Article

The pathogenesis of psoriatic arthritis and associated nail disease: Not autoimmune after all?

Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds and Chapel Allerton Hospital, Leeds, UK.
Current opinion in rheumatology (Impact Factor: 4.89). 06/2009; 21(4):340-7. DOI: 10.1097/BOR.0b013e32832c6ab9
Source: PubMed
ABSTRACT
Both psoriasis and psoriatic arthritis (PsA), and by implication psoriatic nail disease, have been considered as autoimmune disorders. This was based on the assumption that T-cell-directed responses against common skin and synovial antigens led to shared immunopathological mechanisms at these different sites, which was indirectly supported by the human leucocyte antigen-Cw6 disease association. This study draws on recent microanatomical and genetic studies of PsA, psoriasis and psoriatic-associated nail disease to show how the prevailing autoimmunity concepts for psoriatic disease need to be redrawn, especially in the case of joint and nail disease.
Recent microanatomical studies confirm that normal tendon and ligament insertion points to bone (entheses), the key territory for the inflammatory reaction associated with PsA, being subject to microdamage that strongly points to a role for microtrauma in the joints, which is reminiscent of Koebner responses in the skin. Furthermore, the nail is functionally integrated with entheses associated with the distal phalanx that provides anchorage to the skin and joint. Although type 1 psoriasis is strongly linked to the human leucocyte antigen-Cw6, recent genetic studies have suggested that both joint and nail disease do not share this association.
These microanatomical and genetic insights have important implications for a better understanding of PsA and nail disease and for an improved understanding of the psoriatic disease spectrum.

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The pathogenesis of psoriatic arthritis and associated nail
disease: not autoimmune after all?
Dennis McGonagle
a
, Michael Benjamin
b
and Ai Lyn Tan
a
Introduction
Just over a decade ago, the prevailing view on the
pathogenesis of psori asis and psoriatic arthritis (PsA)
was that a common, hitherto-unidentified autoantigen
in both the skin and the synovial membrane leads to T-
cell-driven autoimmune responses [1]. The presence of
T cells in both inflamed synovial and skin tissue, the
human leucocyte antigen-Cw6 (HLA-Cw6) association
and the response of the skin to cyclosporin all vindi-
cated that paradigm [2

,35]. In hindsight, this was an
oversimplification as much of the target organ involve-
ment of PsA attacked structures completely devoid of
synovium, especially the entheses (insertions points of
ligaments or tendons) of the spinal column [6]. This
study synthesizes the recent genetic, imaging and
tissue microanatomical data, together with changing
concepts on immunology disease classification to show
how new concepts on the pathophysiology of PsA
are emerging.
Changing concepts of psoriatic arthritis
pathogenesis from imaging studies
The importance of the enthesis as a potential key driver
in PsA was largely overlooked in the English literature
because radiographically evident entheseal changes were
only seen in a subset of chronic PsA cases. However,
the association between enthesitis and PsA was better
appreciated in the French literature [7]. It was only with
the use of MRI and ultrasound that the extent of enthe-
sitis-associated disease in PsA became evident. The
original MRI assessment of PsA compared with rheuma-
toid arthritis (RA) using T1-we ighted images showed that
knee disease in both types of arthropathy was similar
[8,9]. However, T1-weighted imaging of the hand using
gadolinium diethylenetriamine pentaacetic acid (Gd-
DTPA) contrast agent showed that a subset of PsA cases,
but not RA cases, had prominent extracapsular changes
[10]. But it was the advent of fat suppression MRI in early
untreated spondyloarthritis (SpA) that finally changed
a
Section of Musculoskeletal Disease, Leeds Institute
of Molecular Medicine, University of Leeds and Chapel
Allerton Hospital, Leeds and
b
School of Biosciences,
Cardiff University, Cardiff, UK
Correspondence to Professor Dennis McGonagle,
PhD, FRCPI, Professor of Investigative Rheumatology,
Section of Musculoskeletal Disease, Leeds Institute of
Molecular Medicine, Chapel Allerton Hospital,
Chapeltown Road, Leeds LS7 4SA, UK
Tel: +44 113 3924747; fax: +44 113 3924991;
e-mail: d.g.mcgonagle@leeds.ac.uk
Current Opinion in Rheumatology 2009,
21:340347
Purpose of review
Both psoriasis and psoriatic arthritis (PsA), and by implication psoriatic nail disease,
have been considered as autoimmune disorders. This was based on the assumption
that T-cell-directed responses against common skin and synovial antigens led to
shared immunopathological mechanisms at these different sites, which was indirectly
supported by the human leucocyte antigen-Cw6 disease association. This study draws
on recent microanatomical and genetic studies of PsA, psoriasis and psoriatic-
associated nail disease to show how the prevailing autoimmunity concepts for psoriatic
disease need to be redrawn, especially in the case of joint and nail disease.
