1.

6 Learning Issues 1

1.6.1 Anatomy and physiology of normal joint

1.6.2 Normal immunity

1.6.3 Normal metabolism of purin

1.6.4 The pathophysiology of joint pain

1.6.5 The pathophysiology of dyspnea

1.6.6 The pathophysiology of rheumatoid arthritis

1.6.7 The pathophysiology of systemic lupus erythematosus

1.6.8 The pathophysiology of sprain and strain

1.6.9 The pathophysiology of gout arthitis

1.6.10 The pathophysiology of osteosarcoma

1.6.11 The pathophysiology of polymyalgia rheumatica

1.6.12 The pathophysiology of rheumatic fever

2.2 Answers of Learning Issues 1

2.2.1 Anatomy and physiology of normal joint

The joint is an area that connects the two bones (Horowitz et al, 2019).
Components found in the joints and their functions include:

1. Cartilage
Cartilage is a specific connective tissue to lubricate the surface of the joint and to
provide resistance to the stresses that the joint receives. This structure does not have
blood vessels, lymph vessels, and nerves so it is prone to be affected by internal and
external injury from the environment (Fox et al, 2009).

2. Synovial membranes
Synovial membrane is a mesenchymal tissue that limits joint arthritis, bursae, and
tendon membranes. This structure consists of intima inner layer and subintima outer
layer. Intima inner layer consists of one or two layers of synoviocytes that are rich of
macrophages, while the outer subintima layer consists of three layers of synoviocytes
that are rich of fibroblasts, collagen, and other extracellular matrices (Sousa et al,
2014).

3. Synovial fluid
Synovial fluid is produced by the synovial membrane, especially in the inner layer
intima. This fluid serves to lubricate the cartilage, chondrocyte activity, and provide
nutrition to the joints. Macrophages are also present in synovial fluid. Fibroblasts
express CD55 surface markers to separate themselves from macrophages. Under
pathological conditions, synovial macrophages contribute to cartilage destruction due
to overproduction of proinflammatory cytokines and the release of TGF-β, BMP-2,
and BMP-4 (Sousa et al, 2014).

4. Ligaments
Ligament’s function is to support and limit joint movement (Horowitz et al,
2019).

5. Tendons
Tendons have a role to attach bones to muscles to control joint movements
(Horowitz et al, 2019).

6. Meniscus
The meniscus is a part of the curve and is mainly present in the knee joint
(Horowitz et al, 2019).
2.2.2 Normal immunity

Immunity is the body's ability to protect itself by holding or removing foreign

objects (such as bacteria or viruses) or abnormal cells (cancer cells) that are potentially
harmful. The first line of defense against foreign intruders is the epithelial barrier that
surrounds the outer surface of the body (skin) and lines the body cavities (such as the
digestive tract and lungs) in contact with the external environment. blood leukocytes
(white blood cells) and tissue cells derived from leukocytes also help the body's
defenses. These cells work together in two ways to prevent disease: (1) by actually
damaging invading bacteria or viruses through phagocytosis and (2) by forming
sensitized antibodies and lymphocytes, which can destroy or make agents less active.

Leukocytes
There are six types of white blood cells commonly found in blood. The six cells
are polymorphonuclear neutrophils, polymorphonuclear eosinophils,
polymorphornuclear basophils, monocytes, lymphocytes, and sometimes plasma cells.
Neutrophils and tissue macrophages that primarily attack and destroy bacteria, viruses,
and other harmful agents that invade the body.

Lymphoid tissue, collectively, is the tissue that produces, stores, or processes

lymphocytes. These tissues include the bone marrow, lymph nodes, spleen, thymus,
tonsils, adenoids, appendixes and lymphoid tissue aggregates in the lining of the
digestive tract called Peyer’s patch or gut-associated lymphoid tissue (GALT).
Lymphoid tissue is in strategic places to inhibit the entry of microorganisms before
they have the opportunity to spread far. For example, lymphocytes that occupy the
tonsils and adenoids are in an advantageous place to respond to inhaled microbes,
while microorganisms that enter through the digestive tract are immediately
encountered by lymphocytes in the appendix and GALT. Potential pathogens that gain
access to the lymph are filtered through the lymph glands, where the pathogens are
exposed to lymphocytes and macrophages lining the lymphatic channels by the lymph
nodes in the lymph. Through the work of the lymphocyte population and its
macrophages, the spleen cleanses the blood that passes through it from
microorganisms and other foreign objects and removes obsolete red blood cells. The
thymus and bone marrow play an important role in processing T and B lymphocytes,
to prepare both for implementing specific immune strategies.

The protective community is produced by the cooperation of two separate but

interdependent immune system components: the innate immune system and the
adaptive or acquired immune system. The response of these two systems
differ in terms of time and selectivity of their defense mechanisms.

The innate immune system includes the body's non-specific immune response that
reacts immediately to exposure to a threatening agent. This non-specific response is a
built-in (existing) defense mechanism that non-selectively defends the body from any
kind of foreign or abnormal objects, even at the initial exposure to it. This response
provides a first-line defense against a variety of threats, including infectious agents,
chemical irritants, and tissue injury due to trauma or burns. The response of the
adaptive immune system is mediated by B and T lymphocytes. Each B and T cell can
recognize and defend itself against only one particular type of foreign body, for
example one type of bacteria.

There are two classes of immune response obtained: antibody-mediated

immunity, or humoral immunity, which involves the formation of antibodies by B
lymphocyte derivatives known as plasma cells, and cell-mediated immunity, which
involves the formation of active T lymphocytes, which directly attack cells that are not
is desirable.

Because antibodies are present in the blood, antibody-mediated immunity is

sometimes known as humoral immunity, as a reference from the ancient Greeks who
used the term humors to contain bodily fluids.

Default defenses include:

1. Inflammation, a non-specific response to tissue injury, when the phagocytic
 specialists of neutrophils and macrophages play a large role, together with supportive
input from other types of immune cells.

2. interferon, a group of proteins that non-specifically defends against viral infections.

3. Natural killer cells, a special group of lymphocyte-like cells that spontaneously and
non-specifically lyses (break down) and thereby destroy host cells infected with
viruses and cancer cells.

