2. INTRODUCTION
A heterogeneous group of
rheumatic diseases
Spondyloarthropathy (SpA)
Includes:
Psoriatic arthritis (PsA)
Entero-associated arthritis (EA)
Reactive arthritis (ReA)
Ankylosing spondylitis (AS)
Undifferentiated spondyloarthritis (uSpA)
• Estimated worldwide prevalence: 0.5-1.9%
• There is a classic correlation between the prevalence of SpA and the
prevalence of HLA-B27 gene in a given population
• The exact etiology and pathogenesis are still unknown
3. HYPOTHESES OF PATHOGENESIS
● SpA is strongly
associated with the
MHC class I antigen,
HLA-B27
● Primary function of
HLA-B27 ‒ β2-
microglobulin complex
is to present short
antigenic peptides for
recognition to CTLs
MHC : major histocompatibility complex CTLs : cytotoxic T lymphocytes
4. HYPOTHESES OF PATHOGENESIS
3 unique features of HLA-B27 that contribute to disease pathogenesis:
● HLA B-27 is a highly polymorphic molecule
Advantage With heterozygosity, give a selective advantage to the
immune system against the diversity of microorganisms and their antigens
Disdvantage Extreme polymorphism and potential mutations in MHC
increase the chance of developing autoimmune diseases
● HLA-B2705 and HLA-B2704 are the most strongly associated with SpA
Peptide binding
specificity
A tendency to
misfold
Predisposition for forming
heavy chain homodimers
5. HYPOTHESES OF PATHOGENESIS
5 major hypotheses that explain the role of HLA-B*27 in SpA:
● Arthritogenic peptide hypothesis
● Misfolded HLA-B*27 hypothesis
● Cell-surface homodimer formation hypothesis
● Hypothesis on the malfunctioning of ERAPs
● Hypothesis based on gut microbiome changes
All or most of these mechanisms contribute to disease in individuals
SpA pathogenesis could well be the result of different combinations of
these mechanisms in different populations ethnic-specificity
7. BONE PATHOGENESIS MECHANISM
Bone remodeling is mediated by osteoclasts, osteoblasts, bone lining cells
and osteocytes
● Osteoclasts: responsible for breaking down bone tissue by creating an
acid compartment and then release proteases (e.g. TRAP) to degrade
inorganic and bone components
● Bone lining cells: remove any remaining debris via MMPs chemotactic
agents (PTH, TNFα, PGE2) upregulate RANKL expression mature
osteoclast formation
● Osteoblasts: synthesize bone
● Osteocytes: participate in formation of bone and the maintenance of
matrix
TRAP : tartrate-resistant acid phosphatase
MMPs : matrix metalloproteinases
PTH : parathyroid hormone
PGE2 : prostaglandin E2
TNF :tumor necrosis factor
8. BONE PATHOGENESIS
MECHANISM
● PTH stimulates the proliferation
and differentiation of
osteoprogenitors to mature
osteoblasts via IGF-1
● IGF-I and PTH induce RANKL and
MCSF from mature osteoblasts to
promote osteoclastogenesis
● PTH elevates cAMP levels and
inhibits Mef2-stimulated Sost
promoter activity ↓ expression of
sclerostin, ↑ bone formation rate
IGF : insulin-like growth factor MSCs : mesenchymal stem cells (
● 1,25(OH)2D3 stimulates
osteoblastogenesis via
differentiation of MSCs to
osteoblasts
● Calcitonin increases osteoblast
proliferation and suppresses bone
resorption by inhibiting the activity
of osteoclasts
● Estrogen inhibits bone resorption
by directly inducing apoptosis of
the bone-resorbing osteoclasts
● Androgens can also indirectly
inhibit osteoclast activity and bone
resorption via effects on
osteoblasts/osteocytes and the
RANKL/RANK/OPG system
● Besides systemic hormonal
regulation, other growth factors,
such as IGFs, TGF-, FGFs, EGF,
WNTs, and BMPs, also play a
significant role in regulation of
physiological bone remodeling
9. BONE PATHOGENESIS MECHANISM
Bone pathophysiology is an integral part of all SpA conditions and is
intriguing given the complexity of mechanisms that result in either net loss
of bone mass, increased general bone turnover, or bone gain
The
spectrum
of
bone
effects
(‘lesions’)
in
spondyloarthritis
10. BONE PATHOGENESIS MECHANISM
a. Romanus lesions (long arrows):
osteosclerosis at the vertebral
enthesis attachment of both the
anterior longitudinal ligament and
anterior intervertebral disc annulus.
