JOINT ARTHRITIS

JOINT

by Robert C. Mellors, M.D., Ph.D.

II. ARTHRITIS

The rheumatic diseases are conditions in which pain and stiffness of some part of the musculoskeletal system are prominent clinical symptoms. Arthritis is a term commonly used when the joints themselves are the major seat of rheumatic disease. There are many types of arthritis, but to the rheumatologist the term arthritis or synovitis represents a specific inflammatory disorder of a synovial (or diarthrodial) joint which is clinically manifested by redness, warmth, swelling, and loss of function. The term arthralgia indicates joint pain without associated inflammation. Joint diseases are commonly manifested by joint pain with, or without, the presence of inflammation.

A survey of the prevalence of major diseases suggests that about 10% of the U.S. population of all ages suffer from some form of arthritis, most commonly, osteoarthritis, rheumatoid arthritis, or gout. Arthritis and other rheumatic conditions are among the most common disabilities in the U.S. and by year 2020 are predicted to affect about 59 million (~18% of all) people in this country (MMWR 45 (#23) : 487-491, 1996).

1. Mechanisms of Arthritis

There are many (perhaps as many as 100 or more) clinical types of arthritis, but most cases can be placed in one of five major groups: - arthritis caused by specific microorganisms, such as septic arthritis due to staphylococcal infection or Lyme disease caused by a spirochete; - arthritis of unknown, possibly infectious, etiology, such as rheumatoid arthritis (RA); - degenerative forms of joint disease/osteoarthritis (OA); - metabolic arthritis, such as gout; - arthritis resulting from trauma (or overuse).

Overall, arthritis and related syndromes are currently classified into nine categories on the basis of clinical and pathological features and pathogenetic mechanisms.

a. Arthritis Related to Recognized Infectious Agents:

Direct Joint (or Bone) Infection. Direct infection can be caused by gram positive or negative cocci and rods, tuberculosis, atypical mycobacteria, a spirochete, fungi, and viruses. Arthritis frequently accompanies a number of common virus infections, such as hepatitis B, rubella, post-rubella vaccination. Lyme disease, a systemic disorder manifested by an RA-like arthritis, skin rash, cardiac and neurological involvement, is caused by spirochetal infection with Borrelia bergdorferi transmitted by a tick bite and responsive to appropriate antibiotics. Lyme disease was once categorized as a systemic disease of unknown cause in a class with rheumatoid arthritis.

Arthritis Related to Recognized Infectious

In those patients who develop joint involvement during hepatitis B infection, the tissue deposition of soluble immune complexes containing HBsAg-antiHBsAg is thought to initiate the inflammatory process. A similar mechanism may occur in the arthritis associated with rubella virus.

Reactive Arthritis

Some microorganisms indirectly lead to reactive arthritis mediated by immune reactions to microbial antigens, especially in genetically predisposed hosts. The arthritis accompanying rheumatic fever, which follows group A hemolytic streptococcus infection, is the prototype reactive arthritis. Other examples occur predominately in HLA-B27 positive individuals and include the arthritis associated with enteric infections caused by salmonella, shigella, yersinia, and campylobacter. Although the microorganisms leading to reactive arthritis can also produce direct joint infections, they usually cause the indirect reactive form of arthritis.

b. Arthritis of Unknown Cause Related to Immunological and Genetic Factors:

Diffuse Connective Tissue Diseases

This group of diseases includes rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA), systemic lupus erythematosus (SLE), scleroderma/progressive systemic sclerosis (PSS), polyarteritis nodosa (PAN), and dermatomyositis (DM). Multiple immunological and genetic factors are implicated in the pathogenesis of the connective tissue diseases.

- Immune complexes.- (Type III) immune-complex mediated mechanisms of tissue injury and inflammation are involved in the pathogenesis of RA, SLE, and PAN. These complexes are formed by anti-IgG autoantibodies (rheumatoid factors) in RA, by antinuclear autoantibodies in SLE, and by anti-HBV antibodies in some patients with PAN (refer to: Immunopathology).

- Tissue-reactive antibodies.- Autoantibodies to cells, such as antibodies to erythrocytes, lymphocytes, platelets, and neuronal cells, and to other cell components, such as phospholipids, appear to have pathogenetic roles in some patients with SLE.

- Genetic factors.- There is a significant association between RA or SLE and certain class II (HLA-DR) antigens encoded within the major histocompatability complex (MHC). Since class II genes can regulate immune responsiveness, such an association may be a reflection of pathogenetic mechanisms underlying the induction of autoimmunity.

Seronegative Spondyloarthropathies (SNSA). Previously called "rheumatoid variant diseases", this group of inflammatory joint disorders is typically seronegative for rheumatoid factor and is characterized by the involvement of sites of insertion of ligaments and capsules into bones (this site is called the enthesis, this group of disorders the enthesopathies), resulting in sacroiliitis, spondylitis (arthritis of the spine), and other abnormalities.

- Genetic factors.- All diseases in this group have a strong association with class I HLA-B27 antigen. This group includes ankylosing spondylitis (AS), psoriatic arthritis, Reiter’s syndrome, spondylitis associated with chronic inflammatory bowel disease, such as ulcerative colitis, and reactive arthritis following enteric bacterial infections (dysentery).

c. Arthritis Associated with Primary Diseases of Cartilage or Bone:

Osteoarthritis (OA) is the most common joint disorder and is characterized by progressive focal degeneration of the articular cartilage, sclerosis of the subchondral bone, and formation of bony outgrowths or "osteophytes" at the joint margins. Most of the current theories on the pathogenesis focus upon primary alterations in the articular cartilage.

d. Arthritis Induced by Crystals:

The deposition of various crystals within the articular tissues can cause an acute inflammatory response and acute synovitis and lead to chronic destructive arthritis. Gout - the factors, in addition to hyperuricemia, leading to the precipitation of urate crystals in tissues and the mechanisms by which these crystals induce gouty inflammation are complex and poorly understood. Large deposits of urate crystals (tophi) can produce destructive changes in joints and result in chronic deforming arthritis. Calcium pyrophosphate deposition disease (CPPD) - the acute synovitis of CPPD is probably due to the rupture of preformed deposits of calcium pyrophosphate dihydrate from cartilage into the adjacent synovial cavity. Hydroxyapatite arthropathy - deposition of hydroxyapatite crystals can cause an inflammatory synovitis and tendonitis, but a destructive, minimally inflammatory shoulder disorder (the "Milwaukee shoulder") is also associated with the tissue deposition of these crystals.

e. Joint or Soft Tissue Disorders Related to Trauma:

The following disorders of joints or soft tissues (muscles, tendons, ligaments, bursae) are caused or exacerbated by trauma (or overuse) - tendonitis, bursitis, traumatic arthritis, fractures/stress fractures, muscle strains and sprains, ligamentous and meniscal tears, and myonecrosis.

f. Arthritis Associated with Infiltrative Systemic Diseases:

The clinical and pathological manifestations of the following diseases are related to diffuse organ infiltration by proteinaceous materials, metals, or cells. Joint disorders can be a presenting or prominent manifestation of each of these diseases (Table).

