Rheumatic fever

RHEUMATIC DISEASES RHEUMATIC FEVER & RHEUMATOID ARTHRITIS

RHEUMATIC FEVER

WHAT IS RHEUMATIC FEVER?

Rheumatic fever is a systemic inflammatory disease that can involve connective tissue of the heart, nervous system, skin, and joints.

Rheumatic fever develops after streptococcus infections plus allergic responce.

Rheumatic fever can occur at any age but primarily affects children from 5 years old to 15 years old.

Rheumatic fever develops about 20 days after strep throat or scarlet fever.

The streptococcus infection which leads to rheumatic fever may be asymptomatic in a third of all cases.

MORPHOLOGICAL SIGNS OF RHEUMATISM

1. systemic progression of connective tissue deorganization (mucoid swelling, fibrous changes, cellular reaction, sclerosis)

2. damage of the vessels

3. immunopathological processes: specific cellular reaction is rheumatic granuloma(Aschoff-Talalaev’s) – in the center there is a focus of fibrinoid necrosis with macrophages with hypertrophic nuclei, epithelial cells located in the fan-like manner, later a crown of lymphocytes appears.

Strep throat

Scarlet fever

CAUSES

Rheumatic fever can occur after an infection of the throat with a bacterium called Streptococcus pyogenes, or group A streptococcus.

Group A streptococcus infections of the throat cause strep throat or, less commonly, scarlet fever. Group A streptococcus infections of the skin or other parts of the body rarely trigger rheumatic fever.

The exact link between strep infection and rheumatic fever isn't clear, but it appears that the bacterium "plays tricks" on the immune system.

The strep bacterium contains a protein similar to one found in certain tissues of the body.

Therefore, immune system cells that would normally target the bacterium may treat the body's own tissues as if they were infectious agents — particularly tissues of the heart, joints, skin and central nervous system.

This immune system reaction results in inflammation.

RISK FACTORS

Factors that may increase the risk of rheumatic fever include:

Family history. Some people may carry a gene or genes that make them more likely to develop rheumatic fever.

Type of strep bacteria. Certain strains of strep bacteria are more likely to contribute to rheumatic fever than are other strains.

Environmental factors. A greater risk of rheumatic fever is associated with overcrowding, poor sanitation and other conditions that may easily result in the rapid transmission or multiple exposures to strep bacteria.

MAIN VARIANTS OF RF

Cardio-vascular formPolyarthritis

CARDIO-VASCULAR FORM Rheumatic perycarditis Rheumatic myocarditis Rheumatic epycarditis

RHEUMATIC PERICARDITIS

More often – exudative inflammation in perycardium

Variants of exudates – serous, hemorragic, fibrinous, mix. Never purulent

SEROUS PERICARDITIS

Hart is increase in size (a lot) due to serous exudate between inner and external leis of pericard

Serous exudate –contains a lot of water, low level of cells and low concentration of plasmatic proteins ( 2%-4%)

That*s why - Cardiac failure is very extensive but prognosis is better.

FIBRINOUS PERICARDITIS

Hart is bit increase in size due to dry exudate between inner and external leis of pericard

Fibrinous exudate –does not contain water (dry exudate), contains high level of cells and high concentration of plasmatic proteins (fibrin)

Cardiac failure is very extensive and prognosis is very bed.

That*s why - Fibrinous pericarditis - may be cause of death

FIBRINOUS PERICARDITIS

Rough pericardium, thick,

non-transparent

FIBRINOUS PERICARDITIS

FIBRINOUS PERICARDITIS

RHEUMATIC MYOCARDITIS

3 variants – 1.Local proliferative – with granulomas (they

are build with macrophages - Anichkov cells) 2. Local exudative with serous exudate 3. Diffuse exudative with serous exudate

LOCAL INTERSTITIAL EXUDATIVE MYOCARDITIS

Mild form

Local infiltration on interstitial tissue(lymphocytes, neutrophils etc.)

Hyperemia, edema

Outcome: reabsorption of exudate or formation of small focal cardiosclerosis

NODULAR PRODUCTIVE MYOCARDITIS

Moderate form

Histologically can see systemic blood congestion in interstitial tissue, infiltration(lymphocytes, histiocytes, neutrophils, eosinophils), granulomas in stroma around vessels, moderate focal degeneration of cardiomyocytes and protein & fat degeneration in cardiomyocytes.

Outcome: mild(small diffused) cardiosclerosis, restoration of cardiomyocytes structure.