There is a syndesmophyte
(arrowhead) arising from a previously
fractured vertebra (short arrow).
Osteoproliferative lesions in
spondyloarthritis
b. Erosion and osteosclerosis at the
Achilles’ tendon insertion (thin
arrow), osteoproliferation (entheso-
phyte) at the plantar fascia origin
(wide arrow) and osteoproliferation
(periosteal irregularity) of the os
peroneum (arrowhead), which is a
sesamoid bone in the peroneus
longus tendon attached to the tendon
on all its sides by entheses.
11. BONE PATHOGENESIS MECHANISM
Hypotheses on the development of arthritis in SpA
A. Primary lesion is
enthesitis, and synovitis
is secondary to the
release of proinflam-
matory mediators from
the enthesis
B. Different tissues of the
skeleton (including the
enthesis, the synovial
membrane and the bone
marrow) can be affected
by TNF and IL-23/IL-17-
mediated inflammation
at the onset of arthritis
12. BONE PATHOGENESIS MECHANISM
Activation of entheseal
cells
Triggering of new tissue
formation
Restoration of tissue
integrity or tissue
remodelling
Production of pro-
inflammatory
Chronic inflammatory
process in which
cytokines (e.g. TNF)
play a pivotal role
13. BONE PATHOGENESIS MECHANISM
Factors that contribute to chronicity:
- Structural properties of HLA-B27
- Activation of the immune system by the presence of IBD or infection
- Polymorphisms in cytokines and cytokine processing molecules that lead
to either more severe inflammation or delayed clearance of inflammation
However, under most circumstances (e.g. in the absence of genetic
predisposition), entheseal stress may not lead to chronic changes and
homeostasis is likely to be restored
IBD : inflammatory bowel disease
14.
15. BONE PATHOGENESIS MECHANISM
The development of SpA
is dependent on a multi-
step process that leads
to chronic or recurrent
inflammation but also to
the triggering of new
tissue formation,
completely or partially
independent of
inflammation
16. CLINICAL RELEVANCE: Osteoporosis and fragility fracture
● Osteoporosis is common in ankylosing spondylitis, related to both
systemic inflammation and decreased mobility
● Other feature in AS: vertebral fracture (as a flare-up or as a a consequen-
ce of bone complication)
Major risk factors: low BMD at the femoral neck and total hip, male, longer
disease duration, higher BASDAI, higher BASRI, IBD
● Intervertebral disc fractures are associated with severe neurological
complications
● Most data on fragility fracture risk and osteoporosis relate to a diagnosis
of AS rather than the broader SpA or axial-SpA (axSpA) definition
18. CLINICAL RELEVANCE: Osteitis
● Osteitis MRI high signal on fat-suppressed sequences bone marrow
edema (BME)
● In axSpA, osteitis/MRI BME may indicate increased bone turnover
● Inflammation and ischaemia (noted as a cause of osteitis in other
conditions) are plausible candidate that triggers of increased bone
turnover
● In typical AS bone lesions, there is a sequence of osteitis/erosion
(caused by inflammation) followed by osteosclerosis
20. CLINICAL RELEVANCE: Osteoproliferation
● Osteoproliferation at entheses is a defined consequence of progressive
axSpA (i.e. AS), but is not an ubiquitous finding in axSpA
● Enthesopathy pain may relate more to inflammation and neuropeptide
elaboration in surrounding ‘enthesis organ’ tissues
soft tissues designed to respond and adapt to
mechanical stress
Entheses
Osteoproliferation
in entheses
affect the mechanical properties of entheses
and their attached tendons and ligaments
21. CLINICAL RELEVANCE: Osteoproliferation
● Osteoproliferation at entheses is a defined consequence of progressive
axSpA (i.e. AS), but is not an ubiquitous finding in axSpA
● Enthesopathy pain may relate more to inflammation and neuropeptide