Arthritis Associated with Infiltrative Systemic Diseases

Disease

Infiltrative Process

Amyloidosis

Amyloid of immunoglobulin light chain or serum AA protein origin

Sarcoidosis

Granuloma composed of epithelioid cells and giant cells

Iron storage disease

Iron

Hemochromatosis

g. Arthritis as a Manifestation of Systemic Diseases:

Joint disorders can be a presenting or dominant manifestation of the following systemic diseases (Table).

Arthritis as a Manifestation of Systemic Diseases

Systemic Disease

Clinical Findings

Sickle cell disease

Bone infarcts with bone pain

Hemophilia A (factor VIII deficiency) and B (factor IX deficiency)

Joint destruction related to recurrent hemarthroses

Endocrine disorders

Diabetes

Neuropathic (Charcot) joint

Hyperparathyroidism

Synovitis, resorption of joints

Acromegaly

Severe osteoarthritis

Hyperlipidemia and hypercholesterolemia

Tendonitis, tenosynovitis, polyarthritis

Cancer, cyanotic heart disease, lung disorders, chronic infection

Hypertrophic osteoarthropathy:clubbing, periostitis, arthritis

h. Arthritis Associated with Heritable Disorders of Connective Tissue:

Genetic, often heritable, defects of collagen or elastic fibers can cause prominent musculoskeletal abnormalities (Table).

Arthritis Associated with Heritable Disorders of Connective Tissue

Disorder

Basic Defect

Joint Disorder

Marfan syndrome

Uncertain: collagen or elastin

Joint pain and swelling, hypermobility, OA

Ehlers-Danlos

Collagen, various types

Hypermobility, dislocations

Osteogenesis imperfecta

Collagen type I

Fractures, scoliosis, hypermobility

i. Bone or Joint Disorders Related to Metabolic Bone Diseases:

Bone and joint pain and fractures can be prominent manifestations of osteoporosis and osteomalacia (refer to: Metabolic Bone Diseases). Osteoporosis is characterized by a decreased mass of normally mineralized bone. Osteomalacia is caused by an excess of unmineralized bone resulting from an impairment of bone mineralization. The causes of these bone diseases and conditions associated with them are discussed elsewhere (refer to: Metabolic Bone Diseases) and are summarized herewith (Table).

Causes of Osteoporosis/Osteopenia and Osteomalacia

Osteoporosis/Osteopenia	Peripheral resistance to vitamin D:
Osteomalacia	Genetic/heritable disorders of connective tissue
Aging	chronic renal failure
Reduction of vitamin D metabolites:	Rheumatoid arthritis
Endocrine abnormality:	dilantin/phenobarbital
vitamin D malabsorption	Scurvy
estrogen deficiency	Hypophosphatemia:
abnormal vitamin D metabolism	Heparin therapy
glucocorticoid excess	malnutrition
low UV light/ diet lack	Cancer:
primary hyperparathyroidism	malabsorption
loss of kidney parenchyma	multiple myeloma
Immobilization	chronic dialysis
Liver disease	leukemia/lymphoma
Alcoholism	renal phosphate wasting

2. Osteoarthritis (OA): Degenerative Joint Disease (DJD)

General Considerations.

Osteoarthritis is the most common rheumatic disease and is characterized by progressive deterioration and loss of the articular cartilage accompanied by formation of bony outgrowths ("osteophytes") about the margins of the joints and by thickening and sclerosis of the subchondral bone.

OA is often asymptomatic, but joint pain, limitation of motion, crepitus (a crackling sensation when the joint is moved), and joint enlargement or deformity are prominent symptoms in some patients.

OA can be classified as primary (idiopathic) or secondary, depending upon the absence or presence of an underlying local or systemic condition. Secondary OA may develop at any age in a joint damaged by trauma, disease (such as tuberculosis, gout, RA), and deformity (such as congenital dislocation of the hip). Primary OA without discernable relation to another disease occurs mainly in middle-aged or elderly individuals, typically affects the distal joints of the fingers (Heberden’s nodes), and may involve hip, knee, vertebrae, and other joints.

Recently, some families were found to have a Mendelian pattern of inheritance of primary generalized OA and to show coinheritance of OA with specific alleles of the gene for type II procollagen, a precursor of the major protein of cartilage. Molecular genetic studies of one such family with hereditary primary OA revealed a single base mutation in the gene for type II procollagen in all affected family members. The mutation resulted in the substitution of cysteine (not normally found in human type II collagen) for arginine in the collagen protein. The abnormal cartilage deterioriated prematurely, leading to OA. This mutation was not present in unaffected family members nor in other subjects tested. (Ala-Kokko, L., Baldwin, C.T., Moskowitz, R.W., and Prockop, D.J., Single base mutation in the type II procollagen gene (COL2A1) as a cause of primary osteoarthritis associated with a mild chondrodysplasia. Proc. Natl. Acad. Sci. USA, 87, 6565-6568, 1990)

A typical x-ray of OA shows "joint space" narrowing (indicating a loss of articular cartilage), marginal osteophyte formation, and subchondral bony sclerosis.

3093: Osteoarthritis of distal interphalangeal joints of fingers.

Pathology

The main pathological features of OA comprise injury and loss of the articular cartilage and alterations in the shape of the articular surfaces. The earliest gross changes are softening or loss of stiffness of the articular cartilage ("chondromalacia"), related to depletion of the matrix proteoglycans, and roughening of the articular surface brought about by unmasking and fragmentation of the collagen fibril structure of cartilage, a change called cartilage "fibrillation".

Microscopically, the fibrillated cartilage shows clefts or fissures which begin in the superficial layers and deepen as the cartilage is eroded and worn away from the surface by tangential flaking, pitting, and grooving.

3094: Early osteoarthritis (of hip) showing fibrillation of articular cartilage and colonies ("clones") of regenerating cartilage cells. H&E.

Colonies ("clones") of regenerating cartilage cells may be seen near the margins of the fissures or in lower layers of the cartilage.

Eventually, all of the cartilage is worn away from the load-bearing surface down to the level of subchondral bone. The underlying exposed bone becomes vascularized, thickened (sclerotic), and its surface, although pitted and grooved, acquires a highly polished ivory-like ("eburnated") appearance.

3095: Highly polished ("eburnated") appearance of exposed subchondral bone in advanced osteoarthritis of knee.

Also, fibrous-lined "cysts" (radiolucent spaces) containing connective-tissue mucin are formed in the bone just underneath the exposed surface, as seen in OA of a large joint such as the hip.

3096 Fibrous-lined "cysts" under the exposed subchondral bone in advanced osteoarthritis (of hip). H&E.

It is not clear whether such cysts evolve from synovial fluid pressed through defects on the exposed surface of bone or, alternatively, from areas of osteoclastic resorption and remodeling of ischemic sclerotic bone.

Bony outgrowths, so-called osteophytes or "spurs", develop about the margins of the osteoarthritic joint.

3097: Osteophyte ("spur") formation in osteoarthritis (of interphalangeal joint).

Osteophytes grow by endochondral ossification and, in effect, enlarge the available joint surface. Although generally regarded as a manifestation of the osteoarthritic process, osteophytes are also associated with aging in the absence of any other evidence of OA. Osteophytes producing palpable enlargements about the distal interphalangeal joints of the hands are called Heberden’s nodes and are often an early manifestation of OA.