IMMUNOPATHOLOGICAL PROCESSES : RHEUMATIC GRANULOMA(ASCHOFF-TALALAEV’S)

DIFFUSE INTERSTITIAL EXUDATIVE MYOCARDITIS

Severe form

Histologically can see formation of nodular granuloma surrounding connective tissue of vessels, diffuse congestion & edema in stroma, diffuse infiltration of histiocytes, lymphocytes, neutrophils, eosinophils, and local degeneration of cardiomyocytes.

Outcome: 1. acute cardiac failure

2. diffuse cardiac sclerosis

MYOCARDITIS

ASCHOFF’S BODY IN RHEUMATIC MYOCARDITIS

RHEUMATIC ENDOCARDITIS

Mural variant Chordal variant Valvular variant is the most important-mitral valve-aortic valve-combine pathology_______________________________________________

In all cases – never tricuspidal valve

RHEUMATIC ENDOCARDITIS

According to A.I.Abrikosov, valvular endocarditis is classified into:

1. diffuse or valvulitis

2. acute warty (verrucouse) endocarditis 3. fibroplastic

4. relapsing (recurrent) warty (verrucouse) endocarditis

Morphological form of endocarditis

Macroscopic Histological

1. Diffuse -normal configuration of valves. -disorganization of connective tissue in thickness of valves (mucoid swelling, fibrinoid necrosis).

2. Acute warty -normal configuration of valves with thrombus

-some stages of connective tissue disorganization (mucoid swelling & fibrinoid changes), celullar reaction, thrombosis with rough surface of thrombus.

3. Fibroplastic -valves become irregularly thick with rough surface

-in valves, zone of fibrosis, calcification & vascularization, vessels are absent.-in sclerosis, can see vascularization & connective tissue.

4. Relapsing warty -valves become irregularly thick, dense & whitish-some zones involve inconsistency of stone (in zone of calcification) & thrombosis

-old changes: sclerosis with vascularization, calcification & hyalinosis. Result: granuloma& specific diffused cellular reaction, infiltration of leukocytes, plasmaic cells, deformation of valves, & thrombus.

-new changes in new attack: zone of disorganization of connective tissue, granuloma & unspecified diffused cellular reaction & cellular infiltration.

ACUTE WARTY ENDOCARDITIS IN CASE OF RHEUMATIC FEVER

Thin, elastic cusp

Valvular disorders

RHEUMATIC DISEASE. THE CARDIOVASCULAR FORM.

NEOVASCULARIZATION OF THE

MITRAL VALVE

AORTAL STENOSIS

ACUTE WARTY ENDOCARDITIS MYOCARDITIS

MITRAL STENOSIS

Heart failure

This is the heart of a 44 year old woman who had rheumatic fever and had been treated for congestive heart failure for about one year. There is extreme fibrosis of the mitral valve with fusion of commissures and rigidity of the leaflets, leading to both stenosis and insufficiency. Note that the cordae, which are normally like fine linen threads, look more like ropes here. Note the enormous atrial dilation. As you would suspect, this woman had hypertension.

RHEUMATISM IN VESSELS Morphological forms of rheumatic vasculitis:

1. destructive: prevailing in vessel wall2. proliferative: proliferation of cells in vessels (macrophages, mast cells)3. mixed: small focus of degeneration, in background formation of microthrombosis, regeneration of cells, small fossa of destruction of brain & small hemorrhages. This form prevalently affect children.

Rheumatic vasculitis includes fibrinoid changes of the walls. In capilarries, there is endothelium proliferation followed by desquamation, so called endotheliosis. Vascular permeability increases sharply.

Outcome: vascular sclerosis(arteriolosclerosis, arteriosclerosis, capillarosclerosis).

VASCULITIS

VASCULITIS

RHEUMATOID VASCULITIS

Rheumatoid vasculitis with skin ulceration on the dorsum of the foot

RHEUMATOID ARTHRITIS

RHEUMATISM IN JOINTS: POLYARTHRITIS

Marked changes in the synovial membrane & preservation of articular cartilage

Histological changes:

-serous, fibrinous exudative in cavity of joint

-mucoid & fibrinous swelling of synovial membrane

-proliferation of synovial sites

-vasculitis of synovial membrane

Clinical appearance: variety & plurality of affection of joints

Outcome: resolution of exudate, restoration of structure of tissue without deformation

WHAT IS RHEUMATOID ARTHRITIS? Rheumatoid arthritis (RA) is an autoimmune

disease that causes chronic inflammation of the joints.