Recent findings
Recent microanatomical studies confirm that normal tendon and ligament insertion
points to bone (entheses), the key territory for the inflammatory reaction associated
with PsA, being subject to microdamage that strongly points to a role for microtrauma in
the joints, which is reminiscent of Koebner responses in the skin. Furthermore, the nail is
functionally integrated with entheses associated with the distal phalanx that provides
anchorage to the skin and joint. Although type 1 psoriasis is strongly linked to the human
leucocyte antigen-Cw6, recent genetic studies have suggested that both joint and nail
disease do not share this association.
Summary
These microanatomical and genetic insights have important implications for a better
understanding of PsA and nail disease and for an improved understanding of the
psoriatic disease spectrum.
Keywords
enthesis, nail, osteitis, psoriasis, psoriatic arthritis
Curr Opin Rheumatol 21:340347
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the simplistic synovial autoimmunity view of PsA, as it
was clear that clinically unsuspected enthesitis was
visible in a substantial proportion of cases at disease
presentation. Fat suppression MRI in early disease also
showed that enthesitis was sometimes associated with a
florid and extensive adjacent osteitis [11]. This was
noteworthy, as previous bone scintigraphy studies [12]
had shown prominent osteitis in a subset of PsA cases that
could now be linked to the enthesis concept. Several
studies [1315] have since shown using both fat suppres-
sion MRI and ultrasound that enthesitis is commonly
evident in diseased synovial joints in SpA.
With respect to the axial skeleton that may be involved in
PsA, some of the original MRI studies [16] in SpA focused
on the assessment of sacroiliac joint (SIJ) synovitis. Fat
suppression MRI studies [17] have clearly shown that it is
usually a diffuse enthesitis/osteitis that is the dominant
feature of axial SpA including PsA (Fig. 1) and has been
confirmed on histology. As yet, no MRI studies concen-
trating on axial PsA have been published. Of note, a similar
pattern of MRI-evident disease with enthesitis/osteitis has
been described in many PsA manifestations including
synovitis, acne, pustulosis, hyperostosis and osteitis
(SAPHO), dactylitis and in distal interphalangeal (DIP)
joint disease [1820]. It is now recognized that MRI-
determined osteitis is a harbinger for future radiographic
joint damage with joint fusion and radiographic sacroiliitis
[21]. It is thus likely that the classical feature of joint
ankylosis in PsA follows a sequence of diffuse severe
osteitis with eventual cartilage destruction and then com-
plete jointfusion that may occur in the spine, small joints or
large joints including the hip (Fig. 2). Imaging has also
helped clarify the basis for dactylitis and tenosynovitis,
both of which are strongly linked to PsA. Historically, the
strongest link in dactylitis has been with tenosynovitis, but
high-resolution MRI shows an association with enthesitis/
diffuse osteitis in the same joint [14,19].
A recurrent theme in MRI imaging of PsA is that irre-
spective of the site involved, the inflammatory reaction in
early disease does not respect a specific ‘antigen
boundary’ such as the synovium in early RA, but disease
is more widespread and even at presentation involves
virtually every joint structure (Fig. 3). On the basis of
these imaging findings, in addition to other disease
features set out below, an alternative model to autoim-
munity in PsA has been suggested, whereby the pattern
of disease is better conceptualized in relationship to the
biomechanics of the joint, especially adjacent to the
enthesis in which the response to both shear and com-
pressive forces might dictate disease [22,23].