4. The complement system, a group of inactive plasma proteins which, when activated
sequentially, will damage foreign cells by attacking their plasma membranes.

2.2.3 Normal metabolism of purin

De novo synthesis of purine nucleotides

Pathway:
ribose 5-phosphate → phosphoribosyl pyrophosphate (PRPP) → (10 steps) → inosine-
5'-monophosphate (IMP) → (2 steps each) → adenosine-5'-monophosphate (AMP) or
guanosine-5'-monophosphate (GMP)
Nitrogen or carbon donors:
2 glutamines, glycine, aspartate, hydrogen carbonate (HCO3-), 2 tetrahydrofolic acids
(THF)
Energy donators:
ATP and GTP

Phases
1. PRPP synthesis
Reaction:
ribose 5-phosphate + ATP → PRPP + AMP
Enzyme:
PRPP synthetase (ribose-phosphate pyrophosphokinase)

2. IMP synthesis
Key enzyme (committed step of the de novo synthesis):
glutamine PRPP amidotransferase
Reaction:
PRPP + glutamine → 5 phosphoribosylamine (PRA), glutamate, PPi
- Four out of 10 steps require ATP hydrolysis
- Two out of the 10 steps require THF as a cofactor
Regulation
- Allosteric activation by PRPP
- Allosteric inhibition by AMP, GMP, and IMP

AMP and GMP synthesis

AMP synthesis: oxygen atom at C6 atom of IMP exchanged by an amino group (NH2
group)
1. First reaction step:
IMP + aspartate + GTP → adenylosuccinate + GDP + Pi
Enzyme:
adenylosuccinate synthetase
2. Second reaction step: adenylosuccinate → adenosine-5'-monophosphate (AMP) +
fumarate
Enzyme: adenylosuccinate lyase

GMP synthesis: attachment of an amino group to the C2 atom

1. First reaction step:
IMP + H2O + NAD+ → xanthosine monophosphate (XMP) + NADH + H+
Enzyme:
IMP dehydrogenase
Clinical significance:
IMPdehydrogenase is inhibited by mycophenolic acid
2. Second reaction step:
XMP + ATP + glutamine → guanosine-5'-monophosphate (GMP) + AMP + PPi +
glutamate
Enzyme: guanylate synthetase(xanthylate aminase)

Kinases phosphorylate AMP and GMP :

yield ATP and GTP, respectively.

Inhibitors of de novo purine synthesis

1. 6-mercaptopurine (6-MP): inhibit conversion of PRPP to IMP
Prodrug of 6-MP: azathioprine
2. Mycophenolate and ribavirin: inhibit inosine monophosphate dehydrogenase
3. Hydroxyurea: inhibits both de novo purine and pyrimidine synthesis via
ribonucleotode reductase
Salvage pathway
Free purine bases can be directly attached to PRPP to yield purine nucleotides.
This purine nucleotide synthesis pathway is associated with significantly less energy
consumption than de novo synthesis.
Description:
recycling of the purine bases adenine, guanine, and hypoxanthine
Substrate:
PRPP with adenine or PRPP with guanine and hypoxanthine
Product:
AMP or GMP and IMP
Enzymes:
adenine phosphoribosyltransferase (APRT) and hypoxanthine-guanine
phosphoribosyltransferase (HGPRT)
Regulation:
inhibition of APRT by adenine nucleotides, inhibition of HGPRT by IMP and GMP
 Purine nucleotide degradation
Purine nucleotides are degraded via reaction steps that are different than those used for
assembly. Because the purine ring system cannot be enzymatically cleaved in humans,
purine is metabolized into uric acid and excreted in urine as urate anion.
Description:
degradation of purinenucleotides to the respective nucleotideswith subsequent
oxidation of the xanthine that is formed to uric acid
Reaction steps in AMP degradation:
AMP → adenosine → inosine → hypoxanthine → xanthine → uric acid
Reaction steps in GMP degradation:
GMP → guanosine→ guanine→ xanthine→ uric acid
Reaction steps in XMP degradation:
XMP → xanthosine → xanthine → uric acid
Important enzymes
- Adenosine deaminase: catalyzes the deamination of adenosine to inosine
- Xanthine oxidase (xanthine dehydrogenase): catalyzes the conversion of
hypoxanthine to xanthine and xanthine to uric acid
- Guanine deaminase: catalyzes the deamination of guanine to xanthine

2.2.4 The pathophysiology of joint pain

Mechanisms of pain
Pain classification
Traditionally, pain has been regarded as being either nociceptive (arising in
response to tissue injury) or neuropathic (arising in response to nerve injury).
Although this distinction has had some therapeutic utility, it has served to maintain the
Cartesian concept of a fixed immutable pain system that faithfully transmits
information from a site of injury to pain centres within the brain. Although this is
largely true after acute injury, it is clear from epidemiological studies that in the
presence of persistent disease a range of additional factors, often unrelated to the
musculoskeletal system, serve to modify activity within pain (nociceptive) pathways.
Implicit in recent classification schemes is the notion that acute and chronic pain
states are different and that functional changes within the nociceptive system are
important in determining the signs and symptoms experienced by individuals with
somatic disease. Currently, four different pain states are recognized. The first of these,
nociceptive pain, refers to those transient symptoms and signs that arise in response to
acute injury and reflects the activation of specialized pain receptors (nociceptors) and
corresponding activity in more central pathways. Under these conditions, symptoms
broadly reflect the initiating stimulus or injury; treatment at a peripheral level is likely
to be successful.
 In contrast, neuroplastic pain (also called inflammatory pain) occurs in response
to more persistent tissue injury and is the most common pain state associated with
musculoskeletal disease. It arises as a result of mediators released from damaged
tissues acting to increase the excitability of the nociceptive pathway and has the effect
of making everyday activities such as standing or walking painful. Effective therapy
requires that attention be directed to both the originating injury and those additional
factors that influence nociceptive activity.
Third, neuropathic pain occurs in the presence of nerve injury, as might occur in
association with carpal tunnel syndrome or after lumbar disc prolapse. Ectopic
expression of ion channels, receptors and related phenomena occur in both injured and
neighbouring non-injured neurons, with resultant regional pain hypersensitivity and
sensory disturbance.
There is currently debate as to the origins of a fourth pain category, idiopathic
pain, which covers such medically unexplained disorders as fibromyalgia syndrome,
irritable bowel syndrome and tension headache. In all of these disorders, evidence for
peripheral pathology is minimal and symptoms are considered to reflect disordered
pain processing at more central levels.