The synovial membrane in OA usually shows fibrosis and minimal inflammatory change except for an unusual variant form called erosive inflammatory OA. The synovial fluid in OA is usually clear and viscous, with the cell count normal or slightly increased.

In some secondary forms of OA, particularly in neuropathic conditions, such as tabes dorsalis and diabetic neuropathy associated with loss of pain sensation, there is often a rapidly destructive osteoarthritic process (neuropathic or Charcot joint) which is accompanied by an extensive deposition of bone and cartilage debris within the synovial membrane and capsule.

Osteoarthritic deformity may result from changes in the shape of the articular surfaces, osteophyte formation, shortening, instability, and subluxation (partial dislocation).

Pathogenesis

Recall that the normal functions of the joints are to provide freedom and stability of motion within a certain range and an equitable load distribution from one bone to another. The shape and alignment of opposing articular surfaces are most important in joint motion. The periarticular ligaments and muscles maintain joint stability. The materials properties of cartilage and bone optimize load distribution. Cartilage carries and distributes load by virtue of the compressibility of matrix proteoglycans and bound water and by the tensile strength and elasticity of the collagen fibril network.

The loss of joint cartilage is central to the pathogenesis of OA. An early, and long prevailing, hypothesis is that OA is caused by the daily "wear and tear" of joint cartilage, that is, by the biomechanical stresses of weight bearing over time, perhaps accompanied by sluggish cartilage maintenance associated with aging.

Currently, the pathogenesis of OA is broadly defined in terms of multifactorial causes and mechanisms adversely affecting cartilage cells and the composition and properties of cartilage matrix. The underlying causes may be genetic as in some forms of primary OA, biomechanical as in many forms of secondary OA, biochemical as in metabolic diseases, and perhaps hormonal or immunologic. Histological and biochemical observations establish that the proteoglycan content of osteoarthritic cartilage is decreased and that this change is associated with disruption of the collagen fibril network (fibrillation). Under this circumstance and with continued use and injury, the joint cartilage splits and fragments and is worn away.

The joint cartilage is not merely worn away passively but has some capacity for regeneration and repair. In the early stages of OA, small clusters (clones) of surviving cartilage cells proliferate and synthesize the chief matrix macromolecules (proteoglycans and collagen II). But in later stages, cartilage maintenance and repair wanes and, with the injury and death of chondrocytes, synoviocytes, and perhaps also inflammatory cells, lytic enzymes (proteases, collagenase, etc.) are released and further degrade the cartilage matrix. The process of degradation exceeds repair, and the joint cartilage breaks down irreversibly and is eroded away.

3. Rheumatoid Arthritis (RA)

General Considerations.

RA is a chronic systemic inflammatory disease of unknown cause and is characterized by polyarthritis, which is often progressive and deforming, and by extraarticular manifestations, such as rheumatoid nodules, arteritis, and pericarditis. RA is commonly (~ 80% of cases) associated with a peculiar group of anti-IgG autoantibodies called rheumatoid factors. RA also has an association with certain class II antigens, such as HLA-DR4, encoded within the major histocompatibility complex.

It is estimated that RA affects about 3% of Americans in the age range of 18-79 years and about 1% of the world’s population.

RA may begin at any age from infancy to the aged. The mean age of onset is about 45 years, and the female preponderance is about three to one.

The clinical manifestations and course of RA are extremely variable and characterized by exacerbations and remissions. The joint symptoms commonly include morning stiffness in and around the affected joints, pain on motion, local soft tissue swelling, warmth, and redness. Joint involvement is typically polyarticular, commonly affects three or more joints simultaneously, and tends to have bilateral and symmetrical distribution. The commonly affected joints include metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the fingers, wrist, elbow, knee, ankle, and metatarsophalangeal (MTP) joints. Bilateral, symmetrical, fusiform swelling and redness of the fingers at the PIP joints are characteristic of RA.

757: Rheumatoid arthritis with inflammatory polyarthritis of proximal and distal interphalangeal joints of fingers.

The 1987 revised criteria for classification of RA are shown in the Table.

The 1987 Revised Criteria for Classification of Rheumatoid Arthritis

Criterion

Definition

Morning stiffness

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

Arthritis of three or more joints

At least three joint areas simultaneously showing soft-tissue swelling or fluid (not bony overgrowth alone) observed by physician. Possible joints include right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints.

Arthritis of hand

At least one joint area swollen in a wrist, MCP, or PIP.

Symmetric arthritis

Simultaneous involvement of the same joint areas on both sides of the body.

Rheumatoid nodules

Subcutaneous nodules, over bony prominences, or extensor surfaces.

Serum rheumatoid factor

Demonstration of abnormal amounts of rheumatoid factor by any method that yields <5% positives in normal control subjects.

Radiologic changes

Radiologic changes typical of RA on posteroanterior views of hand and wrist, which must include erosions or unequivocal bony rarefaction of the involved joints (osteoarthritic changes alone do not qualify).

For classification as RA, at least four of the seven criteria should be satisfied.

Source: Bulletin on Rheumatic Diseases, v.38, #5, 1989. Legends: as used in text above.

Pathology

The morphological changes of RA are divisible into joint lesions which dominate the clinical expression of the disease, and other (extraarticular) lesions which are systemic manifestations.

The most important aspect of RA is joint destruction brought about by pathological changes originating in the synovial membrane and ultimately leading to cartilage destruction, deformity, and ankylosis.

-Synovial membrane.- The primary joint lesion in RA occurs in the synovial membrane of affected joints and is called diffuse proliferative and exudative synovitis:

1. The synovial membrane becomes grossly enlarged (hypertrophic), congested, edematous, and thickened.

3099: Synovectomy specimen: rheumatoid synovitis of knee.

The synovial villi enlarge and elongate, and, ultimately, grow over the perichondrial margins of the joint.

732: Rheumatoid arthritis with hyperplastic synovial villi eroding and replacing cartilage at the joint margin.

2. The synovial lining cells proliferate to cover the expanded surface area and stratify into multiple (4-8) layers.

3100: Rheumatoid synovitis with multiple layers of proliferated (hyperplastic) synoviocytes underlain by lymphocytic infiltration. H&E. Multinucleated giant cells of uncertain, possibly synoviocyte, derivation are occasionally formed near the synovial surface.

3101: Multinucleated giant cells underlying proliferated synovial lining cells in rheumatoid synovitis. H&E.

3. The synovial membrane becomes focally and diffusely infiltrated with chronic inflammatory cells - lymphocytes, macrophages, and plasma cells - along with a scattering of polymorphonuclear leukocytes which are more numerous in the acute stages of the disease.

3102: Needle biopsy (of wrist): dense infiltration of chronic inflammatory cells - lymphocytes, plasma cells, and macrophages - in synovial villus in rheumatoid arthritis. H&E.

3103: Focal aggregations of lymphocytes around small blood vessels in rheumatoid synovitis. H&E.

The lymphocytes collect around small blood vessels and also form characteristic lymphoid nodules (so-called Allison-Ghormley nodules), sometimes with germinal centers similar to those of lymph nodes.

3104: Low power view of lymphoid nodules, some with pale germinal centers, in rheumatoid synovitis. H&E.