The recognition that bo th ‘wrap around tendons in the
ankle and synovial join ts completely or partly lined by
fibrocartilage (including the SIJ) have shared histological,
biomechanical and pathological features has led to the
recognition that these structures behave similarly to
‘functional enthese s’ [22]. An insertion site per se does
not appear to be a prerequisite for disease expression, for
both entheses and functional entheses are sites of
repeated shear and compressive stressing.
Synovitis is a cardinal manifestation of PsA, and a link
with en thesitis was not firmly established until recently
Psoriatic arthritis and associated nail disease McGonagle et al. 341
Figure 1 MRI of sacroiliac joints
Fat-suppressed MRI of the sacroiliac joints of a PsA patient. There was
diffuse bilateral sacroiliitis indicating severe osteitis, illustrating a bone-
based nature of PsA. PsA, psoriatic arthritis.
Figure 2 Plain radiography of a 45-year-old man with psoriatic
arthritis demonstrating complete fusion of the sacroiliac joints
and fusion of the left hip joint, illustrating the new bone
response that, in the sacroiliac joint, has been shown to be
due to osteitis
Data from Marzo-Ortega et al . [17].
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[24]. The recent recognition of a synovio-entheseal com-
plex (SEC) may help resolve the relationship between
synovitis and enthesitis in PsA [25

]. The SEC model
shows how enthesis fibrocartilage could derive lubrica-
tion and nourishment from adjacent synovium in a man-
ner identical to the long appreciated interaction between
articular cartilage and synovium. Hence, all sites of dis-
ease in PsA can be linked to the common denominator
of enthesitis.
The microanatomical and cellular basis for
psoriatic arthritis
A number of detailed microanatomical studies of
entheses have been performed in recent years, and
one of the important concepts to emerge is that there
is often a collection of neighbouring tissues that aid the
enthesis itself in its role of stress dissipation at the hard
soft tissue interface. Collectively, these comprise an
‘enthesis organ’, and this novel concept has helped
rheumatologists and others to understand why enthesis
disease may often be diffuse rather than focal [26]. In
keeping with t he functional demands of the enthesis and
the enthesis organ as a w hole, the contributory tissues are
prone to microdamage at insertion s ites and adjacent
tissues, microscopic inflammatory and vascular changes
both at and near the insertion itself and the immediately
adjacent synovium [27]. Given the known link
with skin psoriasis and tr auma, then these findings of
clinically unrecognized trauma at insertions sites are
especially noteworthy.
The common association of enthesitis and osteitis in PsA
also has an intriguing anatomical basis. It hinges on the
relative absence of compact bone at the attachment sites
of fibrocartilaginous entheses. As Bogduk [28] has elo-
quently stated in relationship to the biomechanics of the
spine, solid blocks of bone are more suitable for static
than dynamic load bearing. He points out that ‘solid
bone’ such as compact bone has a tendency to fracture
along cleavage planes when sudden forces are applied
for example, tensile loads transmitted to bone via tendons
or ligaments. Consequently, at most tendon or ligament
attachment sites in which the ‘footprint is small, there
is a striking paucity of compact bone, and the insertion is
intimately linked to the adjacent marrow cancellous
(spongy) bone network. The marrow fluid that occupies
the spaces between the bony spicules is thus likely to be a
key player in the absorption and dissipation of forces at
the enthesis, and it is likely to be a key factor that has
been overlooked to date in the link between enthesitis
and osteitis in PsA.
The histological studies [29] available from patients with
PsA strongly attest to prominent innate immune-
mediated disease. This key role for macrophages at all
sites of disease including the enthesis has recently been
reviewed [30]. With respect to the diffuse bo ne destruc-
tion that characterizes PsA, it is evident that osteoclastic-
mediated absorption is central to the process [31]. With
respect to skin, bone and synovium, there is evidence for
a prominent role for neutrophilic inflammation
[32,33
,34]. Although T cells are present in the synovium,
an elegant study [35] found that oligoclonal T-cell popu-
lations did not appear to exhibit autoreactivity,
suggesting that they were innocent bystanders that found
their way to the joint nonspecifically as part of the
inflammatory reaction. The importance of this negative
result cannot be overemphasized, given the emerging
knowledge in which innate immune cytokine blockade is
so effective for joint disease [35].