Arthritic pain
At a local level, mediators released from synovium, bone or other tissues will
induce the sensitization of articular pain receptors. The clinical correlate of
sensitization at this peripheral level is that musculoskeletal symptoms will be
localized, with a relatively close relationship to mechanical stimuli such as walking or
standing. Treatment with systemic or topical therapies designed to reduce
inflammatory mediators might be expected to have a beneficial effect, which is in
accord with clinical experience.

In chronic conditions such as osteoarthritis (OA) or rheumatoid arthritis (RA),

neural sensitization will not be confined to the periphery. The finding of increased
areas of punctate hyperalgesia in patients with RA after topical application of
capsaicin is in accord with increased excitability of spinal neurons in this condition.
Clinically, this leads to enhanced pain perception at the site of injury, as well as to the
development of pain and tenderness in normal tissues both adjacent to and removed
from the primary site.
Spinal nociceptive processing in arthritic patients is under the influence of descending
inhibitory controls and inputs from other somatic structures. Both previous pain
episodes and genetic factors are also likely to influence activity. The multiplicity of
mediators involved provides an opportunity for therapeutic intervention, and many of
the commonly used therapeutic strategies including acupuncture, transcutaneous
 electrical nerve stimulation (TENS) and pharmacological agents such as non-steroidal
anti-inflammatory drugs (NSAIDs) and the weaker opioid drugs are likely to be
exerting an effect at this level.
Psychological and social factors have been shown to be the most important
predictors of both the presence and severity of pain in a range of disorders including
RA, OA and persistent low back pain. It seems logical to assume, but remains
unproven, that these external factors modulate nociceptive processing at a supraspinal
or cortical level. The overall effect is to enhance pain perception and to increase pain
reporting and behavioural change, including disability.
Reliance on peripherally or spinally active therapies alone is unlikely to prove
successful in those patients with more general symptoms arising from central
sensitization. Prostanoid and opioid receptors are constitutively expressed in cortical
tissues, and the relevant therapeutic agents are undoubtedly exerting an effect at this
level. Nevertheless, additional measures often using non-pharmaceutical approaches,
including education and cognitive behavioural therapy, may be required.
Despite the progress that has been made over the past several decades to define
key pain processes, the need remains to translate this knowledge into better assessment
techniques and more effective pain therapy. Attempts to devise mechanism-based
approaches to therapy have met with mixed success, in part as a result of lack of
clinical techniques by which to define specific nociceptive processes. Quantitative
sensory tests and cortical imaging can be used to quantify central changes associated
with articular pathology but are not suitable for more general clinical use. In practical
terms, the duration of symptoms is important: the likelihood of a significant central
component increases with time. Referred pain and tenderness away from the site of
joint pathology are suggestive of a neuroplastic pain state, whereas radicular pain is
inevitably associated with neuropathic syndromes.

2.2.5 The pathophysiology of dyspnea

Dyspnea is defined as a subjective experience of breathing discomfort that consists

of qualitatively distinct sensations that vary in intensity and may either be acute or
chronic. Dyspnea is a normal symptom of heavy exertion but maybe pathological if it
occurs in unexpected situations.

Dyspnea is a complex symptom that arises from physiological impairment and

alerts one to the possibility of threatened homeostasis. The discomfort primarily
occurs as a result of either cardiovascular or respiratory system compromise, but may
also be attributed to metabolic derangements, neuromuscular disorders or psychogenic
conditions. The condition is perceived as increased respiratory work/effort, tightness,
or air hunger, which are caused by pulmonary ventilation not matching the drive to
 breathe. The dissociation between pulmonary ventilation and respiratory drive arises
from a mismatch between afferent receptors in the airways, lungs and chest wall
structures, and central respiratory motor activity. In the lungs, juxtacapillary receptors
are sensitive to pulmonary interstitial edema, while stretch receptors signal
bronchoconstriction. Muscle spindles in the chest wall signal the stretch and tension of
the respiratory muscles. Efferent signals are the motor neuronal signals descending to
the respiratory muscles, the most important being the diaphragm.

Three main components contribute to dyspnea: afferent signals, efferent signals,

and central information processing. The central processing in the brain compares the
afferent and efferent signals and dyspnea results when a mismatch occurs between the
two, such as when the need for ventilation (afferent signaling) is not being met by
physical breathing (efferent signaling). The afferent receptors allow the brain to assess
whether the efferent or motor commands to the ventilator muscles are effective,
meeting the required demands of airway pressure, airflow, and/or lung movement.
When these respond inappropriately to the command, the intensity of the dyspnea
increases. The sensory cortex is simultaneously activated when motor signals are sent
to the chest wall, resulting in the conscious sensation of muscular effort and
Breathlessness. There is also a strong psychological component to dyspnea, as some
people may become aware of their breathing in such circumstances but not experience
the distress typical of the condition.

2.2.6 The pathophysiology of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that appears

more frequently in women than men, which is predominantly observed in the elderly.
RA mainly affects the synovial joint lining and can cause progressive disability, early
death, and socioeconomic burden. Early diagnosis is considered as the main
improvement index for the most desirable results (ie, reduced joint damage, less
radiological development, no functional defects, and modification of antirheumatic
drug disease (DMARD) - free remission) and cost effectiveness as the first 12 weeks
after the initial symptoms occur are considered as optimal window therapy. However,
early diagnosis remains challenging because it relies heavily on clinical information
collected from patient history and physical examination supported by blood tests, and
imaging analysis.

