Pathology and Pa Tho Genesis of Arthritis

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Pathology and Pathogenesis of Arthritis

Overview

This module gives an overview of the pathogenesis and pathology first of osteoarthritis and, secondly, ofrheumatoid arthritis.

Specific Objectives:

Upon completion of this module, the student will be able to:

1. Discuss the pathogenesis of OA, identifying genetic, mechanical, cellular, metabolic and biochemicalfactors involved.

2. Describe changes in the joint that occur as OA progresses.3. Identify factors that may influence the pathogenesis of RA, including genes, immune complexes,

cytokines and viruses.

4. Describe changes in the joint that occur as RA progresses.Date of in-class session:

This unit is complementary to the Arthritis sessions and should be completed prior to the second Arthritis TBL

(January 19). The Approach to Arthritis exercise and Monoarthritis, and Polyarthritis modules should becompleted prior to this module, as indicated in the Learning Map.

Estimated preparation time: 60 minutes

Required preparation:

1. Read1. Cecil's Essential Ch 87, pp.779-780. "Osteoarthritis". Subsection titled Pathology. (see FAQs).2. Cecil's Essential Ch 78, pp.735-736 "Rheumatoid Arthritis". Subsections titled Pathology and

Pathophysiology; also see Table 78-1 and Fig. 78-1. (see FAQs).3. Maksimowicz-McKinnon, K Rheumatoid Arthritis (Cleveland Medical clinic) - pathophysiology

section.4. PostGraduate Medicine module on OA. Pathogenesis section. Table 1 and Table 2.

2. Work through this module

Pathogenesis of Osteoarthritis

Osteoarthritis attacks weakened joints. In idiopathic (primary) OA, hormonal, genetic, metabolic and mechanicalfactors appear to be implicated but the etiology remains unclear. In secondary OA, all of these factors one factoris identifiable as the primary cause. Often in secondary OA, mechanical causes are primary and the affected

joint(s) has (or have) been exposed to previous trauma involving repeated and/or excessive loading of thejoint(s). Congenital and development deformities, neurologic disorder and pre-existing arthritis may also incite

secondary OA.

Factors that may contribute to the development of osteoarthritis are explored further below:

Genetic and Hormonal Factors Mechanical Factors Cellular and Metabolic Factors Biochemical Abnormalities


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Genetic and Hormonal Factors

As seen in the Osteoarthritis section of the Polyarthritis module, idiopathic OA is more frequently seen in womenand is hereditary. Mutations in collagen genes (types II, IX, X) appear to contribute to the development ofpremature idiopathic OA. Heberden's nodes are symptomatic of a particular hereditary form of OA thought to be

associated with a gene that is recessive in males and dominant in females.

Mechanical Factors

The composition and structure of articular cartilage define its mechanical properties, making it well-suited toabsorb shock, bear weight, and defining how much weight is too much. Articular cartilage is composed of cells(chondrocytes), surrounded by a matrix and immersed in water. The matrix is 60-80% water, with collagen,proteoglycan and glycoprotein macromolecules making up the remainder of its structure. Each chondrocyte cell is

surrounded by matrix and is nourished primarily via synovial fluid in the joint.

Schematic of articular cartilage structure. Not to scale.

Redrawn from Wroble, 2000.Synovial membrane (SM), articular cartilage (AC), bonespicules (bo) and bone marrow spaces (m) in a synovial

joint. University of Ottawa Histology

Like all weight-bearing structures, articular cartilage has a critical stress (force per unit area) which it cantolerate and above which, it begins to break down. When the joint is exposed to stresses above this critical value,

the unit load on the chondrocytes becomes too high and overburdened chondrocytes begin to die. The death ofchondrocytes cells weakens the matrix by stopping chondrocyte homeostasis in those cells; this leads todegradation of the articular cartilage.

An increased unit load on the chondrocytes may also be the result of changes in the subchondral bone. In Paget'sdisease, for example, damage to the coarse cancellous bone ofteh epiphysis may cause an increase in thestiffness of the subchondral bone. This, in turn, increases the unit load on the chondrocytes and increases the

likelihood that articular cartilage will eventually degrade and OA will develop.

Cellular and Metabolic Factors

In hemochromatosis, excessive iron absorption may contribute to joint pain and the development of OA. In

ochronosis, pigment may be deposited in articular cartilage, contributing to the development of OA in the joint.

