessel (F) becomes a complex group of vessels
(the congerie [C]). In (B) the microvascular nature of the vessels
is clearly seen.

or genetic causes.The discovery that it was only patients

who were positive for the HLA 27 (HLA-B27) who, following genitourinary tract or bowel infections, went on
to develop spinal pain and ankylosis,8 led to the realization that a complex interplay between genetic makeup
and environmental insult might underlie many human
diseases.
There have been numerous investigations into the
nature and function of the HLA-B27 susceptibility gene,
and the reason why the enthesis should be the target of
inammatory damage. Poole9 has recently put forward
an interesting case for a central role for immunity to
the G1 domain of aggrecan in the development of the
enthesopathy. The link with infection has fascinated
many researchers10 some implicating specic organisms.11 Other researchers have pursued the possibility of
the B27 allele being an organism receptor, displaying
molecular mimicry with bacterial antigens, or being
involved with the selection of specic subsets of T

4
lymphocytes.12 Most recently, the suggestion that there
is B lymphocyte-mediated antigen selection has been put
forward.13 Despite all the investigations the cause of the
enthesopathy remains enigmatic.

THE CLINICAL PATHOLOGYOF THE

ENTHESOPATHIES
Non-inammatory enthesopathy
The pathology of non-inammatory enthesopathies is
rarely seen in clinical pathology practice. This is largely
due to the pragmatism of the orthopaedic surgeon
who recognizes a traction spur as such and does not feel
the need to have the diagnosis conrmed histologically!
On those rare occasions that biopsies have been
received in this laboratory (which handles in excess of
2000 bone and joint specimens a year from across
the northwest of England), it has been before the
development of the mature lesion, usually in one of
two contexts: either that of an avulsion injury masquerading as a tumour; or to exclude an inammatory
enthesopathy.
In the former, imaging usually shows an irregular area
of cortical erosion associated with a patchily calcied
soft tissue mass, and sometimes elevation of the
periosteum with speckled calcication. The fear is of an
atypical presentation of a chondrosarcoma or osteosarcoma. Tissue from the defect or soft tissue mass
shows all the hallmarks of early fracture. Sometimes,
particularly in children and young adults, the reactive
process is so orid and the matrix so bizarre that
the initial impression is that the clinical (and imaging)
concerns are correct.The key to recognizing the true diagnosis is the presence of a haphazard mixture
of many dierent tissue types (brous and myxoid tissue,
cartilage, fat and bone), the absence of cellular atypia
and high vascularity. There is frequently haemorrhage
(either red blood cells or residual haemosiderin),
particularly if there has been periosteal elevation
(which is usually caused by tracking of blood at the
time of injury).

Inammatory enthesopathies
The pathology of rheumatoid disease is well covered
elsewhere and will not be described here.14 It is, however,
worth bearing in mind that lymphocytic inammation at
the enthesis might be a reection of rheumatoid disease,
and alerting the clinician to this.This section will concentrate on the spectrum of tissue lesions seen in or associated with the enthesopathies of the seronegative
spondylarthropathies.

CURRENT DIAGNOSTIC PATHOLOGY

The pathology of the seronegative

spondylarthropathies
The work of Ball,2,6,7 Cruickshank15,16 and Bulkley and
Roberts17 have been central to our understanding of the
pathology of the seronegative spondylarthropathies (SS).
Much of their present and subsequent work has examined ankylosing spondylitis,18 but the observations pertain to all these disorders. These authors were the
rst to systematically demonstrate the inammatory
nature of AS, and to emphasize the balance between inammatory tissue damage and subsequent repair in the
pathogenesis of the disease. A recent upsurge of interest
in this group of disorders has led to new observations,
and the application of new technology has changed our
perspective on some aspects of this group of diseases.
One example of this comes from the use of total
body magnetic resonance imaging studies in patients
with SS which has emphasized how extensive the skeletal
disease may be.19 Earlier pathological studies and the
more recent advanced imaging show that the tissue
changes are far from restricted to the entheses. In a paper entitled enthesopathies, it might be possible to give
the impression that this was the only feature of SS. To
redress the balance slightly, some of the more common
extra-articular manifestations will be mentioned, particularly where they may assist the pathologist in diagnosing the underlying syndrome.For greater detail of the full
spectrum of the pathology of SS please see Further
Reading.
Distribution of disease
Within the skeleton the inammatory lesions of SS
are restricted to the enthesis, synovium and articular
capsule. Other skeletal lesions such as amyloidosis and
fracture are essentially secondary phenomena. Extraskeletal inammation is also seen in SS, particularly in
the eye and aorta.
Inammatory enthesopathyand associatedjoint abnormalities
While it has been claimed that the author of the book of
Job was the rst to describe the symptoms of the enthesopathy of AS, and there is palaeopathological evidence
of the disease in antiquity,20,21 it is only in recent years
that we have been oered a reasoned interpretation of
the pathology of the disease. In elective biopsies of focal
tender areas over the iliac crest and greater trochanter
in patients with AS, Ball2 showed that the underlying
lesion is a non-specic, active chronic inammation
concentrated in the enthesis. The chondried and calcied parts of the ligament and the bone to which the
ligament is attached are destroyed by the inammatory
process and replaced by granulation tissue with a variable inltrate of lymphocytes, plasma cells and, less
frequently, polymorphonuclear cells. Marrow adjacent
to the enthesis becomes inamed and oedematous and
loses its haemopoietic cells. The inammatory lesions

