I.

Line out classification of various forms of

inflammatory arthritis.
Study Companion
i.

Inflammatory polyarthritis of known cause: Rheumatoid

ii.
iii.

arthritis (RA), ankylosing splondyloitis.

Degenerative joint disease: osteoarthritis
Infectious arthritis: including septic (pyogenic) arthritis,

iv.

tuberculosis arthritis
Traumatic arthritis: arthritis secondary to fracture and joint

v.

injuries.
Metabolic arthritis: Osteoporosis, rickets disease and Paget
disease

McCance
i.

Infectious arthritis: Inflammation caused by invasion of the

ii.

joint by bacteria, mycoplasmas, viruses, fungi or protozoa.

Noninfectious arthritis: Inflammation caused by immune
reactions or the deposition of crystals of monosodium urate
in and around the joint.
Ex.
RA & ankylosing spondylitis (immune reactions)
Gouty arthritis (crystal deposition)

Robert B. Salter
i.

Specific infections for which causative organisms are

detected
Ex.
a. Pyogenic (pus-producing) infection, includes:
Osteomyelitis
Septic arthritis
Tenosynovitis
b. Granulomatous (granuloma producing) infection,
includes:

ii.

Tuberculous osteomyelitis
Tuberculous arthritis
Nonspecific & idiopathic inflammatory types of rheumatic

iii.

diseases
Ex.
a. Rheumatic fever
b. Transient synovitis
c. Rheumatoid arthritis (RA)
d. Ankylosing splondylitis
Inflammation of musculoskeletal tissue secondary to a

iv.

chemical irritant (metabolic arthritis)

Ex.
a. Gout
Chronic inflammation caused by repeated physical
injury/chronic repetitive strain injury
Ex.
a. Bursitis
b. Tenovaginitis stenosans

II.

Describe the changes in synovium

histology in inflammatory arthritis.
i.
ii.
iii.
iv.

There is synovial hypertrophy and villi formation

Subsynovial tissue contains dense lymphoid aggregate
There is spread of inflammatory cells
Polymorphonuclear (PMS) present in a large number in synovial

fluid but not in the membrane.

v. Inflammatory cells found in membrane are morphonuclear (MN)
type such as lymphocyte, plasma and macrophages

III.

Explain the pathomechanism(s) of joint

destruction in inflammatory arthritis and the

radiographic and pathological changes of the
joint.
a. The nature of autoimmune reaction

- Consist of activated T and B lymphocyte by target antigen

- T cells stimulate other cell in joint to produce cytokines (TNF and
IL-1) that are central mediators of the synovial reaction.

b. The mediators of tissue injury

- Cytokines stimulate cell to poliferate and produce various

mediators of inflammation (such as prostalglandin).
- Matrix proteinase contribute to cartilage destruction.
- Activated T cells and synovial fibroblast produce RANKL which
activates osteoclast and promote bone destruction.
- The hyperplastic synovium rich of inflammatory cells becomes
adherent to and grows over the articular surface, forming pannus,
and stimulate sorption of the adjacent cartilage.
- In the end, pannus produced sustained irreversible cartilage
destruction and erosion subchondral bone.

c. Genetic susceptibility

- Susceptible gene: class II HLA locus and spesifically a region of 4

amino acids located in antigen-cleft that's shared in HLA DRB1*401*
and *404* alleles.
- This HLA-DR allele may bind and display arthitogenic antigen to Tcells.

Pathological Change

The synovium becomes grossly edematous, thickened, and

hyperplastic:
1. Infiltration of synovial stroma by dense perivascular
inflammatory cells.
2. Increase vascularity owing to vasodilatation and angiogenesis,
with superficial hemosiderin deposit.
3. Aggregation of organizing fibrin covering portion of the
synovium and floating in joint spaces as rice bodies.
4. Accumulation of neutrophil in the synovial fluid and along
surface of synovium, but usually not deep in syynovial stroma.
5. Osteoclastic activity in underlying bone, allowing the
synovium to penetrate into the bone, osteoporosis, and
pannus formation.
6. Pannus is a mass of synovium and synovial stroma, consisting
of inflammatory cells, granulation tissue, and fibroblast, which
grows over the articular cartilage and cause its erosion. After
the cartilage has been destroyed, the pannus bridges the
opposing bone forming fibrous ankylosis which eventually
ossifies (bony ankylosis).

IV.