3105: High power view of lymphoid nodule with germinal center in rheumatoid synovitis. H&E.

The plasma cells are often intermixed with lymphocytes.

626: Abundance of plasma cells and lymphocytes in a synovial villus in rheumatoid arthritis. H&E.

The mature plasma cells characteristically have an eccentric "cart-wheel" nucleus and bluish (basophilic) cytoplasm or sometimes pink cytoplasm occasionally packed with spherical hyaline inclusions (aggregates of immunoglobulins) called Russell bodies.

3106: Typical mature plasma cells with an eccentric "cart-wheel" nucleus and bluish (basophilic) cytoplasm (the site of immunoglobulin synthesis) in rheumatoid synovitis. H&E.

3107: Plasma cells with pink cytoplasm containing spherical hyaline inclusions called Russell bodies (immunoglobulin aggregates) in rheumatoid synovitis. H&E.

Except for the acute stage of disease, polymorphonuclear leukocytes are rare in proportion to mononuclear cells infiltrating the synovial membrane. Nevertheless and importantly, neutrophils are usually the most numerous cells in the inflammatory synovial effusion which is almost always present in the joint cavity in the early or active stages of the disease.

4. Fibrin deposition and foci of fibrinoid change and necrosisis are present in, or on, the inflammed synovial membrane in some cases.

3108: Fibrin deposition and fibrinoid change in rheumatoid synovitis. H&E.

The preceding (1-4) changes comprise chronic diffuse proliferative and exudative synovitis which is characteristic, but not diagnostic, of RA.

3109: Chronic proliferative (hyperplastic) and exudative synovitis in long standing rheumatoid arthritis. H&E.

The inflammatory process may continue for months or years. The inflammatory exudate eventually undergoes organization by granulation tissue composed of newly formed capillaries, macrophages, and fibroblasts.

-Articular cartilage.- The synovial inflammatory and granulation tissue adjacent to the margin of the joint covers and adheres to the cartilage as a membrane or pannus (from Latin: a cloth).

733: Rheumatoid synovitis with pannus formation. The hyperplastic and chronically inflammed synovial villus extends over the surface of the articular cartilage as a fibrous inflammatory membrane (pannus) which erodes and replaces the underlying cartilage. H&E.

The articular cartilage under the pannus undergoes degradation and disappears, beginning at the joint margin and extending centrally.

647: Destruction of articular cartilage (of metacarpal joint) by rheumatoid pannus. H&E.

The cartilage matrix is destroyed from above and below, mainly by lytic enzymes (collagenase and proteases) released from synoviocytes and inflammatory cells in the pannus and the synovial effusion. Synovial inflammatory tissue may extend into the subchondral bone by penetrating the bone cortex, resulting in cortical erosion at the joint margin as seen in the clinical x-ray. As the cartilage disappears and the pannus is organized, fibrous adhesions are formed and the bone ends are bound together by fibrous tissue (fibrous ankylosis) or subsequently, with osseous metaplasia, by solid bone (bony ankylosis).

3110: Fibrous ankylosis (fixation) of interphalangeal joint in rheumatoid arthritis. H&E.

Or in some joints, if the pannus is worn away by motion, the exposed bone becomes the articular surface, and secondary osteoarthritic changes may be superimposed. Ankylosis, flexion and hyperextension deformities, dislocations, and severe osteopenia occur in the advanced stages of chronic RA.

624: Dislocations and deformities of metacarpophalangeal and interphalangeal joints in severe rheumatoid arthritis.

3111: Subluxation deformities and severe osteopenia in chronic rheumatoid arthritis treated with corticosteroids.

Deformity and dislocation of misshapen bone ends are caused by muscular imbalance and contracture and favored by laxity of capsule and ligaments in joints previously distended by effusion.

- Tendons and tendon sheaths. - Changes similar to those affecting the synovial membranes may also involve tendons and tendon sheaths ( rheumatoid tenosynovitis). Fibrous adhesions are produced between tendon and sheath, and occasionally the tendon undergoes collagen necrosis and fibrinoid change typical of rheumatoid nodules occurring in other sites, such as skin.

734: Confluent rheumatoid granulomas with central fibrinoid necrosis of tendon collagen. H&E.

- Other (extraarticular) organs. - The extraarticular manifestations of RA occur more often in seropositive patients with severe disease and circulating complexes of rheumatoid factor. 1. Skin. Subcutaneous rheumatoid nodules occur during the course of disease in about 20-25% of patients with RA. The nodules measure up to 2 cm in diameter, are firm, nontender, and palpable in the subcutaneous tissue usually over a bony prominence, such as the elbow. Histologically, a rheumatoid nodule is a granulomatous lesion consisting of a central zone of collagen necrosis and fibrinoid change, a middle zone of epithelioid cells (modified macrophages) often elongated and palisaded, and an outer zone of granulation tissue infiltrated by lymphocytes, plasma cells, and macrophages.

3112: Subcutaneous rheumatoid nodule. H&E.

Similar rheumatoid nodules are sometimes formed in other organs, such as lungs, heart, and tendons as noted above. 2. Blood vessels. Inflammatory vascular lesions (rheumatoid vasculitis) may involve venules, capillaries, arterioles, and arteries of skin or other organs and, rarely, may appear as a systemic necrotizing vasculitis of small and medium sized arteries resembling polyarteritis nodosa. 3. Other organs. Nonspecific inflammatory changes or, occasionally, rheumatoid nodules may be present in the heart (pericarditis is most frequent), lungs (pleuritis, also nodular "coin" lesions), and eyes (keratoconjunctivitis). Peripheral neuropathy may result from nerve entrapment (as in the "carpal tunnel syndrome"). Enlargement (hyperplasia) of regional lymph nodes is common, and palpable splenomegaly occurs in ~10% of patients with RA. The clinical triad of RA with splenomegaly and manifestations of hypersplenism, such as leukopenia, is called Felty’s syndrome.

Pathogenesis

The cause of RA is unknown. The possibility of an infectious etiology is a long standing, but unconfirmed, hypothesis. Multiple factors and complex mechanisms are implicated in the pathogenesis of RA, among them: autoimmune, enzymatic, cytokine and other mechanisms of joint inflammation and destruction; genetic predisposition; and environmental influence.

A genetic predisposition is suggested by the association between RA and certain HLA class II gene products, notably HLA-DR4 antigen which is present in 60-70% of Caucasian patients with RA compared to 20-30% of controls. Since class II genes regulate immune responsiveness, the HLA-DR association with RA, as with some other autoimmune diseases, suggests the possibility of a particular immunological susceptibility, perhaps relating to the induction of autoimmunity.

An intense activity of the immune system in RA is shown histologically by lymphoid hyperplasia of lymph nodes and spleen and by the prominence of lymphocytes, lymphoid nodules, and plasma cells in the hypertrophic and inflammed synovial membranes.