Pathophysiology
Rheumatoid arthritis is a heterogeneous pathogen. The presence of autoantibodies
(seropositivity) is associated with more severe symptoms and joint damage, and
increased mortality. This is most likely due to the formation of immune complexes by
ACPA with antigens containing citrulline and subsequent RF binding, which can cause
abundant complement activation. Detection of autoimmune responses to citrullinated
self-improvement is a major advance. ACPA can bind citrullinated residues to many
independent proteins including vimentin, α enolase, fibronectin, fibrinogen, histones,
and type II collagen. The tissue in which the immune response is activated is
uncertain, but the lungs are attractive candidates, which is consistent with the role for
smoking in rheumatoid arthritis and the presence of shared citrullinated peptides in
lung biopsy and synovial tissue. Circulating ACPA can be detected up to 10 years
before diagnosis - called pre-rheumatoid arthritis. Over time, the concentration and
diversity of ACPA epitopes increases, as does the concentration of serum cytokines,
especially before the onset of articular involvement. ACPA can be an IgG, IgA, or
IgM isotype, is an indication of T-cell assistance, and has a changed glycosylation
status that gives rise to an Fc receptor and a binding citrullinated antigen. ACPA-
producing B cells are present in the synovium and circulation. ACPA itself can be
pathogenic, either by activating macrophages (for example, by binding to tolls such as
receptors through bound antigens, or by binding to Fc receptors, or both), or by
activating osteoclasts through the formation of immune complexes and F-receptor
involvement or, perhaps, by binding citrullinated vimentin membranes, thereby
increasing bone loss. With effective therapy, both RF and ACPA concentrations
decrease, but patients rarely become negative ACPA, whereas RF decreases deeper
and more frequently and patients can experience RF negatives. Anti-carbamylating
and acetate autoantibodies have also been identified in patients with rheumatoid
arthritis; Additional autoantibodies, directed towards modification of other post-
translational proteins may appear. RF is more directly involved in the mechanism of
macrophage activation and induction of cytokine activation than ACPA. ACPA can
form immune complexes that interact with RF, thereby potentiating its effects on the
inflammatory and destructive response. Little is known about the T-cell response that
supports this process. Using HLA-DRB1 * 0401 tetramers, an increase in the number
of citrulline T-helper-1 cells has been found in the circulation of patients with
rheumatoid arthritis, especially in those who have early disease, although their
contribution to the autoimmune mechanism is still uncertain. Lymph node biopsy in
early rheumatoid arthritis shows activation of T-cells that are far from synovium.

Clinical Manifestations
RA is a polyarticular symmetrical disease that involves many joints bilaterally. A
patient with RA usually experiences pain and swelling in the joints of the hands and
feet. Swelling mainly in the wrists and metacarpophalangeal, metatarsophalangeal, and
proximalinterphalangeal joints. This is accompanied by morning joint stiffness lasting
more than 30 minutes and usually up to several hours. This swelling is usually "soft"
because of synovitis and effusion, in contrast to swelling of osteoarthritis which is
"hard" (reinforced). When the fingers are involved, the swelling is centered around the
joint (fusiform) rather than involving the whole digit ("sausage digit"), as seen in
psoriatic arthritis. Small and large joints can be involved, although the distal
interphalangeal joints are rarely affected. Small joints include metacarpophalangeal,
metatarsophalangeal, proximal interphalangeal, and wrist joints. Large joints include
ankles, knees, elbows, and shoulder joints.

Diagnosis
There are no diagnostic criteria for RA. However, the 2010 classification criteria,
although mainly developed for the identification of homogeneous patient populations
in RA clinical studies, can help doctors make a diagnosis. RA classification requires
the presence of at least 1 joint that is clinically swollen and at least 6 out of 10 points
from the scoring system. This 2010 criterion has a sensitivity of 82% and a specificity
of 61%.

Laboratory examination
Abnormal values from laboratory tests are the most typical RA feature.
Erythrocyte sedimentation (ESR) and C-reactive protein (CRP) levels provide the best
information about the acute phase response. CRP levels are shown to be significantly
correlated with disease severity as well as radiographic changes. Increased levels of
this inflammatory marker indicate higher disease activity. These tests may also help in
evaluating the efficacy of treatment.

Automatic antibodies such as RF and anti-CCP are very helpful for the diagnosis
of RA. Anti-CCP antibodies show comparable sensitivity but greater specificity than
RF for the diagnosis of RA. The combination of anti-CCP and RF increases diagnostic
specificity for RA.
2.2.7 The pathophysiology of systemic lupus erythematosus

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease marked

by the forming of various antibodies arranged in an immune complex that cause
inflammatory reaction in many different organs. This disease can manifest widely,
depending on which organ it affects. Sign and symptoms seen in patients with SLE can
differ from the mildest such as arthritis and rash, to the most severe such as nephritis
and cerebral lupus.

Epidemiology

Epidemiologically speaking, lupus is more common in young woman, usually in

their reproductive age. In Asia, lupus is estimated to occur in 17 out of 100.000
people. Even though perceived as a deadly disease, SLE survival rate has been
increasing for the last five decades. Nowadays, SLE has 90% ten years survival rate,
whilst 15 years survival rate is 80%.

Etiology
 Etiology of lupus is still unknown, however some factors are predicted to have
contribute to the disease’s progression. It is assumed that external factors trigger the
development of this disease in people with susceptible gene. There are many gene that
may have relation with this disease, however lupus is often associated with HLA gene.
Based on previous study, HLA DQ1 and DQ2 are stated to have relation with sub-
acute cutaneous lupus, while HLA DR2 is associated with lupus nephritis and HLA
DR3 shows notable musculoskeletal manifestation. Environmental factors such as
ultraviolet B (UVB) in sun light triggers apoptosis of keratinocytes and is predicted to
have the ability to change Ro and RNP’s DNA more immunogenic. Other
environmental factors that may contribute to lupus are medications, physical and
psychological stress. Hormonal factors also contribute to lupus progression, as lupus is
more common in women, estrogen and prolactin are linked to this disease. Estrogen
apparently have the ability to prolong T cells’ life and stimulate B cells to release
cytokines and autoantibodies, thus supporting the development of lupus.