Line out the extra-articular features of

inflammatory arthritis
Heart-- Inflammation occurs most commonly in the pericardium,a
sac-like structure that surrounds the heart. The inflammation causes
pain and sometimes an increase in fluid,which may compress the
heart and impair function. This type of inflammation (pericarditis)
can be detected by a simple occasional test.(ultrasound).
Rarely,does nodules cause scarring within the heart walls, arteries,
or on the valves of the heart.

Lungs --In RA,inflammation of the lungs is common.The most

common site of inflammation is in the pleurae,which is situated
between the lungs and the chest cavity.Most patients involved will
experience pain when breathing in or out. In some patients,the
pleural space which separate the chest walls and lungs,fills with
liquid.

Occasionaly inflammation occurs throughout the lungs. This

condition is called fibrosis and leads to lung scarring Symptoms are
shortness of breath and cough.Breathing tests help to confirm a
diagnosis of fibrosis.

Nervous System--RA can affect the nervous system. The most

common cause arise from the compression of the nerves. This
happens frequently in the hands,and is called carpal tunnel
syndrome. The carpel tunnel is a narrow shallow tunnel in the wrist
through which all of the important nerves, tendons, and blood
supply to the hand pass.

Inflammation within this tunnel,caused by arthritis,or other

conditions, creates pressure on one of the nerves passing through
it,which leads to irritation. Pressure on the nerve results in
numbness,in the palm of the hand and the second,third,and fourth
fingers. Generally the numbness in the hands is worse at night.
C.P.S. is not limited to RA.

RA can also affect nerves in other parts of the body. If RA causes

damage to the joints in your neck,it can lead to bone shifts and
compression of the spinal cord ot the nerves that exit it. The result
is nunbness in the arms and legs.

Blood vessels-- In rare cases,RA can be so wide spread that it causes

inflammation within the linings of blood vessels. Blood vessels
inflammation is called vasculitis. Damage to blood vessels or their
closure can lead to damage in the organs that the blood vessels
feed. Vasculitis is serious because it could damage organs such as
the kidneys or the heart.

Eyes -- RA can affect the eyes,either directly by inflammation or

indirectly by damaging the tear ducts. When the tear ducts are
damaged their secreations decrease,and dry eyes will result,
particularily at night. Inflammation of the cornea can cause
distorted vision and sometimes damage the eye. Some RA patients
also have Sjorgens sydrome which is the syndrome described.

V. Understand the immune mechanism in RA

pathogenesis
Pathophysiology

i.

HLA-DR4, HLA-DRB1 & HLA-DP are genes that may be

present in humans but this does not mean that the person

ii.

having this is surely RA positive.

Agents also play roles in causing RA, such as bacteria,
mycoplasmas and viruses (especially Epsteinn-Barr virus

iii.

{EBV})
The genes that are risk factors of RA and also the agents

iv.

may cause a person to have rheumatoid factor (Rf)

Rf consist of IgG & IgM (occasionally IgA) and also the

v.

antigen which is the EBV

Two types of bodys immune react by producing T & B cell.
T cell that functions to phagocytize the antigen and the B

vi.

cells produces the antibody IgG & IgM.

This causes the antibodies to bind together with the
antigen and this whole antibody-antigen complex causes
the body to think that it is an antigen, although the
antibody attached to the antigen is part of the body.
Thus, more T cell stimulation and its production
attacks the antibody-antigen complex causing
autoimmune (attacking hosts self antigen) ->

Vicious cycle
The attack of T cells causes the inflammation as

well.
Side-by-side, T cells also expresse RANKL inducing

vii.

osteoclast for bone resorption to take place.

The inflammation causes damage and eventually swelling

viii.

occurs due to leukocyte infiltration.

Swelling causes synovial thickening by hypertrophy and

ix.

hyperplastic
When swelling takes place, eventually more blood supply is
needed as to do so, more blood vessels are needed. In a
way, occlusion of blood vessels take place due to
hypertrophied endothelial cells, fibrin, platelets and

x.

inflammatory cells.
The following reaction causes reduced blood flow that
eventually causes hypoxia.

xi.

During hypoxia, metabolic acidosis occurs and this releases

hydrolytic enzyme causing synovial erosion, pannus and
joint inflammation.

Patofisiologi:
Secara singkat patofisiologi dari Rheumatoid Arthritis dapat
dirangkum sebagai suatu proses autoimun dimana tubuh memicu
terjadinya reaksi imun sekunder oleh limfosit T dan B yang
menyerang persendian.