342 Spondyloarthropathies
Figure 3 High resolution fat-suppressed postcontrast MRI of a
distal interphalangeal joint of a 39-year-old woman with an 8-
month history of psoriatic arthritis demonstrating involvement
of all joint structures in the distal interphalangeal joint that had
only a 5-week history of clinical signs and symptoms
There was evidence of diffuse bone oedema (asterisk) and joint fluid
(arrow head), as well as enhancement of the soft tissue around the nail
bed (open arrow) and the collateral ligaments (arrows). All these
changes demonstrate that the entheses form the epicentre of patho-
logical changes in PsA. Unlike rheumatoid arthritis, in which the syno-
vium is the primary joint target for the immune response, the inflammatory
reaction associated with PsA DIP disease may involve virtually every joint
structure from the subungal bone to the proximal interphalangeal joint
enthesis. This likely underscores associations with characteristic bone
and nail disease. DIP, distal interphalangeal; PsA, psoriatic arthritis.
Page 3
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Do recent animal models tell us about human
psoriatic disease?
Animal models have been used to better elucidate the
pathophysiology of psoriatic disease, and these have
generally concentrated on the skin. Either T-cell-depen-
dent experimental psoriasis or T-cell-independent psor-
iasis, both of which depend on the macrophage for full
phenotypic expression of joint disease, has been
described [36,37]. Conditioned knockout of c-jun and
jun-b in keratinocytes has recently been reported [38].
Intriguingly, mice not only developed a psoriasiform skin
disease but also an arthritis providing evidence in this
system that the skin was essential in driving joint immuno-
pathology [38]. What this means for PsA in humans is
unclear, as a link between clinical severity of skin disease
and arthritis is generally absent, and the c-jun protein
may actually be normal in the psoriatic skin in humans
[39]. Also, as outlined below, the immunogenetics of
human psoriatic disease suggests a stronger link between
skin disease and T cells, but in this animal model, joint
disease appeared to be more T-cell-dependent [38].
These findings probably further underscore the concept
that psoriasis is a pretty distinctive human disease that is
hard to recapitulate.
The importance of nail disease and the distal
interphalangeal joint
Another enigmatic feature of PsA was that it was more
strongly associat ed with nail disease than psoriasis alone
[40
]. Although this observation may not be of the great-
est clinical relevance to rheumatologists, as outlined
later, it is of the utmost relevance to a better under-
standing of PsA disease pathophysiology. Even though
DIP joint and nail disease may not represent the biggest
clinical burden in p soriasis and PsA, the involvement of
this territory m ay be a key to a better understandi ng of
disease pathophysiology. It has been recognized for over
half a centu ry that the prevalence of PsA-associated nail
disease was greater t han the burden of disease associated
with psoriasis alone [41]. It has also recently been shown
that the presence of psoriatic nail di sease is more likely to
be associated wi th the development of PsA [40
]. To
better explore the basis for nail disease, our group have
undertaken high-resolution MRI studies [20,42] and
have confirmed a critical role for the entheses and shown
that it was at the epicentre of the disease process (Fig. 3).
However, the adjacent nail and bone were sometimes
conspicuously involved, further underscoring the con-
cept of a diffuse tissue immunopathology that might be
difficult to explain in term s of c lassical autoimmune
responses.
Histologically, it turns out that the nail and the enthesis
are linked via the DIP joint extensor tendon [20].
Moreover, the extensor tendon at its enthesis sends
superficial fibres that make a substantial contribution to
the formation of a thick periosteum on the dorsal aspect
of the distal phalanx. At this s ite, dense fibrous con-
nective tissue links the nail plate to the periosteum (and
hence indirectly to the extensor tendon itself). This is
in addition to a lateral lamina of fibrous tissue that links
the extensor and flexor tendons, probably via the col-
lateral ligaments at the sides of the DIP joint [43].