elaboration in surrounding ‘enthesis organ’ tissues
Progressive entheseal osteoproliferation is well recognised to be a profound
indicator of long-term disability in SpA
Prevention of osteoproliferation at entheses in SpA is an extremely
worthwhile goal of disease treatment
22. SUMMARY
The exact etiology and pathogenesis of spondyloarthritis is still unclear
Factors contribute to the pathogenesis of SpA:
Individual
susceptibility
Infection &
intestinal dysbiosis
23. SUMMARY
1. The pathomechanism of bone abnormalities is an integral part of this
disease
2. The range of skeletal effects that occur in SpA includes:
● Ankylosing spondylitis
● Fragility fractures
● Focal and sub-entheseal osteitis and erosions
● Osteoproliferation, either in skeletal ligaments or peripheral
tendons (enthesophytes) or axially (syndesmophytes)
● Osteosclerosis
PATOMEKANISME TERJADINYA ABNORMALITAS TULANG PADA SPONDYLOARTHRITIS
Spondyloarthritis (SpA) merupakan kelompok penyakit rematik yang terdiri dari beberapa kondisi dengan fitur klinis yang tumpang tindih, seperti arthritis yang melibatkan skeleton aksial dengan nyeri punggung inflamatori, uveitis, keterlibatan dermatologis dan gastroenterologis dan berhubungan secara genetik dengan gen HLA-B27.
Kelompok ini termasuk arthritis psoriasis, entero-associated arthritis, arthritis reaktif, ankylosing spondylitis dan spondyloarthritis yang tidak terdiferensiasi
Etiologi dan patogenesis spondyloarthritis yang tepat masih belum diketahui. Namun, beberapa bukti menunjukkan bahwa genetika memainkan peran penting dalam kerentanan individu, sementara faktor lingkungan, yang mengakibatkan infeksi dan disbiosis usus, juga berkontribusi pada patogenesis SpA
Fungsi utama HLA-B*27 dalam kompleks dengan 2-mikroglobulin adalah untuk mempresentasikan peptida antigenik pendek untuk pengenalan limfosit T sitotoksik.
Tiga fitur unik dari HLA-B*27, termasuk spesifisitas pengikatan peptida, kecenderungan untuk misfolded, dan kecenderungan untuk membentuk homodimer heavy chain dapat berkontribusi pada patogenesis penyakit
Tiga fitur unik dari HLA-B*27, termasuk spesifisitas pengikatan peptida, kecenderungan untuk misfolded, dan kecenderungan untuk membentuk homodimer heavy chain dapat berkontribusi pada patogenesis penyakit
HLA B-27 adalah molekul yang sangat polimorfik yang saat ini lebih dari 223 subtipe telah diketahui. Tingginya jumlah polimorfisme, dalam kombinasi dengan heterozigositas, memberikan keuntungan selektif pada sistem imun terhadap keragaman mikroorganisme dan antigennya. Namun, polimorfisme ekstrim dan mutasi potensial pada MHC meningkatkan kemungkinan untuk perkembangan penyakit autoimun. Thus, these molecules play an essential role in the regulation of the host’s immune response, by initiating tolerance, and CTL or helper T cell responses, by presenting peptides to T cell receptors.
Beberapa hipotesis utama masing-masing menjelaskan peran HLA-B*27 dalam SpA: hipotesis peptida artritogenik, hipotesis HLA-B*27 yang misfolded, hipotesis pembentukan homodimer permukaan sel, hipotesis tentang tidak berfungsinya Endoplasmic Reticulum Aminopeptidase (ERAP), dan hipotesis berdasarkan pada perubahan mikrobioma usus.
Selain itu, dengan mempertimbangkan bahwa frekuensi polimorfisme alel HLA-B*27 dan ERAP1 bersifat spesifik terhadap etnis, penting untuk dipahami bahwa patogenesis SpA bisa jadi merupakan hasil dari kombinasi yang berbeda dari mekanisme ini pada populasi yang berbeda (Gambar 1)
Ilustrasi hipotesis peran patogenetik molekul HLA-B*2705 pada spondyloarthritis dapat dilihat pada gambar
1. Pertama, peptida artritogenik yang ditampilkan oleh HLA-B*27 yang properly folded dapat dikenali oleh sel T CD8 + autoreaktif, yang mengakibatkan inflamasi.