ENTHESOPATHIES

ligament to form a new enthesis above the original bone

surface.
Individual lesions are small but recur, the net result
being the gradual formation of a bony spur protruding
from the site of the original enthesis into and along the
attached ligament. During maturation of the spur, the
woven bone undergoes remodelling to mechanically
stronger lamellar bone.
Bony spurs may form at the periphery of cartilaginous, brous or diarthrodial joints and may lead to ankylosis especially in joints with relatively low mobility,
e.g. intervertebral and sacro-iliac joints.

Figure 2 This is an erosive, inammatory enthesopathy.This

biopsy comes from the insertion of the outer bres of the annulus brosus into the vertebral rim (enthesis).There is erosion of
the bone by a lymphocytic inammatory cell inltrate immediately adjacentto the intervertebral disc (IVD).

are self-limiting and often short-lived. The lesions

left after the inammation are repaired by direct
deposition of reactive, woven bone, which lls in the
defect and becomes attached to the eroded end of the

Intervertebral discs (IVD). An enthesopathy occurs at the

attachment of the outer bres of the annulus brosus to
the anterior and the anterolateral aspect of the vertebral body adjacent to the vertebral rim (Fig. 2).The erosive
lesions vary in size, but may be suciently large to be
seen radiologically. Bony repair leads to the formation of
a bony spur known as a syndesmophyte (Fig. 3), which
may ultimately form an ankylosing bony bridge between
the rims of adjacent vertebrae (Fig. 3). Initially, this may
be only a few millimetres wide. Syndesmophyte formation is usually followed by a slow but relentless progression to complete ankylosis of the IVD (Fig. 4). There is
no inammation during this phase, the progression
being secondary to immobilization of the disc by the
syndesmophyte.
Imaging and pathological studies indicate that the disease is multifocal. All spinal segments can be involved
with the exception of the atlanto-axial joint, probably
because of its very high degree of mobility.
As ankylosis progresses the increasingly immobile
spine may fracture under normal loading. Typically, this
occurs at the weakest point, the junction of an intervertebral disc (by now almost completely replaced by bone)

Figure 3 This gure shows three stages in the evolution of an ankylosing syndesmophyte.When the inammation resolves, new
bone formation (healing response) starts.The newly formed bone tracks towards the centre ofthe outer bres ofthe annulus fromthe
superior (green arrows) and inferior (yellow arrows) margins of the IVD. Gradually, the process progresses until there is full bony
ankylosis (C).

CURRENT DIAGNOSTIC PATHOLOGY

Figure 4 This gure incorporates an X-ray (A) and a histological section (B) of progressive time points in the non-inammatory
ankylosis that follows the formation of a complete syndesmophyte.Immobilization of the joint leads to progressive replacement of the
intervertebral disc (IVD) by bone (yellow arrows).

and the vertebral end plate. The corresponding

neural arch may also fracture22 (Fig. 5).This process was
originally described as spondylodiscitis and was thought
to be due to infection. While this is not the case,
the increased degree of mobility aorded by the
fracture causes the two bone surfaces to rub on one another generating fragments of bone at the fracture site.
This lesion never heals spontaneously because of continuous movement, the fragments of bone eliciting a destructive macrophage and foreign body-type giant cell/
osteoclast response, histologically closely resembling
tuberculous osteomyelitis.23 This tissue is sometimes
biopsied and care has to be taken to ensure correct
interpretation.
Atlanto-axial dislocation and spinal fracture may cause
neurological complications in AS but otherwise the ankylosing process in the spine is not usually associated
with overt neurological disturbances.
Sacro-iliac joints. The sacro-iliac joints are classically affected in SS. Although the disease is not simply an
enthesitis,24 in the relatively early stages of disease,
when radiographs show irregularity of the joint margins,

the main histological ndings are peripheral ankylosis

due to capsular ossication and endochondral
ossication. The radiological appearances at this
stage are sometimes referred to as erosions because of
the irregular margins of the joint, but histology
shows this to be an incorrect assessment of the
pathology.25 As endochondral ossication occurs it does
so at varying rates in dierent parts of the joint giving
rise to a series of small bony spurs. It is the intervening
areas, i.e. the more slowly ossifying segments of
cartilage, that are the histological equivalents of the radiological erosions.
Inammation in diarthrodial joints
Synovium. Involvement of diarthrodial joints in SS is
very common. Typically, there is synoviocyte hypertrophy and hyperplasia and a predominantly lymphoplasmacytic subintimal inammatory cell inltrate. It is possible
to distinguish this from other types of synovial inammation. Particularly in Reiters syndrome, there is often a
polymorph inltrate in the supercial subintima and synoviocyte layer. Immunocytochemical studies show that