Therefore, there is a close functional integration
between the nail, the joint and its associated tendons
and ligaments, which likely explains the known associ-
ation between the DIP joint arthritis and nail disease
[44
]. Although the nail is a n aneural structure and
psoriasis itself is usually a painless condition, up to
50% of cases of nail disease are associated with pain
[45]. The ‘DIP nail-enthesis apparatus’ offers a novel
perspective on this disease (Fig. 4).
Psoriatic arthritis and associated nail disease McGonagle et al. 343
Figure 4 A diagrammatic representation of the distal inter-
phalangeal joi nt of a finger to show that the extensor tendon
not only ha s a bony e nt hesi s on the base of the distal phalan x
but also attaches to the nail plate via a she et-like superficial
lamina
In order to secure its attachment and dissipate stress concentration, the
ET also gives rise to a DL that forms a thickened periosteum over the
dorsal surface of the DP. The two fascial attachments of the ET probably
reflect its poor lever arm by contrast, the deep FT has a more
favourable distal attachment. Beneath the superficial lamina of the ET
is a region of highly vascular FAT with the vessels being derived from the
DA that run longitudinally in the fingers. The vessels pierce the SL at
intervals. DA, digital arteries; DL, deep lamina; DP, distal phalanx; E,
enthesis; ET, extensor tendon; FAT, fibro-adipose tissue; FT, flexor
tendon; IP, intermediate phalanx; NP, nail plate; SF, synovial fold; SL,
superficial lamina; VP, volar plate.
Page 4
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Why asymmetrical disease in psoriatic
arthritis and why the trauma link?
Bone fide autoimmune diseases inevitably attack a
particular antigenic territory and inexorably, but pro-
gressively, completely destroy that target tissue. Good
examples include the autoimmune destruction of the
thyroid or the beta cells of the pancreas in type 1 diabetes
mellitus. In the case of RA, which has predominant
features of autoimmunity, the synovium, which is the
principal joint target organ, is diffusely involved, span-
ning from the synovium associated with the joint
between the odontoid process and the anterior arch of
the atlas to the small synovial metatarsophalangeal joints.
In the absence of clinical disease, subclinical synovitis is
common in RA that was first shown using arthroscopy but
later on ultrasound [4649].
Although diffuse symmetrical disease can be a feature of
PsA, it is o ften characteristically asymmetrical and may
involve the lower limbs more frequently than the upper
limbs. Given that the genetic and environmental factors
(or those outside the body) are evidently the same in a
given individual, then these observations point towards
some factors that are intrinsic to the target joints as being
key drivers of the disease process. The same logic applies
to individual patients in which mutilating arthritis
and new bone formation may simultaneously occur in
different joints.
Furthermore, a clinical clue to this characteristic feature
of PsA is that a precedi ng clinically recalled injury is
present in 9% of cases compared with 1% of RA [50].
What is the basis for this joint koebnerization? First and
foremost, it is important to recall that Koebner responses
are commonly linked with skin disease. These clinically
evident links with trauma have obvious parallels with the
histological findings of microdamage in normal insertions
as ou tlined ab ove.
Recent clues from genetic studies into
psoriatic arthritis-related pathogenesis
A search of PubMed under ‘genetics’ and ‘psoriatic’
yields almost 1000 hits, so the emphasis herein will be
focused on genetic studies [5,5153] that are most perti-
nent to joint disease. The im portance of HLA-Cw6 for
type 1 psoriasis is well recognized. Recent genome-wide
association studies [54,55,56

] have shown several
putative links with skin psoriasis including cathelicidins
and epidermal barrier proteins.
The overlap between nail and joint disease does not end
with microanatomical similarities but seems to have clear
immunogenetic overlaps. Although the link between psor-
iasis and HLA-Cw6 is well established, it is especially
interesting that both the joint and nail may lack this
association. Recent studies [2

] have shown that the link
between PsA and arthritis may simply reflect an association
with skin disease alone. Similar to the joint, the HLA-Cw6
antigen is not especially associated with nail disease. In
fact, a negative association has been reported [52]. Indeed,
the lack of an HLA-Cw6 association with nail changes has
been reported across different populations [57]. This
points towards an immunopathogensis in the nails more
akin to that of joints than the adaptive immune response
that is presumed to be related to skin diseases.