Pathogenesis

When a cell dies, pieces of cellular materials such as nucleosomes and anionic
phospholipids that used to be embedded within the cell, are presented to the cell’s
surface. In lupus, these materials will be presumed as antigen, thus trigger immune
response. It is believed that the removal of these apoptotic cells is compromised
because of the impaired phagocytic cells, resulting in suboptimal disposal of dying
cells and antigen recognition in patients with SLE.

SLE develop when T-lymphocyte identifies an antigen-presenting cell (APC).

Next, T-cell receptor binds to the major histocompatibility complex (MHC) portion of
the APC, stimulating cytokines release, inflammation, and B-cell stimulation.
Stimulation to B cell will encourage the release of Immunoglobulin G (IgG)
autoantibodies that can cause tissue damage. Unlike the normal immune response in
healthy adults, autoantigen-specific T cells and B cells may also interact and produce
harmful autoantibodies. To sum up, Hyperactive B cells in conjunction with the
impaired removal of apoptotic cellular material results in the formation of immune
complex that can cause inflammation and tissue damage related to SLE.

Many of the autoantibodies identified in SLE target nuclear components of cells.

One of them is the antinuclear antibodies (ANAs). ANA is essential in the diagnosis of
SLE. It has been identifies that ANAs are anti-double stranded (ds) DNA antibodies,
these antibodies are linked to SLE-induced kidney and skin disease and highly specific
for SLE and are present in a significant number of patients. ANAs also interact with
single-stranded (ss) DNA as well as with RNA. Other examples of ANAs are the anti-
Ro and anti-La antibodies that, when detected during pregnancy, have been linked to
fetal heart damage as well as the anti-Smith (Sm) antibodies, which are a marker of
kidney disease. Second group of autoantibodies targets the phospholipid moiety of the
prothrombin activator complex as well as cardiolipin. These antiphospholipid
antibodies can lead to abnormal clotting as well as loss of pregnancy.

Clinical Presentation

SLE has a wide range of clinical manifestation, 75% of SLE are accompanied
with cutaneous manifestation and a quarter of SLE started off from cutaneous lesion.
Ninety percent patients came with musculoskeletal lesion and half of SLE patients
came with renal involvement. Because of the wide and unspecific clinical
manifestation, Systemic Lupus Internation al Collaborating Clinics (SLICC) group
developed a new set of classification criteria in 2012. The criteria can be seen below:

– Acute cutaneous lupus erythematosus (including “butterfly rash“)

– Chronic cutaneous lupus erythematosus (e.g., localized or generalized discoid lupus

erythematosus)

– Oral ulcers (on palate and/or nose)

– Non-scarring alopecia

– Synovitis (≥ 2 joints) or tenderness on palpation (≥ 2 joints) and morning stiffness (≥

30 min)

– Serositis (pleurisy or pericardial pain for more than 1 day)

– Renal involvement (single urine: protein/creatinine ratio or 24-hour urine protein,

>0.5 g)

– Neurological involvement (e.g., seizures, psychosis, myelitis)

– Hemolytic anemia

– Leukopenia (<4000/μL) or lymphopenia (<1000/μL)

– Thrombocytopenia (<100 000/μL)

Immunological criteria

– ANA level above laboratory reference range

– Anti-dsDNA antibodies

– Anti-Sm antibodies
– Antiphospholipid antibodies (anticardiolipin and anti-β2-glycoprotein I [IgA-, IgG-
or IgM-] antibodies; false-positive VDRL [Venereal Disease Research Laboratory]
test)

– Low complement (C3, C4, or CH50)

– Direct Coombs test (in the absence of hemolytic anemia)

Diagnosis

Diagnostic approach to SLE consisted of history taking, physical examination,

and laboratory examination. As mentioned in previous paragraph, most 75% patients
came with skin lesion. This cutaneous manifestation of SLE is divided into two, lupus
erythematosus (LE)-specific and LE-non-specific. LE-specific manifestation is the
acute cutaneous lupus erythematosus (ACLE), which may occur as a butterfly rash or
in the form of a generalized maculopapular exanthema. Discoid lupus erythematosus
that is followed by alopecia is also commonly seen in patients. The LE-non-specific
manifestations include, among others, vascular skin lesions such as periungual
teleangiectasia, livedo racemosa, Raynaud syndrome. Musculoskeletal lesion such as
tendovaginitis and synovitis are commonly seen in SLE patients. These manifestation
can be confirmed through sonography and/or manetic resonance imaging. Joint
deformation may also occur if chronic recurring arthritis is found. This deforming but
nondestructive joint disease is termed Jaccoud arthropathy. Renal involvement may
also happen in 50% of patients. Lupus nephritis is a glomerular nephritis, typically
with proteinuria and erythrocyturia (particularly dysmorphic erythrocytes) as well as
erythrocyte cylinders in the urinary sediment. Most common cardiovascular
manifestation of SLE include Libman–Sacks endocarditis, as well as pericarditis or
myocarditis and coronary arteritis.

Laboratory examination in SLE is essential in diagnosing SLE. Screening test is

needed before conducting the diagnostic standard test. Complete blood count may
show cytopenias such as thrombocytopenia and/or leukopenia and lymphopenia. A
high erythrocyte sedimentation rate is also a characteristic of SLE. CRP protein may
be normal or slightly increased. Renal parameters such as serum creatinine, urinary
status, and urine sediment should be tested if renal involvement is suspected.

Finally, it is recommended to make a diagnosis after getting antinuclear

antibodies (ANA) analyzed by indirect immunofluorescence tests (HEp-2 cells). In
patients with positive ANA and a homogeneous fluorescence pattern it is useful to
determine anti-dsDNA antibodies. The findings of ELISA (high sensitivity, low
specificity) should be confirmed by radioimmunoassay (RIA, also known as Farr
assay; high specificity, suitable for monitoring). If ANA is found to be positive,
further laboratory exam should also be done according to patient’s clinical
manifestations.
2.2.8 The pathophysiology of sprain and strain

I. Strain
The definition of a muscle strain is a stretch or rupture of a muscle fiber. Mostly muscle
strains occur at the musculotendinuous junction caused by indirect trauma. This strain often
occurs in fast runners or athletes in jumping fields. The cause of this muscle strain is
excessive stretching in the muscles and muscle contractions that are too strong.