ENTHESOPATHIES

Figure 5 (A) A macroscopic specimen and (B) the corresponding radiograph of a late stage in ossication of the intervertebral disc.
The immobility of the ankylosed spine has caused the bone to fracture through the weakest point, the intervertebral disc (green arrows) and the associated facet joint (red arrow).

the synthesis of immunoglobulins by intrasynovial plasma

cells tends to be predominantly of IgG and IgA types in SS
which contrasts with the signicant contribution from
IgM in RA,26 and phenotypic analysis of the inammatory inltrate can also help distinguish SS from rheumatoid disease.27
Synovial uid. On average the synovial uid polymorph
count is lower and the lymphocyte count higher in SS
than RA.28 The peripheral arthropathy in SS is characterized by the presence of synovial uid cytophagocytic
mononuclear cells (CPM)Fmacrophages containing
intracytoplasmic degenerate polymorphs29 (Fig. 6).
These cells do not occur in high numbers but are easily
recognized in cytocentrifuge preparations. CPM are
restricted to the seronegative spondylarthropathies,
occurring in about 40% of cases. Their presence is a
useful diagnostic test. Similarly, synovial uid mast cells
are typical of this group of disorders, although a little
less specic.
Non-articular lesions
Bone. Osteoporosis can be present from the earliest
stages of AS30 and is common in long-standing disease.
It is caused by immobility and the use, at one time common, of steroid therapy.

Ocular. Many seronegative spondylarthropathies are

associated with an acute, unilateral, self-limiting,
non-granulomatous anterior uveitis31,32 and inammatory arthropathy-associated uveitis accounts for about
a third of all cases of severe uveitis.33 Although it may
recur, it rarely, if ever, necessitates biopsy or enucleation
and its histology has therefore not been fully
documented.
Cardiac. Clinical aortic incompetence and associated
disease of the aortic root are observed in up to 10% of
patients with SS.34,35 Although the pathology supercially resembles that of syphilitic aortitis there are
sucient dierences to render spondylitic aortitis
morphologically unique.17
The aortic ring and proximal aorta are dilated and the
aortic valve cusps brotic but the commissures unfused.
This leads to aortic incompetence.36 Fibrosis may extend
below the valve to form a sub-valvular ridge, and into
the base of the anterior leaet of the mitral valve. Rarely
this may result in mitral incompetence but not mitral
stenosis. The coronary ostia may be the site of saccular
aneurysms.
During periods of active disease, the valve ring and
aortic media contain a lymphoplasmacytic inammatory
inltrate leading to destruction of elastic laminae and reactive brosis.37 The vasa vasorum do not show a

CURRENT DIAGNOSTIC PATHOLOGY

Figure 6 This gure shows two dierent views of a cytophagocytic mononuclear cell (CPH). (A) A cytocentrifuge preparation of
synovial uid.The CPM (macrophage engulng a polymorph) is arrowed. (B) ACPMis seen in the unstained wet prep (ref. 28) viewed
by Nomarski phase microscopy. This cell is diagnostic of a seronegative spondylarthropathy.

vasculitis but their lumina are narrowed by bromuscular intimal thickening. The intima and adventitia of the
aorta may be thickened by brous tissue and chronic
inammation.
Pulmonary. Non-tuberculous upper lobe brosis and cavitation are rare complications of SS.38 The initial lesion
is an interstitial pneumonitis in which the alveolar septae
are inltrated by lymphocytes and plasma cells.This progresses to pulmonary and pleural brosis, with bronchiectasis. Secondary fungal infection is a recognized
complication.
Renal. Renal function is usually unimpaired in
patients with SS.39 However, there are a number
of dierent renal pathologies associated with AS.40
Arguably, the most important clinically is amyloidosis
which aects 6% of patients with AS,41 and may lead to
renal failure.

SUMMARY
The pathology of the entheses is diverse and
interesting and in many instances contributes signicantly to patient management. The key points are
detailed below.
PRACTICE POINTS
K
K

Traumatic enthesopathy may mimic a bone tumour

A localized erosive lesion of the cortex may be an inammatory enthesopathy
The late stage vertebral fractures may resemble tuberculous osteoarthritis
In the seronegative spondylarthropathies characteristic features are a neutrophil inltrate in the
supercial synovium cytophagocytic mononuclear
cells and/or mast cells in the synovial uid

ENTHESOPATHIES

RESEARCH DIRECTIONS
K

The role of infective organismsinthe pathogenesis of

enthesopathies
The pathogenic signicance of cytophagocytic
mononuclear cells
The factor/s that mightexplainthe tissue distribution
of lesions

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FURTHER READING
Klippel J H, Dieppe P A. Section 6 F Infection-related rheumatic diseases and spondylarthropathies. In: Rheumatology, 2nd edn.
St. Louis, MO: Mosby,1998.

CURRENT DIAGNOSTIC PATHOLOGY

Freemont A J, Denton J. Atlas of Synovial Fluid Cytopathology.

Dordrecht, The Netherlands: Kluwer Academic Publishers Group,
1991.
Calabro J J, Dick W C (eds). Ankylosing Spondylitis (New Clinical Applications. Rheumatology). Lancaster, UK: MTP Press,1987.