Kedua, rantai HLA-B*27 yang misfolded dan pengikatan BiP menyebabkan stres ER dan aktivasi UPR, yang menyebabkan peningkatan produksi IL-23 dan sitokin proinflamasi lainnya.
Ketiga, homodimer HLA permukaan sel berinteraksi dengan CD4 +Sel T melalui reseptor imun bawaan, seperti KIR3DL2, dan memfasilitasi respons autoimun yang dimediasi sel.
Keempat, perubahan aktivitas ERAP1 dapat mengakibatkan perubahan dalam pemrosesan peptida, dengan konsekuensi patologis
PTH merangsang proliferasi dan diferensiasi osteoprogenitor menjadi osteoblas dewasa melalui IGF-1. Bersama dengan IGF-I, PTH menginduksi RANKL dan MCSF dari osteoblas dewasa untuk mendorong osteoklastogenesis. PTH meningkatkan kadar cAMP dan menghambat aktivitas promotor Sost yang distimulasi Mef2, yang menyebabkan penurunan ekspresi sklerostin dan peningkatan laju pembentukan tulang. 1,25(OH)2 D3 merangsang osteoblastogenesis melalui diferensiasi sel punca mesenkim (MSC) menjadi osteoblas. Kalsitonin meningkatkan proliferasi osteoblas dan menekan resorpsi tulang dengan menghambat aktivitas osteoklas. Estrogen menghambat resorpsi tulang dengan secara langsung menginduksi apoptosis dari osteoklas yang menyerap tulang. Androgen juga dapat secara tidak langsung menghambat aktivitas osteoklas dan resorpsi tulang melalui efek pada osteoblas/osteosit dan sistem RANKL/RANK/OPG. Selain regulasi hormonal sistemik, faktor pertumbuhan lainnya, seperti IGFs, TGF-, FGFs, EGF, WNTs, dan BMPs, juga memainkan peran penting dalam regulasi remodeling tulang fisiologis iddiqui and Partridge, 2016).
Patofisiologi tulang merupakan bagian integral dari semua kondisi spondyloarthritis (SpA) dan merupakan hal yang kompleks mengingat adanya mekanisme yang mengakibatkan hilangnya massa tulang, peningkatan pergantian tulang secara umum, atau penambahan tulang. Kisaran efek skeletal yang terjadi pada SpA, termasuk ankylosing spondylitis (Tabel 1), meliputi: pengeroposan tulang secara umum (osteoporosis), fraktur fragility, osteitis dan erosi fokal dan sub-entheseal, osteoproliferasi, baik pada ligamen skeletal atau tendon perifer (enthesophytes) atau aksial (syndesmophytes), dan osteosklerosis (Gambar 3). Kisaran efek skeletal ini merefleksikan potensi patofisiologi penyakit untuk mempengaruhi sel-sel (berpotensi 'pembentuk tulang') dari tulang dan non-tulang, baik pada skala fokal atau lebih umum. Efek ini bisa terjadi pada pasien yang sama dari waktu ke waktu atau bahkan secara bersamaan. SpA adalah salah satu dari sedikit kondisi di mana osteoproliferasi pada entheses (area anatomi di mana serat tendon, ligamen dan kapsul masuk ke dalam tulang melalui koneksi fibrocartilaginous, yang dihipotesiskan sebagai lokasi utama pada penyakit SpA) merupakan bagian penting dari patofisiologi tersebut, sebuah gambaran klinis yang telah dikenal sejak lama
a. Lesi Romanus (panah panjang): osteosklerosis pada perlekatan entesis vertebra dari ligamen longitudinal anterior dan anulus diskus intervertebralis anterior. Terdapat syndesmophyte (panah) yang timbul dari vertebra yang sebelumnya fraktur (panah pendek).
B. Erosi dan osteosklerosis pada insersi tendon Achilles (panah tipis), osteoproliferasi (enthesophyte) pada origo fascia plantar (panah lebar) dan osteoproliferasi (periosteum yang ireguler) os. peroneum (panah), yang merupakan sesamoid bone di tendon peroneus longus yang melekat pada tendon di semua sisinya dengan entheses.