Patofisiologi Rheumatoid Arthritis dapat dibagi menjadi beberapa

tahap sederhana:
1. Rheumatoid Arthritis dimulai dengan teraktivasinya T-helper
oleh antigen yang dipresentasikan oleh APC (antigen
presenting cell, kemungkinan besar Makrofag).
2. Sel T-helper yang teraktivasi menghasilkan cytokine yang
mengaktivasi Makrofag dan sel Limfosit-B di ruang sendi.
3. Makrofag yang teraktivasi menghasilkan enzim yang bersifat
degradatif dan faktor lain yang merangsang proses inflamasi.
Sedangkan limfosit-B yang teraktivasi menghasilkan antibodi
yang memiliki efek terhadap unsur dalam tubuh.
4. Cytokin yang dilepaskan baik oleh Makrofag maupun LimfositB bekerja tidak hanya sebagai proinflamator (unsur yang
mempercepat respon peradangan) namun juga menyebabkan
perkembangan abnormal dari fibroblas dan sel synovial (misal
IL-1 dan TGF-). Tidak hanya itu, cytokin ini juga merangsang
pembentukan enzim proteolytic dan enzim penghancur matrix
(matrix degrading enzyme) oleh sel-sel tersebut.

10

5. Fibroblas, sel stromal, dan sel Limfosit T-helper yang

teraktivasi menghasilkan RANK ligand (Receptor activator of
nuclear kappa-B ligand) yang berfungsi dalam diferensiasi dan
aktivasi
osteoklas.
Pembentukan
RANK
ligand
ini
memperparah kondisi tulang di persendian.
6. Kondisi diperparah dengan T-helper yang mengaktifkan sel
endotelial pembuluh darah yang mengakibatkan akumulasi
dari sel inflamasi.
7. Akhirnya, akumulasi sel inflamasi dan proliferasi fibroblas
yang berlebihan menghasilkan pannus yang memberikan efek
imobilisasi pada sendi.

Further reading:
-

Robins Pathology
Harrisons Internal Medicine
Salter Textbook of Disorders
Musculoskeletal System

and

Injuries

of

the

11

Radiographic Examination:
i.
ii.
iii.
iv.
v.
vi.

VI.

Evidence of periarticular soft tissue swelling and joint effusion

Osteoporosis
Osteolytic erosions in subchondral bone
Narrowing of the cartilage space
Subluxation & dislocation (hands & feet)
Bony ankylosis- wrist and ankles

Line out the laboratory test used in the

diagnosis of RA and SLE, with particular

attention to the rheumatoid factor (Rf) and
anti-nuclear antibodies (ANAs)

Laboratory

tests,

which

support

the

diagnosis

if

positive and/or elevated:

o Rheumatoid factor (RF) and anti-cyclic citrullinated peptide
(CCP) antibodies.
A positive result for either test increases overall
diagnostic sensitivity, while the specificity is increased
when both tests are positive.
Rf is used to detect and measure the level of an
antibody that acts against the blood component gamma
globulin, this test is often positive in people with
rheumatoid arthritis.
Despite this, both tests are negative on presentation in
up to 50 percent of patients and remain negative during
follow-up in 20 percent of patients with RA.

12

o Erythrocyte sedimentation rate (ESR) and serum Creactive protein (CRP) levels
Both the ESR and CRP are typically elevated in RA.
This test measures how fast red blood cells cling
together, fall and settle (like sediment) in the bottom of
a glass tube over the course of an hour. The higher the
rate, the greater the amount of inflammation.

Tests that are done for differential diagnosis of RA

o Antinuclear antibody (ANA) testing
A negative ANA helps exclude SLE and other systemic
rheumatic diseases
The ANA may be positive in up to one-third of patients
with RA.
Found in the blood of people who have lupus, ANAs
(abnormal antibodies directed against the cells nuclei)
can

also

suggest

the

presence

of

polymyositis,

scleroderma, Sjogrens syndrome, mixed connective

tissue disease or rheumatoid arthritis.
In patients with a positive ANA, anti-double stranded
DNA and anti-Smith antibody testing should also be
performed; these antibodies have high specificity for
SLE.
o Complete blood count (CBC) with differential and platelet
count, tests of liver and kidney function, serum uric acid,
and a urinalysis

13

 The CBC is often abnormal in RA, with anemia and

thrombocytosis consistent with chronic inflammation.
Uric acid test is used to help in diagnosing gout, a
condition that occurs when excess uric acid crystallizes
and forms deposits in the joints and other tissues,
causing inflammation and severe pain.
Liver

and

kidney testing

abnormalities

indicate

disorder other than RA

o Radiographs of the hands, wrists, and feet

Characteristic

joint

erosions

may

be

observed

in

patients presenting with symptoms for the first time

and, hence, aid in diagnosis.

