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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