The serum as well as synovial fluid obtained from ~80% of adult patients with RA and 10-20% of children with JRA contain rheumatoid factors, which are a group of autoantibodies with specificity for determinants on the Fc fragment of human (or rabbit) IgG. These anti-IgG autoantibodies belong to human IgM, IgG, and IgA classes and are called, respectively, IgM, IgG, and IgA rheumatoid factor. IgM rheumatoid factor in serum is routinely determined by the latex agglutination test. Although rheumatoid factor is absent in some patients with otherwise typical RA, the titers in RA show some correlation with the severity and progression of the disease. Rheumatoid factor is present at low titers in a small proportion (<5%) of normal individuals, particularly the elderly.

Rheumatoid factor is not specific for RA and occurs also in other diffuse connective-tissue diseases as well as in some infectious and noninfectious diseases (Table). Prolonged antigenic stimulation may be a common denominator in many of these conditions.

Diseases with Frequent Occurrence of Serum IgM Rheumatoid Factor

Diffuse Connective Tissue Diseases:

Infectious Diseases:

Rheumatoid arthritis

Bacterial endocarditis

Sjogren’s syndrome

Tuberculosis

Systemic lupus erythematosus

Syphilis

Progressive systemic sclerosis

Infectious hepatitis

Polymyositis/dermatomyositis

Leprosy

Noninfectious Diseases:

Cirrhosis of liver

Sarcoidosis

Waldenstrom’s macroglobulinemia

IgM and IgG rheumatoid factors in patients with RA form immune complexes with autologous IgG in the circulation and in the synovial fluid. The complexes formed by IgG rheumatoid factor are unique in that they polymerize by self-association, that is, each molecule functions as antigen and as antibody, and no other source of antigen is required. While rheumatoid factors are produced, as are conventional antibodies, in lymph nodes and spleen, the unique feature in RA is that IgM and IgG rheumatoid factors are the principal antibodies synthesized locally by plasma cells infiltrating and accumulating in the inflammed synovial tissues

3113: Frozen section "stained" with fluorescein-labelled reactant (aggregated human IgG) for rheumatoid factor. Rheumatoid factor-forming cells in germinal centers (white) of lymph node in seropositive rheumatoid arthritis. IF.

748: Rheumatoid factor-forming plasma cells (white) in enlarged synovial villi in seropositive rheumatoid arthritis. IF.

3114: Rheumatoid factor being formed by plasma cells in synovial membrane and by germinal centers in lymph node in seropositive rheumatoid arthritis. Fluorescein-labelled reactants for rheumatoid factor: aggregated human IgG (green), rabbit immune complexes (red). IF.

The extravascular formation and deposition of IgG-anti-IgG complexes in synovial membrane, synovial fluid, and cartilage in RA can lead to the classical pathway of C’ activation, the influx of neutrophils, and C’- and neutrophil-mediated tissue injury and inflammation. The phagocytosis of immune complexes by neutrophils, macrophages, and macrophage-like (type A) synoviocytes brings about the release of lytic enzymes (proteases and collagenase) and prostaglandins (PGE2) which can degrade cartilage matrix and initiate inflammation. The extraarticular lesions, such as rheumatoid nodules, are also related to the tissue deposition of circulating complexes of rheumatoid factor. Other potential sources of immune complexes in RA include those resulting from antigenic stimulation by components of joint tissues (collagen, synovial antigens) and inflammatory exudates (denatured IgG, fibrin).

The initiating stimulus for the synthesis of rheumatoid factors remains undefined, particularly since anti-IgG autoantibodies are produced in many different diseases of an autoimmune, infectious, and non-infectious etiology (Table). A common feature of many of these diseases and of rheumatoid factor production is the presence of persistent antigenic stimulation. Interestingly, rheumatoid factor is synthesized in vitro by human B-cell lines transformed by Epstein-Barr virus (EBV) which is, as are some other microbial agents, a polyclonal B cell activator. Nevertheless, there is no firm evidence linking EBV or any other infectious agent to the etiology of RA.

Cell-mediated immune mechanisms and cytokines are now the focus of study in the pathogenesis (and therapy) of RA. Historically, some 20-30% of patients with primary agammaglobulinemia were said to develop a seronegative (RF-negative) RA-like disease, suggesting that cellular immunity alone could mediate RA. T-lymphocytes, mainly T-helper/inducer cells and many of them activated, are the most abundant cells infiltrating the rheumatoid synovial membrane. Numerous potential antigen-processing cells, among them macrophages, macrophage-like (type A) synoviocytes, and interdigitating reticular cells strongly expressing HLA-DR antigen are closely related to the activated T-cells and B-cells. Many types of cytokines are produced by activated macrophages, T-lymphocytes, and synovial cells in inflammatory arthritis. TNF (tumor necrosis factor) and IL-1, whose production is stimulated by TNF, are overexpressed in the rheumatoid synovial membrane and synovial fluid, and these proinflammatory cytokines are considered to be major contributors to the persistent inflammation and to cartilage and bone destruction in RA.

Recent advances in the biologic therapy of active RA include the use (i.v. injection) of new classes of immunomodulatory drugs that inhibit or block the biological activity of major proinflammatory cytokines in RA synovia, notably TNF and IL-1. The TNF inhibitors include: a genetically engineered, soluble form of TNF receptor (etanercept, Enbrel) that specifically binds to and neutralizes TNF (alpha and beta) and blocks interaction with cell surface TNF receptors; and human-mouse hybrid monoclonal anti-TNF-alpha antibody (infliximab, Remicade) that specifically binds to and neutralizes TNF-alpha and blocks interaction with cell surface TNF-alpha receptor. Also approved for RA is an oral, immunomodulatory and anti-inflammatory agent (leflunomide, Arava), a pyrimidine synthesis inhibitor, that blocks critical TNF-dependent gene activation.

Juvenile Rheumatoid Arthritis (JRA). The all inclusive term juvenile arthritis encompasses the 80 or so clinical entities and syndromes, among them JRA, which cause arthritis in children (Table, partial list).

Classification of Juvenile Arthritis (partial list)

Diffuse Connective Tissue Diseases

Juvenile rheumatoid arthritis

Systemic lupus erythematosus

Dermatomyositis

Systemic vasculitis

Scleroderma

Seronegative Spondyloarthropathies

Juvenile ankylosing spondylitis

Psoriatic spondyloarthritis

Reiter’s syndrome

Inflammatory bowel disease (regional enteritis, ulcerative colitis)

Infectious Arthritis

Bacterial arthritis (staphylococcal, gonococcal, tuberculous infection)

Viral arthritis

Fungal arthritis

Lyme disease

Reactive Arthritis

Rheumatic fever

Yersinial arthritis

Other Diseases (not listed)

Source: Bulletin on Rheumatic Diseases, v.38, #6, 1989.

JRA, also called juvenile chronic arthritis and known as Still’s disease, is a chronic systemic polyarthritis of unknown etiology with onset at less than 16 years of age. RA is similar in many respects in both children and adults, but there are certain differences, among them, the more frequent occurrence in JRA of high fever, rash, lymphadenopathy, monoarticular or oligoarticular (4 or fewer joints) involvement, little or absent joint pain, and the infrequency in JRA of subcutaneous nodules and rheumatoid factor (~10-20% seropositivity). JRA is classified into three subtypes on the basis of the type of disease onset during the first 6 months: systemic (~20% of cases), oligoarticular (~35%), polyarticular - 5 or more joints (~45%). The synovial pathological changes in JRA are similar to those of adult RA.