Following studies are done in selected patients:

o Serologic studies for infection
In patients with a very short history (for example, less
than six weeks) particularly those who are seronegative
for

anti-CCP

and

rheumatoid

factor,

we

perform

serologic testing for human parvovirus B19, hepatitis B

virus (HBV), and hepatitis C virus (HCV). In areas
endemic for Lyme disease, we perform serologic studies
for Borrelia as well.
o Synovial fluid analysis

14

 Arthrocentesis is performed and synovial fluid analysis

for the diagnosis or exclusion of gout, pseudogout, or an
infectious arthritis if a joint effusion is present and if
there is uncertainty regarding the diagnosis, particularly
in

the

setting

monoarthritis,

oligoarthritis,

or

asymmetric joint inflammation.

Synovial fluid testing should include a cell count and
differential, crystal search, as well as Gram stain and
culture.
Synovial fluid analysis should also be obtained to
exclude infection or crystalline arthropathy in patients
who undergo glucocorticoid injections for symptomatic
relief.
o MRI and ultrasound
MRI and ultrasound are more sensitive than radiography
at detecting changes resulting from synovitis and may
be helpful in establishing the presence of synovitis in
patients

with

normal

radiographs

and

uncertainty

regarding either the diagnosis or the presence of

inflammatory changes, such as patients with obesity or
subtle findings on examination.

15

VII.

Describe the principles in the treatment

of rheumatoid arthritis, particularly the role

of disease modifying anti-rheumatic drugs
(DMARDs) to preserve joint function and to
prevent disease progression
DMARDs: Suppresses the body's overactive immune and/or
inflammatory systems. They take effect over weeks or months and
are not designed to provide immediate relief of symptoms.
Other medicines, such as pain relievers, nonsteroidal
antiinflammatory drugs (eg, ibuprofen or naproxen), and,
sometimes, prednisone, are given to provide faster relief of ongoing
symptoms. DMARDs are often used in combination with these
medications to reduce the total amount of medication needed and
to prevent damage to joints

Methotrexate blocks the enzyme dihydrofolate reductase,

affecting the lymphocyte and macrophage. By doing so, it
affects production of a form of folic acid, which is needed for
actively growing cells. It remains unclear exactly how
methotrexate decreases arthritis activity.

Direct inhibitory effect on proliferation and stimulate apoptosis

in immune inflammatory cells.

Other DMARDs:

Sulfasalazine

Hydroxychloroquine

Leflunomide

16

Azathioprine

Cyclosporine

Differential Diagnosis of RA
Fibromyalgia
- Chronic musculoskeletal syndrome characterized by widespread
joint and muscle pain, fatigue and tender points
- Increased sensitivity to touch, absence of systemic or localized
inflammation, and fatigue and sleep disturbances are common
- Tender points
o
o
o
o
o
o
o
o
o

Occiput
Trapezius
Supraspinatus
Gluteal
Greater trochanter
Low cervical
Second rib
Lateral epicondyle
Knee

Pathophysiology:
- Have lowered mechanical and thermal pain thresholds, high pain
ratings for provoking stimuli and altered temporal summation of
stimuli.

Manifestation:
- Tender points in the following locations
- Pain begins in one location and spreads
17

- Pain feels like burning

- Pain felt when waking up in the morning
- Sleeping difficulty
- Headaches, irritable bowel syndrome, sensitivity to cold

Evaluation & Treatment

- Vit. D
- Anti-inflammatories
- Preglabin
- Patients education

Lyme Disease
- Multisystem inflammatory disease caused by the spirocheten
Borrelia burgdoferi transmitted by tick bites and vector borne illness
- Children is a risk factor
- B. burgdoferi is difficult to culture since it escapes
immunedefenses
- 3 stages:
o Localized infection: erythema of migrains (rash), fever,
malaise, myalgias & arthralgia
o Disseminated infection: erythema migrans, arthralgias,
meningitis, neuritis or cardiovascular sysmptoms.
o Late persistent infection: arthritis, encephalopathy or
polymeuropathy.

18

Treatment:
- Doxycycline (not for children)
- Amoxicillin

Osteoarthritis

19

Psoriatic Arthritis
The patterns of psoriatic arthritis involvement are as follows:

Asymmetrical oligoarticular arthritis

o

Hands and feet are affected first Inflammation

"sausage" appearance (dactylitis).

Knee is also commonly involved.

Symmetrical polyarthritis
o

Differentiated from RA by the presence of:

Distal interphalangeal (DIP) joint

Relative asymmetry
Absence of subcutaneous nodules
Negative test result for rheumatoid factor (RF).
Milder than RA, with less deformity.

