I. Line out classification of various forms of inflammatory
arthritis.
Study Companion
i. Inflammatory polyarthritis of known cause: Rheumatoid arthritis
(RA), ankylosing splondyloitis.
ii. Degenerative joint disease: osteoarthritis
iii. Infectious arthritis: including septic (pyogenic) arthritis, tuberculosis
arthritis
iv. Traumatic arthritis: arthritis secondary to fracture and joint injuries.
v. Metabolic arthritis: Osteoporosis, rickets disease and Paget disease
McCance
i. Infectious arthritis: Inflammation caused by invasion of the joint by
bacteria, mycoplasmas, viruses, fungi or protozoa.
ii. 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
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b. Granulomatous (granuloma producing) infection, includes:
Tuberculous osteomyelitis
Tuberculous arthritis
ii. Nonspecific & idiopathic inflammatory types of rheumatic diseases
Ex.
a. Rheumatic fever
b. Transient synovitis
c. Rheumatoid arthritis (RA)
d. Ankylosing splondylitis
iii. Inflammation of musculoskeletal tissue secondary to a chemical
irritant (metabolic arthritis)
Ex.
a. Gout
iv. 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. There is synovial hypertrophy and villi formation
ii. Subsynovial tissue contains dense lymphoid aggregate
iii. There is spread of inflammatory cells
iv. 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
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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 T-cells.
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Pathological Change
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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.
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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 having this is surely
RA positive.
ii. Agents also play roles in causing RA, such as bacteria, mycoplasmas
and viruses (especially Epsteinn-Barr virus {EBV})
iii. The genes that are risk factors of RA and also the agents may cause a
person to have rheumatoid factor (Rf)
iv. Rf consist of IgG & IgM (occasionally IgA) and also the antigen which is
the EBV
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v. Two types of body’s immune react by producing T & B cell. T cell that
functions to phagocytize the antigen and the B cells produces the
antibody IgG & IgM.
vi. 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
host’s self antigen) -> Vicious cycle
The attack of T cells causes the inflammation as well.
Side-by-side, T cells also expresse RANKL inducing
osteoclast for bone resorption to take place.
vii. The inflammation causes damage and eventually swelling occurs due
to leukocyte infiltration.
viii. Swelling causes synovial thickening by hypertrophy and hyperplastic
ix. 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 inflammatory cells.
x. 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.
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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 Limfosit-B 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, cytokinα ini juga merangsang pembentukan enzim proteolytic dan enzim penghancur matrix (matrix degrading enzyme) oleh sel-sel tersebut.
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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:
- Robin’s Pathology- Harrison’s Internal Medicine- Salter Textbook of Disorders and Injuries of the Musculoskeletal System
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Radiographic Examination:
i. Evidence of periarticular soft tissue swelling and joint effusion
ii. Osteoporosis
iii. Osteolytic erosions in subchondral bone
iv. Narrowing of the cartilage space
v. Subluxation & dislocation (hands & feet)
vi. Bony ankylosis- wrist and ankles
VI. 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.
o Erythrocyte sedimentation rate (ESR) and serum C-reactive protein
(CRP) levels
Both the ESR and CRP are typically elevated in RA.
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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, Sjogren’s 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
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 a disorder other
than RA
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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
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 a 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
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radiographs and uncertainty regarding either the diagnosis or the
presence of inflammatory changes, such as patients with obesity or
subtle findings on examination.
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
Azathioprine
Cyclosporine
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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 Occiput
o Trapezius
o Supraspinatus
o Gluteal
o Greater trochanter
o Low cervical
o Second rib
o Lateral epicondyle
o 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
- Pain feels like burning
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- 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.
Treatment:
- Doxycycline (not for children)
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- Amoxicillin
Osteoarthritis
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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).
o 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)
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)
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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).
Joint-space narrowing in the
interphalangeal joints, possibly
with ankylosis
Increased joint space in the
interphalangeal joints as a result of destruction
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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
Criteria of Sjogren Syndrome
Ocular symptoms - Dry eyes for more than 3 months, foreign-body
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
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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 anti–SSA or anti–SSB 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
Presence of antinuclear antibodies, especially anti-Ro and anti-La
Presence of RF
Presence of anti–alpha-fodrin antibody (reliable diagnostic marker of
juvenile Sjögren 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
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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 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)
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