3115: Chronic proliferative and exudative synovitis (of knee) in juvenile rheumatoid arthritis. H&E.

The clinical course of JRA is usually remitting by adolescence, but a small group of patients (~15% of all cases) with polyarthritis or systemic onset and seropositive for rheumatoid factor has a poor outcome.

3116: Polyarthritis and muscle atrophy in chronic juvenile rheumatoid arthritis.

Seronegative Spondyloarthropathies (SNSA). Also called "rheumatoid arthritis variants", this group of diseases is typically seronegative for rheumatoid factor and is characterized by inflammatory involvement of the sacroiliac joints, the small posterior intervertebral (apophyseal) articulations, and adjacent soft tissues, including intervertebral ligaments and joint capsules, resulting in sacroiliitis, spondylitis (arthritis of the spine), and other abnormalities. This group includes ankylosing spondylitis (AS), also called Marie-Strumpell disease, Reiter’s syndrome (a triad of non-gonococcal urethritis, conjunctivitis, and arthritis seen in young men), psoriatic arthritis, spondylitis associated with chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease), and reactive arthritis following bacterial dysentery.

3117: Ankylosing spondylitis (Marie-Strumpell disease).

All diseases in this group have an association with class I HLA-B27 antigen, most strikingly shown by AS and Reiter’s syndrome (Table).

Association of HLA-B27 Antigen and Seronegative Spondyloarthropathies

Arthritis

Relative Risk

Ankylosing spondylitis

90X

Reiter’s syndrome

40X

Yersinia or Salmonella arthritis

20X

Psoriatic arthritis with spinal involvement

11X

Spondylitis associated with inflammatory bowel disease

Juvenile chronic arthritis with spinal involvement

Approximately 90-95% of white patients with AS and 50% of black patients with AS are HLA-B27 positive, compared to normal control frequencies of 6-8% and 4% respectively. The prevalence of AS in a random population of B27 positive individuals is less than 2%. The pathological changes in the spinal, sacroiliac, and other joints affected by AS are similar to those of RA and, in advanced disease, lead to fibrous and bony ankylosis and, ultimately, with bone spurs forming around the fused vertebrae, the radiographic picture of a "bamboo" spine. Among the extraarticular manifestations of AS are acute anterior uveitis and, less commonly, aortitis.

4. Suppurative (Septic) Arthritis

Acute suppurative arthritis is caused by joint infection with pyogenic microorganisms (staphylococci, streptococci, gonococci, and others), is characterized by purulent inflammatory changes in the synovial membrane and synovial fluid, and, if not promptly recognized and appropriately treated, leads to destruction of the articular cartilage and joint. The infection of a joint occurs most commonly by hematogenous spread of microorganisms from some other site and less frequently by extension from a neighboring infection or by introduction through a penetrating wound or following surgery.

The clinical manifestations may include the sudden onset of a tender red swollen joint, usually a weight-bearing joint (commonly the knee), and systemic symptoms associated with bacteremia, such as shaking chills and fever. Gonococcal arthritis may present as polyarthritis.

When infection is suspected, joint effusions should be aspirated under sterile conditions, synovial fluid culture and gram stain performed, and synovial fluid analysis undertaken (Table).

Synovial Fluid Analysis

Normal

Inflammation

Bacterial Infection

Color

Colorless to pale yellow

Yellow

Yellow to green

Clarity

Transparent

Opaque/turbid

Opaque/purulent

WBC/mm3

< 200

5,000 - 75,000

>50,000->100,000

PMNs

< 25%

> 50%

> 75%

Glucose

Nearly equal to blood

Less than blood

Gram stain

Negative

Positive (~65%) *

Culture

Negative

Often positive*

*Except gonococcal arthritis in which gram stain and culture positivity occurs in less than 50% of cases.

The most common causes of suppurative arthritis are staphylococci (particularly in the very young and old), streptococci, gonococci (in healthy young sexually active individuals), Hemophilus influenzae (in children <2years of age), and gram-negative rods, such as E. coli and Pseudomonas.

The synovial membrane, a richly vascular structure, is readily invaded by bloodborne bacteria which can replicate in the joint lining and are recoverable from the synovial fluid. The bacteria are phagocytosed by synoviocytes and polymorphonuclear leukocytes, resulting in cell necrosis and the release of proteolytic enzymes and mediators of cartilage destruction and inflammation. If the infection is untreated, the articular cartilage is destroyed by the purulent exudate, resulting in the exposure of subchondral bone and eventual obliteration of the joint space by fibrous (or rarely bony) ankylosis.

649: Pyogenic osteomyelitis and suppurative arthritis leading to joint destruction. H&E.

5. Tuberculous Arthritis

Tuberculous arthritis is usually caused by contiguous infection from tuberculous osteomyelitis (Refer to: Bone Tuberculosis), which latter almost always results from the hematogenous spread of M. tuberculosis from an infection elsewhere, such as the lungs or occasionally some other site (mediastinal or aortic lymph nodes, kidney, bowel).

The presentation of tuberculous arthritis is often monoarticular and most often involves the hip, knee, or intervertebral joints.

616: Tuberculosis of knee: the femoral condyles are eroded and destroyed by tuberculous infection of bone and joint.

Tuberculosis of the spine, also called Pott’s disease, commonly affects the thoracic and lumbar vertebrae and usually comprises both tuberculous osteomyelitis and tuberculous arthritis. The inflammatory and destructive process involves adjacent vertebral bodies and the intervertebral disc, leading to collapse and kyphotic angulation of the spine and, in some cases, cord compression or meningitis.

634: Tuberculosis of spine (Pott’s disease) with vertebral collapse and kyphotic angulation.

Microscopically, the synovial membrane in tuberculous arthritis is characterized by the presence of epithelioid granulomas with caseous necrosis and Langhans’ multinucleate giant cells. Nevertheless, atypical mycobacteria and fungal infections, such as coccidioidomycosis, can also produce granulomatous synovitis.

3118: Coccidioidomycosis synovitis (of Knee). H&E.

A definitive diagnosis of tuberculous arthritis is made by identifying acid fast bacilli in the synovial tissue biopsy or isolating M. tuberculosis in cultures of synovial tissue or synovial fluid (positive cultures in up to 80% of cases).

6. Lyme Disease

Lyme disease is a systemic inflammatory disease caused by spirochetal infection with Borrelia bergdorferi, an antibiotic-sensitive treponema-like organism transmitted by the bite of infected deer ticks. Lyme disease is the most common tick- or insect-borne disease in the U.S., and more than 10,000 new cases of Lyme disease occur each year. The chief manifestations may include a characteristic skin rash at the site of the bite followed in weeks to months by the development of cardiac or neurological involvement or RA-like arthritis.

Lyme disease, named after the Connecticut town where it was first recognized, was initially thought to be a form of JRA. Although now reported to exist in almost every state and several countries, Lyme disease is most prevalent in northeastern coastal states (NY, NJ, CT, MA) where the principal vector is the deer tick Ixodes scapularis, whose main animal hosts are white-footed mice, a reservoir for the spirochetes, and white-tailed deer. The spirochetes are introduced into human skin during the ingestion of blood by infected nymphal or adult forms of the tick which are most active during the spring and summer months.