Classification of muscle strains:

-Strain class I. Mild muscle strain, only a few muscle fibers that are stretched or torn. At this
stage normal muscle strength
-Strain level II. Moderate stage, with more stretched fiber and more severe muscle pain.
There is also mild swelling, decreased muscle strength and sometimes bruises.
-Strain level III. Muscle tears are quite large, sometimes causing a "pop" sensation. This
stage is a serious injury that causes loss of muscle function, as well as pain, swelling,
tenderness and discoloration. Can be seen there is a muscle gap under the skin.

Symptoms of muscle strains include:

-Muscle aches and tenderness, especially after sudden stretching activity

-Pain usually increases when the muscle is moved but disappears at rest

-Muscle swelling, discoloration or both

-Muscle cramps or spasms

-Decrease until the loss of muscle strength

-Pop when an injury occurs

-Muscle gap under the cult.

Additional examination: x-ray and monocytosis.

II. Sprain
Most ankle sprain injuries are caused by an increased moment of supination in the
subtalar joint, which is often the result of the position and magnitude of the ground reaction
force which is projected vertically on initial foot contact.
Mechanism:
1. ankle inversion accompanied by internal rotation of the foot
2. plantarflection accompanied by subtalar joint inversion
 3. Sometimes there is an external rotation of the heel resulting in an ankle injury

symptoms: pain, swelling, bruising, and decrease until the loss of function to walk.

Additional examination:

2.2.9 The pathophysiology of gout arthritis

Pathophysiology
First Phase
This stage occurs due to an increase in uric acid derived from purine metabolism
that comes from diet and the breakdown of body cells. In normal circumstances the uric
acid formed will then be broken down by the uricase enzyme into a substance that is
soluble in urine so that it is easily excreted. The absence of this uricase enzyme can
cause an increase in uric acid levels.
About 90% increase in uric acid levels is caused by the inability to excrete uric
acid in the urine due to genetic defects in renal anion transporters which results in
excessive uric acid reabsorption. This can also be caused by the use of several drugs
such as aspirin, diuretics and alcohol, and decreased kidney function.
About 10% increase in uric acid can occur due to excessive production of uric
acid due to genetic defects of enzymes that break down purines, increase the destruction
of DNA of purine-containing cells in chemotherapy, and high dietary purine intake.

Second Phase
This phase is an acute attack marked by inflammation, usually in the
metatarsofalang digiti I joint, dorsum of the foot, ankle, knee, wrist and elbow joint.
This phase occurs as a result of the transfer of monosodium urate to the joint fluid and
causes a resistance reaction from neutrophil cells, which triggers an inflammatory
reaction by several inflammatory cytokines and is characterized by red, painful, hot, and
swollen joints.

Third Phase
This phase is often known as the asymptomatic intercritical phase which is the
phase without symptoms but monosodium urate crystals remain deposited in joint fluid.
This situation can last up to 10 years. Without good handling of gout can cause acute
attacks that are repeated due to several triggers such as local trauma, high-purine diet,
stress, and the use of diuretics.

Fourth Phase
This phase is the phase of chronic gouty arthritis which is characterized by the
appearance of tofus (monosodium urate deposits in some joints but without signs of
inflammation). This TOFUS can rupture itself and often cause secondary infections. In
this phase, joint damage often occurs, impaired kidney function and cardiovascular
disorders.

Symptoms
Sudden and severe pain in the joints, usually in the middle of the night or early
morning.
Pain in the joints. Pain can feel warm to the touch and look red or purple.
Stiffness in the joints causes limited movement.
The joints most commonly affected are the joints of the big toe, ankle, knee,
elbow, wrist, and fingers.
 If gouty arthritis is not treated for a long period of time, crystals can form lumps
under the skin around the joints. They are called tophi. They are not sick, but can affect
the way the joints look. If crystals accumulate in the urinary tract, they can form kidney
stones.
There are several stages of gouty arthritis and different symptoms at each stage:
Asymptomatic hyperuricemia is the period before the first gout attack. There are no
symptoms, but high blood uric acid levels and crystals begin to form in the joints.
Acute gouty arthritis or attacks of gout occur when something (such as eating and
drinking) causes uric acid levels to surge and causes overcrowding of crystals that have
formed in the joints that triggered the attack. Inflammation and pain caused usually
attacks at night and lasts for the next eight to 12 hours. Symptoms subside after a few
days and may disappear within a week to 10 days. Some people have never had a
second attack, but it is estimated that 60 percent of people who have a gout attack will
have a second attack in a year. Overall, 84 percent may have another attack in three
years.
Gouty arthritis interval is the time between attacks. Although there is no pain, but
the uric acid does not disappear. Inflammation, although in a low level, can damage the
joints. When a person has gout interval arthritis, lifestyle changes and appropriate
treatment can be done to manage gout. In addition, to prevent future attacks or the
occurrence of chronic gout.
Chronic gouty arthritis develops in people with gout who have high uric acid
levels for several years. The attacks become more frequent and the pain may not go
away like they used to. Joint damage can occur, which can cause loss of mobility. With
proper management and care, this stage can be prevented.

Physical examination
Physical examination of patients with gouty arthritis can be found signs of
inflammation such as swelling, warmth, erythema, and pain in the monoarticular joint,
but in some cases it can occur in several joints. In chronic arthritis usually found tofus
in the ears, fingers and toes, prepatella bursa, olecranon, and eyes.

Supporting examination
The simplest and most available investigations are measuring blood uric acid
levels.

Acute Management
Management of the acute phase of gout can use non-steroidal anti-inflammatory
drugs, colchicine, and corticosteroids.
Non-steroidal Anti-Inflammatory Drugs (NSAIDs)
Non-steroidal anti-inflammatory drugs (NSAIDs) in arthritis gout play a role in
controlling inflammation and reducing pain. This NSAID is a first-line drug for treating
acute gouty arthritis. NSAIDS commonly used to treat gout are:
Indomethacin 150-200mg / day for three days and continued with 75-100mg / day for
the following week if necessary
Naproxene 2x500 mg given for 2-5 days
Celecoxib 2x200mg given for 2-5 days
Side effects that can occur due to the use of NSAIDs are edema in pretibia and
gastric ulcer. In chronic gouty arthritis with uncontrolled uric acid levels, low-dose
NSAIDs can also be used prophylactically.