Patomekanisme tentang perkembangan arthritis pada SpA dapat dilihat pada gambar 4. Hipotesis pertama adalah hipotesis enthesitis, di mana lesi primer adalah entesitis, dan sinovitis yang merupakan sekunder dari pelepasan mediator proinflamasi dari enthesis (A).
Hipotesis kedua menunjukkan bahwa jaringan skeleton yang berbeda (termasuk enthesis, membran sinovial dan sumsum tulang) dapat dipengaruhi oleh inflamasi yang dimediasi TNF dan IL-23/IL-17 pada onset artritis
Activation of entheseal cells could lead to a double phenomenon: triggering of new tissue formation and production of pro-inflammatory molecules. The former can lead to restoration of tissue integrity or tissue remodelling. The latter phenomenon can develop into a chronic inflammatory process in which cytokines such as TNF play a pivotal role.
Hubungan antara peradangan dan ankilosis di SpA. Peristiwa utama dianggap 'tekanan entheseal'. Faktor biomekanik dan kerusakan mikro kemungkinan berperan dalam hal ini. Stres entheseal menyebabkan pemicu reaksi inflamasi akut dan sel progenitor. Dalam keadaan tertentu, peristiwa akut dapat berubah menjadi situasi kronis di mana peradangan dan/atau ankilosis menonjol. Jalur yang berbeda mengatur peradangan kronis dan pembentukan jaringan baru, tetapi jalur ini cenderung saling mempengaruhi. Faktor genetik
Osteoporosis (ie, low bone mineral density) is common in ankylosing spondylitis, related to both systemic inflammation and decreased mobility. Vertebral fracture risk is increased; acute back pain in these patients is not always a flare-up of the disease, as it can be related to bone complications. Intervertebral disc fractures in the ankylosed spine are associated with severe neurological complications.
Most data on fragility fracture risk and osteoporosis relate to a diagnosis of AS rather than the broader SpA or axial-SpA (axSpA) definition.
Major risk factors for vertebral fractures in patients with AS include low BMD at the femoral neck and total hip, male gender, longer disease duration, higher BASDAI, higher BASRI, and possibly infammatory bowel disease.
A low BMD is common in patients with AS with progressive disease. However, increased BMD can be due to artefacts related to the presence of syndesmophytes or other structural lesions as ankylosed posterior arch and periosteal bone formation.
Prevalence is higher in studies using quantitative CT at the spine, as this technique allows measurement of central areas of vertebral bodies, avoiding the cortex and bone constructions. The prevalence of osteoporosis (based on dual energy X-ray absorptiometry measurements) in patients within the first decade after diagnosis is 16% and 13% at the lumbar spine and femoral neck, respectively.2
Osteoporosis can occur in AS because of reduced physical activity, and decreased functional capacity related to pain, stiffness and ankylosis. However, low BMD is found in patients with early disease, before any structural changes.
Vitamin D receptor gene may contribute to BMD differences in patients with AS, and some polymorphisms are also linked to inflammation.
Sacroiliac inflammation is the earliest feature of AS with inflammatory granulation tissue eroding the sacroiliac joint. The inner and thinner iliac cartilage is eroded before the thicker outer sacral sided cartilage. This leads to fibrocartilage tissue replacing the joint space followed by bony ankylosis of sacroiliac joints. There is diffuse osteoporosis of the vertebrae. The inflammation stars at the junction of the intervertebral disc and body. Inflammation and erosion proceeds at the bone disc interface and new bone formation occurs from the edges of the annulus fibrosus known as syndesmophytes.
Spinal fractures should be distinguished from VFs, since they are not related to osteoporosis or low BMD and are the consequence of trauma (frequently minor traumatisms) in patients with an ossified spine. This event is a major complication in SpA, but is not strictly considered comorbidity, and thus its prevalence and mechanisms will not be detailed in this review.
