2. Systemic inflammatory rheumatoid disease
doi:10.1093/rheumatology/kes113
Environmental factors, such as smoking and infection, may also influence the development rate of progression and severity of RA
The HLA complex helps the immune system distinguish the body's own proteins from proteins made by foreign invaders such as viruses
and bacteria
Gene provides instructions for making a protein that plays a critical role in the immune system
Recent findings suggest a genetic basis for disease development, expressing two HLA-DRB1, it is part of a family of genes called the
human leukocyte antigen (HLA) complex
The exact cause of RA remains unknown (idiopathic), but genetic and environmental influences clearly participate.
Dysregulated adaptive immunity can precede the clinical manifestation joint disease for many years
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by the progressive chronic inflammation of multiple joints
3. Early rheumathoid arthritis
The earliest event in RA pathogenesis is activation of the innate
immune response, which includes the activation of dendritic cells by
exogenous material and autologous antigens
Humans are exposed to millions of potential pathogens daily, through
contact, ingestion, and inhalation
Our ability to avoid infection depends in part on the adaptive immune
system, which remembers previous encounters with specific pathogens
and destroys them when they attack again
Adaptive immune responses, however, are slow to develop on first
exposure to a new pathogen as specific clones of B and T cells have to
become activated and expand (take a week)
Therefore, during the first critical hours and days of exposure to a new
pathogen, we rely on our innate immune system to protect us from
infection.
4. Early diagnosis-progressif treatment
Early diagnosis is
considered as the key
improvement index for
the most desirable
outcomes
Reduced joint
destruction
Less radiologic
progression
No functional
disability
Disease modifying
antirheumatic drugs
(DMARD)
Early diagnosis
remains challenging
as it relies heavily on
the clinical
information gathered
from the patient’s
history and physical
examination
supported by blood
tests, and imaging
analysis.
5. With poorly controlled or severe
disease
There is risk that extra-articular
manifestations such as keratitis,
pulmonary
granulomas,pericarditis/pleuritis,
small vessel vasculitis, and other
non specific extra-articular
symptoms will develop
While there is currently no cure
for RA, the treatment strategy
aims to expedite diagnosis and
rapidly achieve a low disease
activity state (LDAS)
Universally applied
pharmacologic therapy with non-
steroidal anti-inflammatory drugs
(NSAIDs) and corticosteroids have
proven effective in relieving
stiffness and pain
https://doi.org/10.1038/s41413-018-0016-9
6. Pathophysiology
The hallmark of rheumatoid
arthritis is synovitis
Synovitis caused by the influx
of mononuclear cells (T cells,
B cells, plasma cells, dendritic
cells, macrophages and mast
cells) or local activation (FLS)
The synovial lining then
becomes hyperplastic, and the
synovial membrane expands
large component of cell
activity that generates and
perpetuates inflammation
(pannus), its contains
numerous cytokines and
proteases
Cytokines (esp. TNF-α and
IL-1) and proteolytic
enzymes
Destruction of articular
cartilage
Cytokines produced by pro-
inflammatory effector T-cells
increase bone resorption by
osteoclasts
Bone reabsorption
(erosion/destruction)
7. Joints
Fibrous : synarthroses, minimal
to none ROM, no cartilage
(sutures of the skull)
Fibrocartilagenous :
amphiarthroses, limited ROM,
cartilage (pubic symphysis, sacro-
iliac, intervertebral)
Synovial :
diarthrosis, wide
ROM, cartilage and
ligaments (most of
extremity joints,
atlanto axial, costo-
vertebral, temporo
mandibular)
8. Articular manifestations
Chronic disease (>6 weeks
of symptoms)
Systemic inflammatory
Cardinal sign of
inflammation
Erythrocyte sedimentation
rate (ESR) and C-reactive
protein (CRP) are markers
of inflammatory conditions
increases also WBC >2000
cells/mm3
Symetrical joints
involvement (autoimmune
disease)
Polyarticular (>5 joints)
Stiffness predominate (>1
hour-morning stiffness)
improves with activity
Pain worse in the morning
but improves with activity
(better in the evening)
11. Treatment of rheumatoid arthritis
Surgical for advance disease
only
Medication
Non-steroidal anti-inflammatory
drugs (NSAIDs) = for
symptomatic relief only, they do
not modify the disease nor alter
disease progression
Disease modifying
antirheumatic drugs (DMARD)
are immunosuppressive and
immunomodulatory
agents (synthetic & biological),
it’s the core of RA therapy
Immunosupressants including
steroids
12. Physiotherapy management
TENS is generally a short-acting therapy (6–24 hours), and the most beneficial frequency is 70 Hz, it also has a high placebo effect
Electrostimulation is used in patients with RA to relieve pain. Transcutaneous electrical nerve stimulation (TENS) therapy is the most
commonly used method
With temperatures of 30° Celsius or lower, effects of these enzymes are negligibly small. Normal intra-articular temperature is 33° Celsius,
whereas it may rise up to 36° Celsius in patients with RA
Levels of destructive enzymes such as collagenase, elastase, hyaluronidase, and protease are affected by the temperature of local joints
Cartilage-destroying enzymes are produced within the inflamed joints of patients with RA
Cold application is preferred in active joints where intra-articular heat increase is undesired
By using heat, analgesia is accomplished, muscle spasm relieved, and elasticity of periarticular structures obtained. Heat can be used before
exercise for maximum benefit
Physiotherapy modalities are commonly used in the treatment of RA, include cold/hot applications, electrical stimulation, and hydrotherapy
Kavuncu V, Evcik D. Physiotherapy in rheumatoid arthritis. MedGenMed. 2004 May 17;6(2):3.