Rheumatoid arthritis can also cause inflammation of the tissue around the joints, as well as in other organs in the body.

Autoimmune diseases are illnesses that occur when the body's tissues are mistakenly attacked by their own immune system.

The immune system contains a complex organization of cells and antibodies designed normally to "seek and destroy" invaders of the body, particularly infections.

Patients with autoimmune diseases have antibodies in their blood that target their own body tissues, where they can be associated with inflammation.

Because it can affect multiple other organs of the body, rheumatoid arthritis is referred to as a systemic illness and is sometimes called rheumatoid disease.

While rheumatoid arthritis is a chronic illness, meaning it can last for years, patients may experience long periods without symptoms.

However, rheumatoid arthritis is typically a progressive illness that has the potential to cause joint destruction and functional disability.

RHEUMATOID ARTHRITIS (INFECTIOUS POLYARTHRITIS)

Is a chronic disease with progresseive deorganization of the connective tissue of the articular membranes and cartilages which cause its deformation.

Pathology: Musculoskeletal system. Rheumatoid arthritis causes a broad spectrum of morphologic alterations, the most severe are manifested in the joints. Intially the synovium becomes edematous, thickened, & hyperplastic transforming its smooth contour to one covered by delicate & bulbous fronds. A dense perivascular inflammatory infiltrate composed of lymphoid follicles, plasma cells & macrophages fills the synovial stroma. The vascularity is increased with superficial hemosiderin deposits & scattered giant cells. Aggregates of organizing fibrin cover portions of the synovium & float in the joint space as rice bodies. Neutrophils accumulate in the synovial fluid & cluster along the surface but usually do not penetrate deep to the synovnocytes.

RHEUMATOID ARTHRITIS

Low magnification revealed

marked synovial hypertrophy.

High magnification revealed

subsynovial tissue containing a

dense lymphoid aggregate.

CLINICAL APPEARANCE OF RHEUMATOID ARTHRITIS

variety & plurality of affection of

joints

RHEUMATOID ARTHRITIS

Mild early swelling of

the metacarpal joints and

the wrist

RHEUMATISM IN NERVOUS SYSTEM

The damage is connected with rheumatic vasculitis.

Nervous cells degeneration, brain destruction & hemorrhages occur in the brain.

If these changes are clearly marked, they may cause chorea minor(in children).

SYSYTEMIC LUPUS ERYTHEMATOSUS (LIBMAN-SACKS DISEASE)

Is either acute or chronic disease with involvement of connective tissue with marked autoimmunization & damage of skin, vessels, kidneys.

Its incidence is the highest in young women (aged 18-23) & less frequent in elderly women & in men.

Etiology of Lupus Erythematosus is unknown.

Pathology: Lupus Erythrematosus is characterized by different cellular & tissue changes which can be divided into 5 groups:

1. Acute necrotic & degenerative changes of the connective tissue (all stages of deorganization). Fibrinoid is characterized by abundant nuclear protein arted chromatin granules.

2. Subacute interstitial inflammation of all organs including bervous system with involvement of microcirculation(capillaritis, arteriolitis, vasculitis)

3. Changes of sclerotic character caused by the above changes. This group is characterized by onion-like sclerosis in the spleen.

4. Changes of the immune system. Focal accumulation of leukocytes with marked plasmatization are present in the central and peripheral organs. Macrophage activity is increased.

5. Nuclear pathology in the cells of all organs & tissues, particularly in lymphatic nodes. The shape of the nuclei does not change but they gradually lose DNA & look pale after staining. After the death of the cell, the nucleus disintegrates into granules, i.e. hematoxylin bodies, This phenomenon characterizes lupus erythematosus. Neutrophils & macrophages phagocytize hematoxylin bodies & form lupus cells. Their presence in the blood is a significant sign of lupus erythrematosus. Except for blood, they can be found in the bone marrow, spleen, lymphatic glands & walls of the vessels.

Visceral manifestations of lupus erythematosus: lupus endo-, myo- & pericarditis, abacterial warty endocarditis(Libman-Sacks endocarditis).