Osteitis dikenal secara luas sebagai sinonim dengan erosi tulang pada SpA; namun, belakangan ini istilah osteitis pada SpA telah dikaitkan dengan pensinyalan tinggi MRI pada fat-suppressed sequences, yang disebut edema sumsum tulang / bone marrow edema (BME). Pada tulang, di mana terjadi pergantian sel tulang, peningkatan atau penurunan pergantian tulang yang tidak normal tidak selalu menyebabkan pengeroposan tulang (erosi/osteolisis) atau peningkatan densitas tulang (osteosklerosis), meskipun hal ini dapat terjadi dalam kondisi di mana patofisiologi dominan mendorong resorpsi osteoklastik (misalnya migrasi pra-osteoklas pada tulang) atau pembentukan tulang osteoblastik (misalnya penggantian sel MSC pluripotensial terhadap sel osteoblas). Pada spondyloarthritis aksial, adanya osteitis / BME dapat mengindikasikan peningkatan pergantian tulang. Peradangan dan iskemia, yang merupakan penyebab osteitis pada kondisi lain merupakan pemicu peningkatan pergantian tulang. Pada lesi tulang ankylosing spondylitis yang tipikal, analisis klasik radiografi dan studi post mortem secara luas menunjukkan urutan osteitis/erosi (disebabkan oleh peradangan) yang diikuti dengan osteosklerosis. Namun, masih belum jelas sejauh mana osteosklerosis muncul dari resorpsi tulang yang dipicu oleh peradangan, atau dipicu secara independen
Effects of inflammation and stress loading on bone and enthesis tissue in spondyloarthritis
Osteoproliferasi pada entheses merupakan konsekuensi pasti dari spondyloarthritis aksial yang progresif (yaitu ankylosing spondylitis), tetapi bukan merupakan temuan yang umum pada spondyloarthritis aksial. Pembentukan tulang pada entheses pada spondyloarthritis aksial bukanlah merupakan proses yang memicu rasa nyeri. Nyeri enthesopati lebih berhubungan dengan inflamasi dan elaborasi neuropeptida di jaringan 'enthesis organ' di sekitarnya (Clunie and Horwood, 2020).
Konsekuensi signifikan secara klinis dari proses ini adalah bagaimana osteoproliferasi dalam entheses, yang merupakan jaringan lunak yang dapat merespon dan beradaptasi dengan tekanan mekanis, akan mempengaruhi sifat mekanik entheses dan tendon serta ligamen yang melekat padanya. Osteoproliferasi entheseal progresif dikenal sebagai indikator utama disabilitas jangka panjang pada SpA, sebagian karena faktor morbiditas yang timbul dari biomekanik kekakuan skeletal dan fraktur. Dengan demikian, pencegahan osteoproliferasi pada entheses pada SpA merupakan tujuan pengobatan penyakit yang sangat berarti
Osteoproliferation at entheses is a defined consequence of progressive axSpA (i.e. AS), but is not an ubiquitous finding in axSpA. It would seem likely that bone formation at entheses in axSpA is not a pain-triggering process, similarly thought to be the case in DISH enthesopathy. Enthesopathy pain may relate more to inflammation and neuropeptide elaboration in surrounding ‘enthesis organ’ tissues.
Of significant consequence clinically is how osteoproliferation in entheses, which are soft tissues designed to respond and adapt to mechanical stress, will affect the mechanical properties of entheses and their attached tendons and ligaments.
Progressive entheseal osteoproliferation is well recognised to be a profound indicator of long-term disability in SpA, partly due to morbidity arising from the biomechanics of skeletal stiffness and of course fracture. Accordingly, prevention of osteoproliferation at entheses in SpA is an extremely worthwhile goal of disease treatment.
The exact etiology and pathogenesis of spondyloarthritis is still unclear.
However, some evidence suggests that genetics plays an important role in individual susceptibility, while environmental factors, resulting in infection and intestinal dysbiosis, also contribute to the pathogenesis of SpA.
One of the important things to know in spondyloarthritis is that the pathomechanism of bone abnormalities is an integral part of this disease. This mechanism is the basis for and clinically correlated with spondyloarthritis. The range of skeletal effects that occur in SpA includes ankylosing spondylitis, fragility fractures, focal and sub-entheseal osteitis and erosions, osteoproliferation, either in skeletal ligaments or peripheral tendons (enthesophytes) or axially (syndesmophytes), and osteosclerosis.