PMID: 15266230; PMCID: PMC1395797.
13. Non-Inflammatory Osteoarthritis
Knee osteoarthritis is characterized by structural modifications to primarily articular cartilage and the subchondral bone but also Hoffa’s fat pad,
synovia, ligaments and muscles, leading to the concept of observing OA as a WHOLE JOINT DISEASE
On the biochemical level, OA is characterized by uncontrolled production of matrix-degrading enzymes, including aggrecanases (a disintegrin and metallo
protease with trombospondine motifs (ADAMTSs)) and matrix metalloproteinases (MMPs), which result in the destruction of cartilage matrix
Its incidence increases with age, and thus this degenerative disease is a major problem in ageing populations.
This degenerative and progressive joint disease affects around 250 million people worldwide
The disease is characterized by a progressive degradation of articular cartilage leading to loss of joint mobility and function accompanied by chronic pain
Osteoarthritis (OA) is the most common form of arthritis and one of the leading causes of disability
doi:10.3390/genes11080854
15. Cellular and biochemical has been
driven by biomechanical stimulation,
it is not systemic inflammatory
disease “itis”
Information on SF WCC was
available in 55 subjects. An increase
in white cell count category (< 100,
101–250 and > 250–1,000 cells/mm3)
was associated with an increase in
synovial tissue volume (p = 0.028)
and with other MRI-based measures
of disease severity
(doi:10.1002/art.39829)
Effect entire joint as well as
subchondral bone not only cartilage
loss
Many patients has x-ray changes
associated with OA, however they
are asymptomatic
16. Osteoarthritis Risk Factors
Non modifiable :
Age, Sex
(female>Male),
Genetic
Modifiable :
Obesity,
Occupational,
Trauma,
Malalignment
18. Articular Cartilage
Articular cartilage (AC) is avascular, alymphatic, and aneural tissue with
chondrocytes as the only cell type in the cartilage tissue
Besides chondrocytes, AC is formed by the extracellular matrix (ECM),
which is composed of water (more than 70%) and organic components
such as collagen, aggrecan, proteoglycans, glycosaminoglycans and
glycoproteins
All cartilage components are synthesized by chondrocytes,which play a
key role in maintaining the cartilaginous environment by balancing the
production of ECM components (degrading enzymes, providing minimal
and balanced turnover between anabolic and catabolic processes)
AC metabolism is stimulated by mechanical loading, detected by
mechanoreceptors on the cell surface
Through the process of mechanotransduction, mechanical signals
modulate the biochemical activity of chondrocytes, inducing the
biosynthesis of molecules to preserve the integrity of the tissue.
doi:10.3390/genes11080854
19. Resulting in the depletion of matrix components and, due to lack of AC regenerative capacity, leads to irreversible destruction, thus
making it the most apparent triggering cause of OA
Conversely, excessive mechanical loading leads to a quantitative imbalance between anabolic and catabolic activity
The importance of proper mechanical loading is demonstrated by the fact that insuficient biomechanical stimuli, such as
immobilization, can lead to reduced thickness (>10%) and softening of AC in the knee joint, in the absence of normal joint loading
Furthermore, biomechanical stimulus generated by dynamic compression during moderate exercise can reduce the synthesis of
proteolytic enzymes, regulate the metabolic balance, and prevent the progression of cartilage damage
The activation of these mechanoreceptors initiates intracellular signaling cascades, leading to the tissue remodeling process.