The recent demonstration of the interleukin-12B
(IL-12B) subunit association and the IL-23 receptor
(IL-23R) association with psoriasis and PsA points
towards a common immunological basis at least in a
subset of cases [58

,59]. However, this association
appears weaker for PsA and has not been assessed in
nail disease, and further studies are needed [60].
Although a T-cell-based model for skin diseases
appears incontrovertible, great caution is needed in
joint disease because of the lack of evident T-cell-based
immunopathology [61].
Emerging dermatology perspectives from
psoriatic arthritis
Happy w ith the prevailing dogma of synovial and skin
autoimmunity, academic dermatologists and scientists
have almost totally ignored the importance of the joint in
understanding the spectrum of PsA. Academic derma-
tologists talk of a virtual pendulum in relationship to T
cells and keratinocytes and point out how this pendulum
has swung between T cells and keratinocyte in the
case of skin disease [56

,62,63]. This is because a
wealth of experimental data (sometimes conflicting)
has suggested the primacy of each cell type. As brief
examples, w e have the nonobese diabetic (NOD)
mousehuman skin xenografting models in which dis-
ease is T-cell-dependent [64]. At the other end, extreme
genetic ablation of transcr iption factors expressed in
the skin leads to psoriasis that persists in Rag knockout
mice [38].
Further, recent support for the importance of the enthesis
in PsA comes from studies initiated by dermatologists in
psoriasis. Ultrasound studies [65,66
] in psoriasis have
shown that subclinical enthesitis of large insertions is
common in psoriasis. It has also recently emerged over a
30-year period that about 10% of psoriasis cases evolve
into PsA [40
]. The obvious question now is whether the
primary enthesis lesion can be used to predict the devel-
opment of arthritis. Of particular note, the same studies
showed that the presence of nail disease was a risk factor
for PsA, and the nail disease is further discussed below.
The recognition of subclinical entheseal involvem ent in
psoriasis tends to vindicate the recent assertion by Scarpa
344 Spondyloarthropathies
Page 5
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et al. [67] who suggest that we should now be talking
about the psoriatic disease spectrum.
A reappraisal of autoimmunity as the basis
for psoriatic arthritis and nail disease
Both psoriasis and PsA have been designated as auto-
immune diseases. Indeed, the psoriatic disease spectrum
in humans is clearly linked to aberrant adaptive immunity
based on the genetic, clinical and experimental models as
already listed [2

,4,68]. However, these T-cell-based
models fail to explain PsA, and in this study, we have
discussed how the prevailing autoimm une dogma for PsA
needs to be reconsidered.
On the b asis of the lessons from PsA, we ha ve recently
proposed a new immunological disease continuum
(IDC) classification of ‘i nflammation against self’ [69].
The crux of this classification, which is based on genetics
and microanatomical tissue studies, is that there are two
boundaries for inflammation against self, a classical auto-
immune boundary and second innate immunity
boundary. In the case of the skin and joints, tissue-
specific factors including microtrauma and microbial
products lead to innate immune activation a t these
respective sites. It appears that events taking place in
the skin culminate in secondary T-cell responses but
this has not been formally proven. There is much less
evidence for T-cell-dependent responses in the joint and
nail in PsA. According to t he IDC model, skin or joint
inflammation is likely to be intrinsic to the target tissues
that are the opposite of classical autoimmunity in which
autoantibodies alone may be sufficient to cause disease.
The key ‘tissue specific differences’ between skin and
the joint entheses likely underlie the widely divergent
phenotypes of skin and joint and explain the apparently
erratic tem poral distr ibution of psoriatic-related disease
(Fig. 5).