Lyme disease may occur at any age. An expanding red skin lesion, called erythema chronicum migrans (ECM), appears at about 3 days to a month after the tick bite in 50-75% of cases, often accompanied by flu-like symptoms. This early stage may be followed by an intermediate stage consisting of cardiac involvement (arrhythmias, conduction abnormalities) or neurological changes (meningitis, encephalitis, cranial nerve palsy). Late Lyme disease, occuring months to years after the onset of infection, may include a recurrent inflammatory arthritis resembling RA and severe neurological sequelae.

Specific antibodies to B. bergdorferi eventually develop in most patients with Lyme disease, but only a small portion are antibody positive during the early weeks, and some patients remain seronegative.

The pathological changes in Lyme disease are apparently initiated by direct spirochetal invasion of the tissues and are thought to be perpetuated or exaggerated by immune complex- or cell-mediated mechanisms. Spirochetes have been isolated from blood cultures and also demonstrated in biopsies of skin and synovial membrane by silver stains. The progression of the disease is associated with an expansion of the immune response to antigens of B. bergdorferi, presumably a response to persistent infection.

7. Arthritis Associated With Rheumatic Fever

Rheumatic fever is an acute, or recurrent, inflammatory disease which is characterized clinically by fever, polyarthritis, and carditis (Refer to: Heart), histologically by cardiac Aschoff bodies, serologically by rising titers of antibodies, such as anti-streptolysin O (ASO), to streptococcal antigens, and bacteriologically by antecedant, usually pharyngeal, infection with group A streptococci. The inflammatory lesions of rheumatic fever are sterile, develop after a latent period of 2-3 weeks following streptococcal infection, and are attributed to immunologically mediated mechanisms. While not fully understood, the pathogenesis of rheumatic fever is generally attributed to antibody and cellular immune responses (following antecedant group A streptococcal pharyngeal infection in genetically predisposed individuals) directed against streptococcal antigens and against cross-reacting self antigens of certain host tissues, such as heart. The migratory arthritis of rheumatic fever is usually self limited, rarely leads to permanent deformity, and is the prototype of a "reactive arthritis" (Refer to: Mechanisms of Arthritis).

8. Gout and Gouty Arthritis

General Considerations

Gout is a disorder of purine metabolism which is characterized by long standing hyperuricemia and recurrent episodes of inflammatory arthritis (gouty arthritis), usually monoarticular in onset, caused by precipitation of monosodium urate (MSU) crystals and their interaction with leukocytes within the joint and is sometimes accompanied by the formation of gross deposits of urates (tophi) in joints, periarticular tissues, and other sites, such as uric acid stones and crystal deposits in the kidneys.

Gout mainly affect men (~95% of all cases), has a peak incidence in the fifth decade, is the most common type of inflammatory arthritis in men over 40 years of age, and occurs infrequently in women after the menopause. A family history of gout is often obtained in gouty subjects, perhaps in about 25% of cases, although the reported frequency of familial gout varies widely in different clinical series.

Gout is a complication of long standing hyperuricemia which, nevertheless, is not the sole determining factor since the prevalence of hyperuricemia (~2% or more of the population) in the Western world is much greater than that of gout (~0.1-0.4%). Hyperuricemia is defined statistically by comparison to the normal range of serum urate concentrations (taken as the average value plus or minus two standard deviations for healthy control populations by routine methods of analysis) whose upper limit of normal is usually 7 mg/dl for men and 6 mg/dl for women. On this basis, hyperuricemia is a serum or plasma urate level above 7 mg/dl, a value which also exceeds the solubility limit for urate in plasma, at normal pH and body temperature, as determined by physicochemical analysis. The prevalence of gout increases with the serum urate concentration. Some reports indicate a prevalence of gout of less than 2% of subjects with a urate level of 7 mg/dl or less, about 20% at 7.0-7.9 mg/dl, 40% at 8 mg/dl or more, and 90% of subjects at 9 mg/dl or more.

Clinical Manifestations

The natural history of gout is divisible into four phases: asymptomatic hyperuricemia, acute gouty arthritis, intercritical gout, and chronic tophaceous gout, to which can be added gouty nephropathy and uric acid renal stones which occur in 10-25% of gouty subjects.

A period of asymptomatic hyperuricemia almost always precedes the onset of symptomatic gout although serum urate levels are not invariably elevated during an acute attack. Notably also, only 5% or less of individuals with hyperuricemia ever develop gout.

Acute gouty arthritis is typically a monoarticular inflammatory arthritis which initially involves the metatarsophalangeal (MTP) joint of the big toe (acute "podagra") in 75% or more of patients, or the tarsal joint, ankle, or knee in others, and is characterized by the sudden onset of joint pain, exquisite tenderness, swelling, and redness, the appearance of which may be mistaken for a septic joint.

The acute attack of gout usually subsides in a few days in untreated patients with mild disease, or in a few weeks in those with more severe involvement, and the remission lasts for varying intervals of time (months to years), to be followed by recurrent attacks and intervals of remission. The intervals between attacks are usually asymptomatic even though the hyperuricemia persists (intercritical gout).

The deposition of MSU crystals continues in untreated or poorly controlled patients and, following multiple recurrences or polyarticular involvement and a period of about 10 years after the first attack, gross deposits of urates (tophi) form in joints, bursae, tendons, and subcutaneous tissue (chronic tophaceous gout) and eventually erode the cartilage and subchondral bone, resulting in permanent joint changes (chronic gouty arthritis). With the availability of effective drugs for antihyperuricemic therapy, the chronic effects of gout are now less common and occur in only about 10-15% of patients.

Pathogenesis of Hyperuricemia and Gout

Uric acid is the endproduct of purine metabolism, and 70-80% of the uric acid produced each day is excreted in the urine, normally at a rate of 300-600 mg/24 hrs. The concentration of uric acid in body fluids is determined by the balance between the production and excretion of uric acid.

Gout is a complication of hyperuricemia, and the pathogenesis of gout is ultimately related to the pathogenesis of hyperuricemia. The average serum urate level in untreated patients with gout is in the range of 9-10 mg/dl. All of the clinical manifestations of gout are initiated by the crystallization of sodium urate or uric acid from supersaturated body fluids. Hyperuricemia and gout are both caused by either an overproduction of uric acid or renal underexcretion of uric acid, or rarely both.

Hyperuricemia and gout are classified as primary and secondary types (Table) and hyperuricemia also as an idiopathic type with elevated serum urate but without gout.

Classification of Hyperuricemia and Gout

Type

Metabolic Disturbance

Inheritance/Other

Primary:

Molecular defect undefined

Underexcretion (90% of primary gout)

Not established

Polygenic

Overproduction (10% of primary gout)

Not established

Polygenic

Associated with specific enzyme defects

PRPP synthase variants: overactivity

Overproduction of PRPP and uric acid

X-linked

HGPRT, partial deficiency

Overproduction of uric acid; PRPP surplus

X-linked

Secondary:

Associated with increased nucleic acid turnover

Overproduction of uric acid

Proliferative disorders; cytotoxic drug therapy

Associated with decreased renal excretion of uric acid

Decreased glomerular filtration, decreased tubular secretion, increased tubular resorption of uric acid

Renal disease; diuretic therapy

Associated with increased de novo synthesis of purines

Glucose-6-phosphatase deficiency

Overproduction plus underexcretion of uric acid; glycogen storage disease II

Autosomal recessive

HGPRT deficiency, virtually complete

Overproduction of uric acid; Lesch-Nyhan syndrome

X-linked

Idiopathic

PRPP: 5-phosphoribosyl-1-pyrophosphate

HGPRT: hypoxanthine-guanine phosphoribosyltransferase

- Primary hyperuricemia and gout.- Patients in this group may have familial or nonfamilial gout caused by either an overproduction of uric acid (~10% of primary cases) or renal underexcretion of uric acid (~90% of primary cases).