20. Cartilage extracellular matrix changes
Cartilage matrix changes in osteoarthritis defined by degradation of proteoglycans and cleavage of type II collagen fibres by matrix degrading
enzymes ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) and MMPs (matrix metalloproteinases)
21.
22.
23. Chondrocytes changes in OA
Chondrocyte injured
(nature “genetic factor” and
nurture “environment-
biomechanical factors”)
Chondrocyte proliferation
secrete matrix
metalloproteinases,
inflammatory mediators,
collagenase, protease leads
to matrix remodeling
Secondary inflammation in
synovium and subchondral
bone
Significant loss of cartilage
due to chondrocytes dies
and significant changes of
subchondral bone
(osteophytes)
Its a cartilage loss and
bone growth
24. Local Pathological Process
The histopathological scoring of synovitis in synovium obtained from OA patients during total knee arthroplasty showed a
significant correlation between synovitis and pain intensity (Eitner et al., 2017).
A positive relationship between inflammatory changes in the joint and pain was also shown in recent MRI studies, pain in knee OA
fluctuates with changes of bone marrow lesions and synovitis, when bone marrow lesions become smaller, the pain is reduced, and
the risk of frequent pain decreases.
E.g., knee pain occurred in a higher proportion of OA patients with Kellgren/Lawrence (K/L) grade 4 than of OA patients with K/L
grades 2 and 3
Some studies reported associations between the structural damage of the joint (cartilage and bone) and pain (Malfait and
Schnitzer, 2013), frequent pain displayed greater rates of medial cartilage loss (Eckstein et al., 2011), osteophytes were strongly
associated with knee pain (Kaukinen et al., 2016).
A systematic literature search of Bedson and Croft (2008) showed that 15%–76% of the patients with knee pain had radiographic
indications of OA
doi: 10.3389/fnmol.2017.00349
25. BML are patterns from magnetic resonance images (MRI) that have been linked with pain and cartilage
degeneration.
However, earlier bony changes, such as Bone Marrow Lesions (BML detected by MRI), are a relatively recent
discovery and their potential utility in predicting OA progression
Changes in subchondral bone (sclerosis) at late stages of OA, identifiable by plain film X-ray, have long been
recognized as a hallmark of OA
26. Bone Marrow Lession
The MRI signal that defines
BMLs may represent physical
damage (microdamage), or a
response to such damage in
the subchondral bone
From a mechanical
perspective, microdamage can
be generated by a single
(monotonic) significant
loading event, or by multiple
(up to millions) cycles at
lower magnitudes
These lesions occur in areas
where there is increased
stress
There is already evidence
that BMLs are strongly
related to OA
Their presence increases the
risk of cartilage loss,
likelihood of OA progression,
and of development of knee
pain
DOI:https://doi.org/10.1016/j.joca.2012.08.020
27. Synovitis
Locally, all of these components can induce hydrolytic enzymes resulting in cartilage breakdown
secondary to proteoglycan and collagen destruction.
In OA, the synovial fluid has been found to contain multiple inflammatory mediators including
plasma proteins, prostaglandins (PGE2), leukotrienes, cytokines, growth factors, nitric oxide
It can be present in early stages of the disease but is more prevalent towards the more advanced
stages and can be related with severity
Synovitis is an infiltration of inflammatory cells into the synovium (a common finding of OA)
28.
29. Osteoarthritis is a biomechanical
disease
doi:10.4414/smw.2012.13583
Pathomechanics
of
osteoarthritis
Cartilage
degradation
Subchondral
bone changes
Decrease joint
congruency
Malalignment
Increased
mechanical
stress
Ligament
derangements
Muscular
impairments
OA is regarded
as a whole joint
disease
31. Conservative osteoarthritis treatment
Diet and weight loss are important therapeutic measures, because they result in a direct reduction of load exerted on
the knee during locomotion
Valgus knee braces and gait modifications with a toe-out gait have been shown to reduce knee adduction moment
significantly (doi: 10.1002/1529-0131(200008)13:4<191::aid-anr3>3.0.co;2-c)
The use of lateral wedge insoles in patients with OA led to a immediate reduction of pain during walking and a
reduction of the knee adduction moment (torque) by 4–14% (doi: 10.1136/bmj.d2912)
Barefoot walking has been shown to reduce the knee adduction moment by 7–13% compared to normal shoes and up to
23% compared to high-heeled shoes in healthy women (doi: 10.1016/S0140-6736(00)04312-9 & doi: 10.1002/art.22123 )
Conservative treatment strategies include footwear interventions, braces, gait modifications, muscle strengthening and
weight loss