Colchicine
The role of colchicine in acute gouty arthritis is to prevent neutrophil
phagocytosis against uric acid crystals, thereby reducing the inflammatory response.
Colchicine can relieve pain in 18-48 hours. Colchicine is indicated in patients with
gouty arthritis <36 hours and starts with a dose of 1-1.2 mg followed by 0.5-0.6 mg
every two hours to the 6 mg limit.

Side effects that can arise are nausea, vomiting, diarrhea, and stomach cramps.
Effective doses will cause side effects of diarrhea in most patients, so education should
be done about this.

To avoid these side effects can be done by reducing the dose. After the acute
phase is resolved, colchicine can be continued with a prophylactic dose of 0.6 mg in two
doses a day.

Corticosteroids
Corticosteroids in patients with gouty arthritis are indicated if the patient cannot
use NSAIDs and colchicine. Steroid use must be selected based on the presence of
comorbidities. Should not be given to tuberculosis patients. In diabetic patients,
corticosteroids can worsen blood glucose control.

The corticosteroid used in gout is Prednisone 20-40 mg per day given for three to
four days. The dose is then gradually reduced for 1-2 weeks.

Patients with gout one or two joints can be managed with drainage followed by
intraarticular injection of triamcinolone 10-40 mg or dexamethasone 2-10 mg combined
with lidocaine. Side effects that occur in the use of steroids are increased sugar levels,
immune suppression, mood changes and fluid retention.

Prophylaxis
Prophylaxis of acute gout attacks can use xanthine oxidase inhibitors, probenecid,
and lesinurad.

Xanthine Oxidase inhibitors

Drugs that are included in this group are allopurinol, pyrazoloprimidine and
analogs of hypoxanthines such as febuxostat. This drug inhibits the change of xanthine
and hypoxantine into uric acid in the body by inhibiting the center of the pterine
molybdenum, the site of activation of the xanthine oxidase enzyme. In general, this drug
is used in patients with increased uric acid due to excessive production.
This group is not used in the management of acute gout because it can aggravate
pain and inflammation. This group can be given after an acute attack subsides or to
prevent recurrent attacks.

Patients with impaired renal filtration should be adjusted to 1x100 mg whereas

under normal circumstances a dose of 1x300mg should be used. Side effects arising
from the use of allopurinol are acute gouty arthritis, due to remodeling of uric acid
crystal deposits due to decreased acid concentration fast veins. This situation usually
occurs in allopurinol therapy that is not regular. To prevent arthritis of gout, allopurinol
can be combined with colchicine.

Probenecid
Probenecid is an agent that can reduce uric acid levels by reducing uric acid
reabsorption in the kidneys and increasing uric acid levels in the urine. Increased levels
of uric acid in the urine can pose a risk of uric acid stones in the kidneys. To prevent
this, it is recommended that after 24 hours of probenecid administration, measurement
of uric acid levels in the urine, if uric acid levels> 800 mg / 24 hours, this drug should
be stopped. To reduce this risk is done by administering drugs that reduce urine acidity
and educate patients to drink plenty of water to prevent urine crystallization.

Lesinurad
This drug is used at a dose once a day and combined with allopurinol at a dose of
300mg of allopurinol and 200mg of lesinurad. The effect of this drug works the same as
probenecid, which increases uric acid excretion in the kidneys so that it is at risk of
causing gout. In patients with impaired kidney function, these drugs are contraindicated.
 Lifestyle Modifications
Lifestyle modifications that are needed in gout patients include diet and physical
activity.
Because uric acid is the result of the breakdown of purine compounds, the consumption
of high purine foods must be limited or eliminated altogether. High purine foods such as
organ meats, sardines, shellfish, alcohol, and soft drinks.
Weight loss in obese gout patients can reduce hyperuricemia. Activities that can
cause trauma to the affected joint should be avoided.

Reference Preparation
Patients with tofus that are too large and fail with oral medication should be
referred to a rheumatologist. The use of the enzyme pegylated uricase or intravenous
pegloticase has been shown to reduce the size of tofus. Side effects of these drugs can
reduce blood pressure so the use of these drugs must be monitored in the hospital.

Surgery
Research by Andrey et al in patients with tofus in the spine and cause
neurological disorders is indicated for surgery namely laminectomy. But this action is a
last resort if conservative therapy fails. Large tofus in the knee and no response to
conservative treatment can be managed with surgery, namely arthroscopic debridement.

2.2.9 The pathophysiology of osteosarcoma

Osteosarcoma (also called osteogenic sarcoma) is the most common type of cancer that
starts in the bones. The cancer cells in these tumors look like early forms of bone cells
that normally help make new bone tissue, but the bone tissue in an osteosarcoma is not
as strong as that of normal bones.

Most osteosarcomas occur in children and young adults. Teens are the most
commonly affected age group, but osteosarcoma can develop at any age. (For
information about the differences between childhood cancers and adult cancers, see
Cancer in Children.)

Where does osteosarcoma start?

In children and young adults, osteosarcoma usually starts in areas where the bone
is growing quickly, such as near the ends of the leg or arm bones:
 Most tumors develop in the bones around the knee, either in the distal femur (the
lower part of the thigh bone) or the proximal tibia (the upper part of the shinbone).
The upper arm bone close to the shoulder (proximal humerus) is the next most common
site.
Still, osteosarcoma can develop in any bone, including the bones of the pelvis (hips),
shoulder, and jaw. This is especially true in older adults.

Subtypes of osteosarcoma

Based on how the cells look under the microscope, osteosarcomas can be
classified as high grade, intermediate grade, or low grade. The grade of the tumor tells
doctors how likely it is that the cancer will grow and spread to other parts of the body.

High-grade osteosarcomas

These are the fastest growing types of osteosarcoma. When seen with a
microscope, they do not look like normal bone and have many cells in the process of
dividing into new cells. Most osteosarcomas that occur in children and teens are high
grade. There are many types of high-grade osteosarcomas (although the first 3 are the
most common).