SYSTEMIC LUPUS ERYTHEMATOSUS

Butterfly skin rash

CLINICAL APPEARANCE OF SYSTEMIC LUPUS ERYTHEMATOSUS

Nosebleeds (epistaxis) Skin nodules (small, painless nodules under the

skin)

Sydenham chorea (emotional instability, muscle weakness and quick, uncoordinated jerky movements that mainly affect the face, feet, and hands)

Arthritis of the knee

Arthritis of the ankle

Migratory Polyarthritis : usually the most common symptom is an arthritis (joint inflammation) that involves the larger joints of the body, especially the knees, ankles, wrists, and elbows, and which lasts a few days before moving to another joint. Joint swelling; redness or warmth

Skin rash (erythema marginatum) Skin eruption on the trunk and upper part

of the arms or legsEruptions that look ring-shaped or snake-

like

A joint is where two bones meet to allow movement of body parts. Arthritis means joint inflammation. The joint inflammation of rheumatoid arthritis causes swelling, pain, stiffness, and redness in the joints.

The inflammation of rheumatoid disease can also occur in tissues around the joints, such as the tendons, ligaments, and muscles.

In some people with rheumatoid arthritis, chronic inflammation leads to the destruction of the cartilage, bone, and ligaments, causing deformity of the joints.

Damage to the joints can occur early in the disease and be progressive.

Moreover, studies have shown that the progressive damage to the joints does not necessarily correlate with the degree of pain, stiffness, or swelling present in the joints.

Rheumatoid arthritis is a common rheumatic disease, affecting approximately 1.3 million people in the United States, according to current census data. The disease is three times more common in women as in men. It afflicts people of all races equally. The disease can begin at any age, but it most often starts after 40 years of age and before 60 years of age. In some families, multiple members can be affected, suggesting a genetic basis for the disorder.

WHAT CAUSES RHEUMATOID ARTHRITIS?

The cause of rheumatoid arthritis is unknown. Even though infectious agents such as viruses, bacteria, and fungi have long been suspected, none has been proven as the cause.

The cause of rheumatoid arthritis is a very active area of worldwide research.

It is believed that the tendency to develop rheumatoid arthritis may be genetically inherited.

It is also suspected that certain infections or factors in the environment might trigger the activation of the immune system in susceptible individuals.

This misdirected immune system then attacks the body's own tissues.

This leads to inflammation in the joints and sometimes in various organs of the body, such as the lungs or eyes.

Regardless of the exact trigger, the result is an immune system that is geared up to promote inflammation in the joints and occasionally other tissues of the body.

Immune cells, called lymphocytes, are activated and chemical messengers (cytokines, such as tumor necrosis factor/TNF, interleukin-1/IL-1, and interleukin-6/IL-6) are expressed in the inflamed areas.

Environmental factors also seem to play some role in causing rheumatoid arthritis.

For example, scientists have reported that smoking tobacco increases the risk of developing rheumatoid arthritis.

WHAT ARE THE SYMPTOMS AND SIGNS OF RHEUMATOID ARTHRITIS? Rheumatoid arthritis usually develops gradually,

but some patients experience sudden onset of symptoms: one day they are perfectly healthy and the next they are dealing with rheumatoid arthritis. Symptoms commonly associated with rheumatoid arthritis include:

Joint pain, joint swelling, joint stiffness, and warmth around the affected joint

Morning stiffness that lasts one or more hours Symmetrical pattern of affected joints, meaning

the same joint on both sides of the body is affected (e.g., both knees)

Small joints of the hands and feet are characteristically involved, although any joint can be affected

Rheumatoid nodules (firm lumps under the skin), found on elbows and hands of about one-fifth of rheumatoid arthritis patients

Fatigue and noticeable loss of energy Low grade fevers and sometimes flu-like

symptoms Loss of appetite, weight loss, anemia

associated with chronic diseases, depression Dry eyes and dry mouth associated with a

secondary condition Sjogren’s syndrome Joint deformity and instability from damage

to cartilage, tendons, ligaments, and bone Limited range of motion in affected joints

Flares and remission of disease activity is characteristic of rheumatoid arthritis

Rheumatoid arthritis may have systemic effects (i.e., affect the organs of the body)

No two rheumatoid arthritis cases are exactly the same. There is so much variety among the symptoms that some researchers suspect rheumatoid arthritis is not one disease but rather several diseases with commonalities.