While the basic renal defect leading to the underexcretion of uric acid in the majority of patients with primary gout is not established, any or all of the following theoretical mechanisms may be involved: reduced glomerular filtration of uric acid; decreased tubular secretion of uric acid; increased tubular resorption of uric acid.

An overproduction of uric acid accounts for a minority of patients with primary gout. Two heritable (X-linked) enzyme defects have been identified within this group of patients, namely, those with PRPP (5-phosphoribosyl-1-pyrophosphate) synthase overactivity and those with partial deficiency of HGPRT (hypoxanthine-guanine phosphoribosyltransferase), enzymes which are involved in the de novo and salvage pathways of purine synthesis, respectively (Figure).

Purine Metabolism

*Control points for uric acid synthesis: PRPP synthase activity; PRPP level: HGPRT (hypoxanthine-guanine phosphoribosyl transferase) activity. Xanthine oxidase is inhibited by allopurinol, an analogue of hypoxanthine.

Briefly and without entering into the biochemical complexities of purine metabolism, uric acid synthesis is "driven" by the intracellular concentration of PRPP which is synthesized de novo by PRPP synthase. Primary gout caused by an overproduction of uric acid is found in two groups of patients with genetically determined (X-linked) enzyme defects (Table) leading to an excess of PRPP and the overproduction of uric acid, namely: overactive PRPP synthase variants which overproduce PRPP; and partial deficiency of HGPRT, an enzyme of the salvage pathway whose underactivity leads to a surplus accumulation of PRPP, the normal enzyme substrate. Males with either of these genetic defects usually develop gouty arthritis at a young age and also have a high incidence of uric acid renal stones.

Aside from the enzyme defects just mentioned, the metabolic changes are not established for other patients with primary gout caused by an overproduction of uric acid. As noted previously, the vast majority (~90%) of patients with primary gout have renal underexcretion of uric acid rather than the overproduction of uric acid, and the underlying defect in these patients is also not defined.

-Secondary hyperuricemia and gout.- Patients with secondary hyperuricemia may have familial or nonfamilial gout caused by either an overproduction of uric acid or renal underexcretion of uric acid (Table).

In patients with secondary hyperuricemia due to an overproduction of uric acid, the uric acid surplus is usually associated with an excessive breakdown of cells and an increased turnover of nucleic acids, as in myeloproliferative disorders, leukemias, multiple myeloma, some carcinomas, and hemolytic anemias, or with massive cell lysis produced by cytotoxic drug therapy.

The overproduction of uric acid in patients with Lesch-Nyhan syndrome, a syndrome characterized by X-linked inheritance, self mutilation, and other neurological abnormalities, is due to virtually complete deficiency of HGPRT, resulting in an accumulation of PRPP and increased purine synthesis de novo.

Secondary hyperuricemia caused by renal underexcretion of uric acid may result from chronic renal disease, diuretic drug treatment (which interferes with the renal secretion of uric acid and causes blood volume contraction), salicylates, and ethanol.

Patients with glucose-6-phosphatase deficiency (von Gierke’s disease/ glycogen storage disease) have both an overproduction of uric acid and renal underexcretion of uric acid.

Pathology - Acute gouty arthritis.-

Acute gouty arthritis usually has a monoarticular onset, most commonly involves the metatarsophalangeal joint of the big toe (~75% or more of patients), instep, ankle, heel, knee, or wrist, and is caused by the formation of monosodium urate (MSU) crystals and their inflammatory interaction with leukocytes in the joint cavity.

The accompanying synovial effusion typically contains an increased white cell count with a preponderance of neutrophilic polymorphonuclear leukocytes (PMNs) and numerous urate crystals which are needle-shaped, 2-10 micrometers in length, strongly, and negatively, birefringent as seen by polarized light microscopy in free form or phagocytized by PMNs.

3119: Monosodium urate (MSU) crystals in synovial effusion of acute gouty arthritis. Polarizing microscopy.

The urate crystals adsorb proteins, including immunoglobulins, in the synovial fluid, and the coating protein may facilitate the phagocytosis of crystals by PMNs, macrophages, and phagocytic synovial lining cells. After the crystals are incorporated into the phagolysosomes of leukocytes, the protein coat is enzymatically degraded but not the crystals, which retain their capacity to disrupt cell membranes. The urate crystals along with degradative enzymes, inflammatory mediators, such as interleukin-1, prostaglandins, leukotrienes, and toxic oxygen radicals, and chemotactic factors are released from the phagocytic cells. The cycle of crystal-induced inflammatory arthritis is repeated over again until the process of crystal formation subsides.

- Chronic tophaceous gout and chronic arthritis.- The formation of urate crystals continues in untreated or poorly controlled patients and, following multiple recurrences or polyarticular involvement, the stage of chronic tophaceous gout is reached. Gross and microscopic deposits of urates form in and about joints, bursae, tendons, subcutaneous tissue, the ear (helix or antihelix), and kidney (medulla or pyramids).

3120: Advanced stage of chronic tophaceous gout.

3121: Chronic tophaceous gout involving tendon (of wrist). H&E.

The tophus is a pathognomonic lesion of gout and consists of masses of crystalline or amorphous urate deposits surrounded by an inflammatory reaction of macrophages, fibroblasts, and distinctive multinucleate foreign body-type giant cells.

3122: Gouty tophus. The urate deposits (amorphous pink areas) have been dissolved by formalin fixation. H&E.

The urate deposits are water-soluble and dissolved by routine histological procedures and are best preserved in tissue biopsies by alcohol fixation and visualized by polarized light microscopy or special silver stains.

3123: Gouty bursitis. The urate deposits (brownish areas) have been preserved by alcohol fixation. Silver stain.

The presence of tophaceous deposits is associated with chronic gouty arthritis. As urates precipitate in the synovial lining and encrust the articular surfaces, the phagocytic (type A) synovial lining cells proliferate and form a pannus which destroys the underlying cartilage.

3124: Histochemical acid phosphatase activity (black areas), a marker for lysosomal enzymes, in synovial lining cells in gouty arthritis (of knee). Enzyme histochemistry.

Tophaceous deposits around joints erode into cartilage and subchondral boneand may cause marginal erosions of bone as seen in clinical x-rays.

3125: Gouty arthritis with urate deposits in subchondral bone. Alcohol fixation and silver stain.

3126: Gouty tophi with marginal erosion of bone at first metatarsophalangeal joints.

Some form of renal involvement (gouty nephropathy) is often present in long standing gout, and uric acid renal stones occur in 10-25% of all patients with gout.