Osteoblastic
Chondroblastic
Fibroblastic
Small cell
Telangiectatic
High-grade surface (juxtacortical high grade)
Other high-grade osteosarcomas include:

Pagetoid: a tumor that develops in someone with Paget disease of the bone
Extraskeletal: a tumor that starts in a part of the body other than a bone (but still makes
bone tissue)
Post-radiation: a tumor that starts in a bone that had once been treated with radiation

Intermediate-grade osteosarcomas

These uncommon tumors fall between high-grade and low-grade osteosarcomas.

(They are usually treated the same way as low-grade osteosarcomas.)

Periosteal (juxtacortical intermediate grade)

 Low-grade osteosarcomas

These are the slowest-growing osteosarcomas. The tumors look more like normal
bone and have few dividing cells when seen with a microscope.

Parosteal (juxtacortical low grade)

Intramedullary or intraosseous well differentiated (low-grade central)

The grade of the tumor plays a role in determining its stage and the type of
treatment used.

2.2.11 The pathophysiology of polymyalgia rheumatic

Polymyalgia rheumatica is the most common inflammatory rheumatic disease in

elderly white people, and it is a common indication for long term treatment with
glucocorticosteroids in patients based in the community.1 2 Although the symptoms
are very characteristic, several other autoimmune, infectious, endocrine, and
malignant disorders can present with similar symptoms. The course of disease is
heterogeneous and unpredictable, and giant cell arteritis is seen in about 30% of
patients.3 Glucocorticosteroids rapidly improve disease symptoms in most patients
but may have serious side effects. This review looks at the current understanding of
diagnosis and the management of polymyalgia rheumatica.

Pathogenesis
The cause of polymyalgia rheumatica is unknown, although both genetic and
environmental factors contribute to disease susceptibility and severity. Some studies
show a cyclical pattern in incidence, which suggests an environmental infectious
trigger, such as parvovirus B19, Mycoplasma pneumoniae, and Chlamydia
pneumoniae.
Polymyalgia rheumatica has a modest familial aggregation. It is linked to the HLA
DR4 allele in white populations. Epigenetic changes and differential expression of
genes that regulate the expression of inflammatory cytokines probably account for
the variable disease phenotypes.

Clinical features
The most characteristic presenting feature of polymyalgia rheumatica is bilateral
shoulder pain and stiffness of acute or subacute onset with bilateral upper arm
tenderness. Patients often develop concomitant hip girdle pain and stiffness, as well
as pain and stiffness in the posterior neck musculature. Muscle weakness is not a
 feature of the disease, although this can be difficult to assess in the presence of
muscle pain; when symptoms are protracted and untreated, disuse atrophy can occur.
Stiffness after periods of rest and morning stiffness of more than one hour are
typical. The stiffness may be so profound that patients have great difficulty turning
over in bed, rising from a bed or a chair, or raising their arms above shoulder
height—for example, to comb their hair. Mild synovitis may be seen in the wrists and
knees, but the feet and ankles are only rarely affected. Especially at the ontset of the
disease, most patients have systemic symptoms including fatigue, loss of appetite,
weight loss, low grade fever, and sometimes depression. Patients are always over the
age of 50 and usually over 65.

Diagnosis
The first step is to assess the patient’s symptoms including pain and stiffness in
the shoulder or hip girdle (or both)—usually of at least one week’s, and more
confidently of at least two weeks’, duration—in the presence of acute inflammatory
markers, including erythrocyte sedimentation rate or C reactive protein. Patients must
be assessed for the presence of giant cell arteritis, which is seen in about 30% of
people with polymyalgia rheumatica. Symptoms of giant cell arteritis include new
headache, jaw claudication (jaw muscle pain on chewing), and visual disturbance.
The temporal artery may be abnormal to palpation; biopsy of this artery usually
yields characteristic findings of vascular inflammation. Such a biopsy should be
considered in any patient with polymyalgic symptoms and new headache.

2.2.12 The pathophysiology of rheumatic fever

-Pathophysiology
This rheumatic fever is thought to be closely related to Streptococcus group A bacterial
infection and followed by an autoimmune process which subsequently develops into
rheumatic heart disease that damages the heart. Streptococcus bacteria that infect can
cause rheumatic fever in 3 ways: direct infection, toxin effect (mostly due to streptolysin O),
and the concept of antigenic mimicry with abnormal immune responses (Kaplan EL, 2005).

Virulence of rheumatic fever is related to its capacity to cause permanent heart damage.
Rheumatic carditis does not cause congestive heart failure if no significant heart valve
lesions are found. Myocarditis that occurs in rheumatic fever (Tandon R, 2012).

-Signs and symptoms

Based on the CDC, the signs and symptoms of rheumatic fever are:
1. fever
2. joint pain, cardiovascular impairment such as chest pain, fatigue. (arthritis), often in the
knees, ankles, elbows, and wrists

3. symptoms of congestive heart failure (chest pain, spasms, tachycardia)

4. fatigue

5. uncontrolled body movements (chorea)

6. the presence of a painless lump around the joint

7. rash is a pink ring with a clear center

In addition, in other literatures, the classification of major and minor criteria is obtained.
Major criteria include carditis and arthritis, followed by chorea, subcutaneous nodule, and
erythema marginatum. Minor criteria include olyathralgia, fever, CRP> 3.0, and prolonged
PR interval (Bach DS, 2015).

-Risk Factors
1. children
2. infected with group A streptococcus

-Diagnosis
Diagnosis based on symptoms with at least 2 major criteria or 1 major criteria
accompanied by 2 minor criteria (Bach DS, 2015). Laboratory tests needed include
Erythrocyte Sedimentation Rate (ESR), CRP, WBC count, and blood culture (Webb R, 2019)

-Management
The first goal of treatment for rheumatic fever is symptomatic therapy to reduce acute
symptoms such as arthritis. The second thing that is of concern is the eradication of group A
Streptococcus using antibiotics. Further management is to overcome the complications of
heart failure that often occurs (Steer and Gibofsky, 2018)