DIAGNOSING RHEUMATOID ARTHRITIS Diagnosing rheumatoid arthritis (RA), in the early stages,

can be difficult. There is no single test that can clearly identify rheumatoid arthritis. Instead, doctors diagnose rheumatoid arthritis based on factors that are strongly associated with this disease. The American College of Rheumatology uses this list of criteria:

1. Morning stiffness in and around the joints for at least one hour.

2. Swelling or fluid around three or more joints simultaneously.3. At least one swollen area in the wrist, hand, or finger joints.4. Arthritis involving the same joint on both sides of the body

(symmetric arthritis).5. Rheumatoid nodules, which are firm lumps in the skin of

people with rheumatoid arthritis. These nodules are usually in pressure points of the body, most commonly the elbows.

6. Abnormal amounts of rheumatoid factor in the blood.7. X-ray changes in the hands and wrists typical of rheumatoid

arthritis, with destruction of bone around the involved joints.

Rheumatoid arthritis is officially diagnosed if four or more of these seven factors are present. The first four factors must have been present for at least six weeks.

Several diseases can masquerade as rheumatoid arthritis, which contributes to the difficulty in diagnosis. These other diseases include:

1. Osteoarthritis, or "regular" arthritis2. Gout3. Fibromyalgia4. Other autoimmune diseases such as

systemic lupus erythematosus (lupus)5. Joint inflammation caused by infections

HOW IS RHEUMATOID ARTHRITIS TREATED?

The main treatment goals with rheumatoid arthritis are to control inflammation and slow or stop progression of RA.

Treatment is usually a multifaceted program of medications, occupational or physical therapy, and regular exercise.

Sometimes surgery is used to correct joint damage.

Early, aggressive treatment is key to good results. And with today’s treatments, joint damage can be slowed or stopped in many cases.

NSAIDs Nonsteroidal anti-inflammatory drug (NSAID)

reduce pain and inflammation but do not slow progression of RA.

Therefore, people with moderate to severe RA often require additional medications to prevent further joint damage.

Most people with RA require a prescription NSAID as they offer longer lasting results and require fewer doses throughout the day.

All prescription NSAIDs carry a warning regarding the increased risk of heart attack and stroke. NSAIDs can also raise blood pressure.

In addition, NSAIDs can cause stomach irritation, ulcers, and bleeding.

DMARDs Disease-modifying antirheumatic drugs

(DMARDs) help slow or stop progression of RA. The most common DMARD used to treat rheumatoid arthritis is methotrexate.

In rheumatoid arthritis, an overactive immune system targets joints and other areas of the body.

DMARDs work to suppress the immune system. However, they aren’t selective in their targets.

Thus, they decrease the immune system overall and increase the likelihood of catching infections.

Biologics The newest and most effective treatments for

rheumatoid arthritis are biologics. Biologics are genetically engineered proteins. They are designed to inhibit specific components

of the immune system that play a pivotal role in inflammation, a key component in rheumatoid arthritis.

Biologics are usually used when other medications have failed to stop the inflammation of rheumatoid arthritis.

Biologics may slow or even stop RA progression. TNF blockers help to reduce pain and joint

damage by blocking an inflammatory protein called tumor necrosis factor (TNF).

There is some evidence that TNF blockers may stop the progression of rheumatoid arthritis.

Recent studies have shown benefits when they are combined with methotrexate.

RHEUMATOID ARTHRITIS - KNEE JOINT

With rheumatoid arthritis, inflammation of the synovial lining causes swelling, pain, redness, warmth, and stiffness of the affected joint. The synovium begins to thicken and inflamed cells release enzymes that digest bone and cartilage. Joint damage and joint deformity may result causing limited range of motion and decreased function of the joint.

A photomicrograph (magnification 200) shows the redundant folds of the synovial lining and intense infiltration with inflammatory cells in RA. The intimal lining layer (solid arrow) is hyperplastic, with multiple layers of cells compared with a normal lining that is one or two cell layers deep. The sublining region (dashed arrow) is marked by accumulation of mononuclear cells such as CD4+ T cells, macrophages and B cells.

RHEUMATOID ARTHRITIS - HIP JOINT

Any joint can be affected by rheumatoid arthritis. Aggressive disease can reduce the range-of-motion of many joints. When the weightbearing joints are affected, such as the hips, knees, and ankles, mobility may be greatly impacted.

Joint erosion, which is visible on x-ray, can be severe and limiting. As the joint becomes eroded and cartilage is damaged, bone-on-bone can be the painful end result. Severe damage to cartilage, tendons, ligaments and bone can cause joints to become unstable and even deformed as rheumatoid arthritis progresses.