Although the classical major histocompatibility complex
(MHC) c lass II and autoantibody-associated diseases
represent disorders in which there i s a failure of central
tolerance, a different scenar io has been proposed for
MHC class I-associated diseases including psoriasis. In
these disorders, it has been proposed that tissue-specific
factors l ead to local inflammation, and that this results
in failure of peripheral tolerance that permits MHC
class I positive T cells to gain access to t he tissue
following their activation by dendritic cells in the
lymphoid system [70]. Psoriasis appears to be more
dependent on this adaptive immune component than
the associated arthritis that appears to be more innate
immune based (Fig. 5).
Conclusion
A synthesis of genetic data, a detailed knowledge of
tissue-specific factors, especially joint physiology and
mechanobiology, in combination with the lessons emer-
ging from targeted therapies, provide a new way to aid in
the dissection of psoriatic disease immunopathogensis.
Given the wealth of interest in the genetics of psoriasis,
the availability of several biological therapies and the
easy access of skin for histological studies, then an under-
standing of PsA and psoriasis should be at the vanguard of
understanding inflammation against self in the human
model.
The central importance of the enthesis in PsA, as defined
a decade ago, has not fully dawned on academic derma-
tologists, many of whom still view the joint-based disease
in terms of the synovial membrane [71]. The meeting of
skin and join t disease at the nail, and the association of all
three with enthesi tis, should offer key new insights into
an improved understanding of disease mechanisms in the
coming years. Indeed, the fruits of this approach are
beginning to emerge.
Psoriatic arthritis and associated nail disease McGonagle et al. 345
Figure 5 Proposed model for viewing the immunpathogenesis
of psoriatic disease
Adaptive immunity boundary (main tissue players
primary and secondary lymphoid organs)
Autoantibody
associated
autoimmunity
HLA-Cw6 associated
Psoriasis (Type 1)
Psoriatic arthritis
Nail disease
MHC class 1
associated
autoimmunity
Polygenic innate
immune medicated
inflammation
Innate immunity boundary
(main tissue players target tissue of immune response)
non HLA-Cw6 associated
Psoriasis (Type 2)
Skin disease, especially type 1 psoriasis, sits closer to the adaptive
innate immune boundary of inflammation. This is based on the recog-
nized HLA-Cw6 association and on response to some T-cell-directed
therapies as outlined in the text. However, joint and nail disease sit closer
to the innate immune boundary. This is based on shared microanatomical
features of disease and lack of defined MHC associations. This raises
the possibility that psoriasis and PsA have a relatively different contri-
bution from the adaptive and innate immunity in the expression of
disease. HLA-Cw6, human leucocyte antigen-Cw6; MHC, major histo-
compatibility complex; PsA, psoriatic arthritis.
Page 6
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Acknowledgement
We would like to thank Dr Helena Marzo-Ortega for providing Fig. 2.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
 of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 428429).
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
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Psoriatic arthritis and associated nail disease McGonagle et al. 347
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    • "Recently, the view on the pathogenesis of psoriatic joint and nail disease has been challenged and a question has been raised of whether psoriatic skin disease shares the same pathogenetic principals as psoriatic joint and nail disease. The alternative pathogenetic model suggests that psoriatic nail and joint disease may be linked to tissue-specific factors that lead to activation of innate immune responses (autoinflammatory basis) rather than adaptive immunity (autoimmune basis)18192021. Additionally, van der Velden et al. cast doubt on whether nail psoriasis is a comorbidity of psoriasis or an isolated disease expression [22]. However, whatever the exact pathogenesis of nail psoriasis is, the disease seems to respond satisfactorily to biological agents [3,78910111213. "
    [Show abstract] [Hide abstract] ABSTRACT: Nail involvement has started playing a major role in the overall assessment and management of psoriatic disease. Biologics indicated for moderate to severe chronic plaque psoriasis are shown to be beneficial in nail disease. This study aimed to assess and compare the serum levels of TNF-α, IL-12/23 p40, and IL-17 in psoriatic patients with and without nail involvement. 52 consecutively selected patients with chronic plaque psoriasis were included in this cross-sectional study. Patients were studied and analyzed after they had been divided into 2 groups regarding the presence (n = 24) or not (n = 28) of nail psoriasis. The mean serum levels of TNF-α were significantly higher in the group of psoriatic patients with nail lesions compared to those without (t-test; 5.40 ± 1.17 versus 3.80 ± 1.63, P = 0.026). However, the median serum levels of both IL-12/23 p40 (Mann-Whitney; 92.52 (34.35-126.87) versus 150.68 (35.18-185.86), P = 0.297) and IL-17 (Mann-Whitney; 28.49 (0.00-28.49) versus 8.59 (0.00-8.59), P = 0.714) did not significantly differ between the 2 groups. These results confirm the important role of TNF-α in the pathogenesis of nail psoriasis and may suggest that anti-TNF agents could be more beneficial in psoriatic nail disease than agents targeting IL-12/23 p40 or IL-17 and its receptors.