Distal interphalangeal arthropathy

Arthritis mutilans

Spondylitis with or without sacroiliitis

Classification of Psoriatic Arthritis

Current psoriasis (assigned a score of 2)

20

A history of psoriasis (in the absence of current psoriasis;

assigned a score of 1)

A family history of psoriasis (in the absence of current

psoriasis and history of psoriasis; assigned a score of 1)

Dactylitis (assigned a score of 1)

Juxtaarticular new-bone formation (assigned a score of 1)

RF negativity (assigned a score of 1)

Nail dystrophy (assigned a score of 1)

Etiology

Genetics
Infections
o Bacterial/viral infection may induce
Trauma
Environmental Factor
Immunologic factors
o Unknown antigen presented to CD4+ T cell activation
Induce proliferation and activation of synovial and
epidermal fibroblasts.

Laboratory Diagnosis

Radiologic Findings

Pencil-in-cup deformity (seen in the image below)Arthritis

mutilans (ie, "pencil-in-cup" deformities).

21

Joint-space narrowing in
the interphalangeal joints,

possibly with ankylosis

Increased joint space in the
interphalangeal joints as a
result of destruction

Fluffy periostitis
Bilateral, asymmetrical, fusiform soft-tissue swelling
Unilateral or symmetrical sacroiliitis
Large, nonmarginal, unilateral, asymmetrical syndesmophytes
(intervertebral bony bridges, seen in the image below) in the
cervical, thoracic, and lumbar spine, often sparing some of the
segments

Treatment

NSAID
DMARD
o Methotrexate
o Sulfasalazine and cyclosporine

Sjogren Syndrome

Systemic chronic inflammatory disorder characterized by

lymphocytic infiltrates in exocrine organs.

Clinical Manifestation

Xerophthalmia (dry eyes)

Xerostomia (dry mouth)
Parotid gland enlargement
Dry skin (xeroderma)
Palpable and nonpalpable purpura, and/or urticarial

22

Criteria of Sjogren Syndrome

Ocular symptoms - Dry eyes for more than 3 months, foreignbody sensation, use of tear substitutes more than 3 times
daily

Oral symptoms - Feeling of dry mouth, recurrently swollen

salivary glands, frequent use of liquids to aid swallowing

Ocular signs - Schirmer test performed without anesthesia (<

5 mm in 5 min), positive vital dye staining results

Oral signs - Abnormal salivary scintigraphy findings, abnormal

parotid sialography findings, abnormal sialometry findings
(unstimulated salivary flow < 1.5mL in 15min)

Positive minor salivary gland biopsy findings

Positive antiSSA or antiSSB antibody results

Etiology

Association with the human leukocyte antigen

Possible disease triggers
Glandular pathology
Extraglandular involvement
Sex hormones

Lab Findings

Elevated erythrocyte sedimentation rate (ESR)

Anemia

Leukopenia

Eosinophilia

Hypergammaglobulinemia

23

Presence of antinuclear antibodies, especially anti-Ro and antiLa

Presence of RF

Presence of antialpha-fodrin antibody (reliable diagnostic

marker of juvenile Sjgren syndrome)

Creatinine clearance may be diminished in up to 50% of

patients

Positive ANA

Rose Bengal or lissamine green staining of eye (cornea or

conjunctiva) to evaluate the extent to which dryness has
damaged the surface of the eye

Systemic Lupus Erythematosus

Multisystem and inflammatory disease

Characterized by large variety of autoantibodies against
nucleic acids, erythrocytes, coagulation proteins,
phospholipids, lymphocytes, platelets and many other self

components.
Autoantibodies produced in SLE are against nucleic acids,

histones, ribonucleoproteins, and other nuclear materials

Deposition of circulating immune complexes containing
antibody against DNA produces tissue damage tissue damage

in individuals with SLE

DNA circulation is usually removed by liver
Removal of circulating DNA is slowed in the presence of
immune complexes, thereby increasing the potential for
deposition in the kidney Inflammation to renal tubular

24

basement membranes, brain, heart, spleen, lung

gastrointestinal tract, skin and peritoneum.

UV light may trigger lupus-like immune reactions flares
Risk factor
o Women
o Black
o 20-40 y.o.
o Twins
o Inheritance
Treatment
o Hydralazine (antihypertensive agent)
o Procainamide (antidysrhythmic drug)
o Aspirin, ibuprofen or naproxen (reduce inflammation)
o DMARD (Methotrexate, azathioprine or
cyclophosphamide)

25

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