RHEUMATOID ARTHRITIS - HANDS

Rheumatoid arthritis most commonly begins in the smaller joints of the fingers, hands, and wrists.

Rheumatoid arthritis can result in hand deformity, joint problems and damage of the fingers, thumb, hand, and wrist including:

rheumatoid nodules joint swelling joint stiffness ulnar drift/ulnar deviation contractures wrist subluxation

Juvenile rheumatoid arthritis

Juvenile rheumatoid arthritis is arthritis that causes joint inflammation and stiffness for more than 6 weeks in a child of 16 years of age or less.

RHEUMATOID ARTHRITIS - SYSTEMIC DISEASE

Rheumatoid arthritis not only affects the joints. Rheumatoid arthritis is a systemic disease which may also affect other organs of the body including the skin, lungs, heart, and kidneys.

Rheumatoid arthritis is more prevalent in women than men. Interestingly, rheumatoid lung disease occurs more frequently in men who are positive for rheumatoid factor, have subcutaneous nodules, and a long disease course.

Rheumatoid arthritis patients also have a higher risk of coronary heart disease than people in the general population.

KNEE REPLACEMENT

Joint damage and deformity can be repaired by knee replacement surgery, which can also reduce pain and restore function. The knee cap is removed and the damaged portion (head) of the femur and tibia are shaved off or resurfaced. The two-part prosthesis (usually metal) is implanted.

HIP REPLACEMENT

Hip replacement surgerycan reduce pain, restore function, and correct joint damage and deformity. The hip is a ball (femoral head) and socket (acetabulum) joint. A total hip prosthesis consists of an acetabular component and femoral shaft which are surgically implanted to replace the damaged parts of the hip.

Joint replacements exist for other joints too, such as the shoulder, wrist, and ankle. Knee and hip replacements are most commonly performed. According to the National Institutes of Arthritis and Musculoskeletal and Skin Diseases, about 435,000 Americans have a hip or knee replaced each year.

RHEUMATOID NODULES MANY PEOPLE WITH RHEUMATOID ARTHRITIS FORM SUBCUTANEOUS NODULES. THESE ARE LUMPS THAT APPEAR ON OR NEAR THE AFFECTED JOINT AND ARE VISIBLE JUST BENEATH THE SKIN.

RHEUMATOID NEUTROPHILIC DERMATITIS

Sweet disease and pyoderma gangrenosum are other neutrophilic disorders sometimes seen in association with rheumatoid arthritis.

RHEUMATOID VASCULITIS

Cutaneous vasculitis may be a complication of rheumatoid arthritis and is characterised by dark purplish areas on the skin (purpura) caused by bleeding into the skin from blood vessels damaged by rheumatoid arthritis. Skin changes caused by rheumatoid vasculitis include:

Skin ulcers (usually leg ulcers) may be extensive and painful Petechiae (purplish spots) or purpura Nail fold or edge breakdown Gangrene In addition to skin changes, rheumatoid vasculitis can cause

many internal symptoms, including sensory or motor neuropathy (loss of sensation), hepatomegaly (enlarged liver), splenomegaly (enlarged spleen), bowel ulcers, and haematuria (blood in urine).

Representative haematoxylin and eosin micrographs of synovium biopsies taken at osteoarthritis or rheumatoid arthritis total knee arthroplasty. (a-c) Osteoarthritis: (a) category 1 (least inflamed), (b) category 2, and (c) category 3 (most inflamed). I, synovium intima; L, lymphoid body; SV, small vessel; V, villus. (d) Rheumatoid arthritis, category 3. Each biopsy was assigned to one of four categories: 0 = normal: synovial intima less than four cells thick, sparse cellular distribution, with few or no inflammatory cells (not shown as normal synovial fluid samples were not accompanied by synovium biopsies); 1 = mild inflammation: synovial intima three to five cells thick, slight increase in cellularity with few inflammatory cells; 2 = moderate inflammation: synovial intima four to six cells thick, dense cellularity with inflammatory cells, may exhibit as small lymphoid aggregates; 3 = severe inflammation: synovial intima five to seven or more cells thick, dense cellularity with inflammatory cells, containing many or large perivascular lymphoid aggregates. Bar = 100 μm.

Histology of rheumatoid synovitis. A. The characteristic features of rheumatoid inflammation with hyperplasia of the lining layer (arrow) and mononuclear infiltrates in the sublining layer (double arrow). B. A higher magnification of the largely CD4+ T cell infiltrate around postcapillary venules (arrow).