    Full-text · Article · Dec 2014
  • Source
    • "PsA is likely to be a heterogeneous disease, as the proportion of NK cells among synovial lymphocytes varies between 3 and 35% (data not shown and [18]), and it has been recently proposed that HLA heterogeneity plays a key role [13]. In particular, reports that PsA can develop in absence of autoreactive T cells [16] and is linked to IL-15 in mice [26] suggested that PsA can be driven by the innate rather than the adaptive immune system [17]. However, the mechanisms by which innate immunity and IL-15 could drive PsA have remained elusive. "
    [Show abstract] [Hide abstract] ABSTRACT: NK cells are large granular lymphocytes that form a critical component of the innate immune system, whose functions include the killing of cells expressing stress-induced molecules. It is increasingly accepted that despite being considered prototypical effector cells, NK cells require signals to reach their full cytotoxic potential. We previously showed that IL-15 is capable of arming CD8 effector T cells to kill independently of their TCR via NKG2D in a cPLA2-dependent process. As NK cells also express NKG2D, we wanted to investigate whether this pathway functioned in an analogous manner and if resting NK cells could be primed to the effector phase by IL-15. Furthermore, to establish relevance to human disease we studied a possible role for this pathway in the pathogenesis of psoriatic arthritis, since there are aspects of this disease that suggest a potential effector role for the innate immune system. We found that PsA patients had upregulated IL-15 and MIC in their affected synovial tissues, and that this unique inflammatory environment enabled NK cell activation and killing via NKG2D and cPLA2. Moreover, we were able to reproduce the phenotype of joint NK cells from blood NK cells by incubating them with IL-15. Altogether, these findings suggest a destructive role for NK cells when activated by environmental stress signals during the pathogenesis of PsA and demonstrate that IL-15 is capable of priming resting NK cells in tissues to the effector phase.
    Full-text · Article · Sep 2013 · PLoS ONE
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    • "Chronic joint inflammation is associated with eventual development of bone erosions; however, new bone formation is also observed in patients with inflammatory arthritis, in particular in PsA patients. The development of bony nodules can be seen at sites different from erosions, suggesting an uncoupling of the osteoblast–osteoclast homeostasis that allows for regulated bone turnover and formation [10]. The potential pathways involved in new bone formation include the Wingless (Wnt), transforming growth factor (TGF)-β/ bone morphogenetic protein (BMP), and prostaglandin (PG) E 2 pathways [11]. "
    [Show abstract] [Hide abstract] ABSTRACT: Psoriatic arthritis (PsA) is characterized by focal bone erosions mediated by osteoclasts at the bone-pannus junction. The bulk of research over the past decade has centered on mechanisms that underlie osteoclastogenesis along with new insights into osteoimmunology; however, recent advances that focus on steps that lead to new bone formation are beginning to emerge. New revelations about bone formation may have direct relevance to PsA given the presence of enthesophytes, syndesmophytes, and bony ankylosis frequently observed in patients with this disorder. In this review, we discuss current developments in the pathogenesis of new bone formation, novel imaging approaches to study bone remodeling and highlight innovative approaches to study the effect of inflammation on bone. Lastly, we discuss promising therapies that target joint inflammation and osteitis with the potential to mediate pathologic bone formation.
    Preview · Article · May 2012 · Current Rheumatology Reports
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