Biochemical Abnormalities

Changes in composition of articular cartilage contribute to the development of OA. As healthy articular cartilageages, its water content decreases. In osteoarthirtic cartilage, water content increases, contributing to the

tendency for this cartilage to swell more than normal. Collagen fibres become thicker than normal and morewater binds to these cllagen fibres. Proteoglycan content and aggregation are both decreased and the length ofglycosaminoglycan chains is shortened.

These changes are summarized succintly in Table 1 of this PostGraduate Medicine module on OA.


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Chondrocytes bearing excessive loads eventually cease to respond to reparative stimuli, as a result proteinsynthesis by chondrocytes also decreases. Acid cathepsin attacks protein cores and is increased in OA cartilage.

Collagenase is found in OA cartilage.

Pathology of Osteoarthritis

As OA progresses, structures in the joint degenerate. First, the articular cartilage breaks down, exposing thesubchondral bone, which then becomes damaged. Eventually osteophytes form. These changes are discussed in

more detial below:

Changes in articular cartilage Changes in subchondral bone Development of osteophytes

Changes in articular cartilage

Loss of Proteoglycans - Histology of osteoarthritic articular cartilage indicates a decrease in proteoglycans fromthe surface of the articular cartilage, evidenced by a decrease in metachromatic staining.

(IMAGE?)

Chondrocyte Cloning - As chondrocytes in overloaded cartilage die, empty lacunae are visible under themicroscope. The remainining viable chondrocytes aggregate into groups in a process termed chondrocyte cloning.

Fibrillation - The first macroscopic change in the osteoarthritic joint is the fibrillation of the cartilage. Multiple, tinysurface cracks develop first in the superficial layer of the articular cartilage and gradually deepen. Synovial fluidflows into these cracks and, as deeper layers of cartilage fibrillate, pieces break off, lodging in the synovium and

leaving the subchondral bone increasingly exposed.

Secondary Synovitis - Fragments of cartilage and bone join to form osteocartilaginous loose bodies in the jointspace. The presence of these bodies in the synovium elicits a foreign-body type inflammatory reaction, causing

the synovium to become hyperemic and hypertrophied.

Changes in subchondral bone

In the region where the articular cartilage is cracked and fibrillated, the subchondral bone responds by forming

new blood vessels (neovascularization). This process induces osteoclastic bone resorption and increased activityin adjacent osteoblasts, resulting in a thickening of the subchondral bone in the exposed area.

Fibrocartilagenous plugs - As neovascularization continues, mesenchymal cells invade (the subchondral bone?where?) and form fibrocartilagenous plugs to replace articular cartilage which has broken off. These plugs fill the

empty space left by degraded cartilage but are poor substitutes functionally and wear out quickly.

Eburnation - The subchondral bone becomes exposed such that it grinds against the opposite joint surface. As thejoint moves, this grinding burnishes the exposed bone. It becomes eburnated - polished, shiny and smooth, with

an appearance like ivory.


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Eburnated osteoarthritic patellae are thick, shiny and

smooth with an appearance like ivory. (PEIR PathologyLibrary).

Exceptionally large subchondral bone cyst in 70-year oldwith degenerative arthritis that raised concern for aneoplasm. At surgery the cyst contained gray, semi-liquid

fluid. The defect was packed with bone chips. (PEIRPathology Library)

Subchondral bone cysts - These cysts form when synovial fluid flows into the bone marrow space following acrack in the eburnated subchondral bone.

Development of osteophytes

In advanced OA, bony spurs called ostephytes develop when mesenchymal tissue of the synovium modulates intoosteoblasts and chondroblasts to form a mass of bone and cartilage. Mechanially, osteophytes serve to increase

the load-bearing area on the joint thus decreasing the load per unit area (i.e. stress). Osteophytes most oftenappear on the periphery of the joint.

Osteoarthritic femoral head showing osteophytes, bone overgrowth, along with evidence of ochronosis and melanin. Note

the pearly greyish appearance of the osteophytes. PEIR Pathology Library.

Pathogenesis of Rheumatoid Arthritis

The etiology of RA is unknown. Various factors appear to influence the pathogenesis of the disease, including

Genetic Factors Humoral Immunity Cellular Immunity Infectious Agents

Genetic Factors

Patients with RA are found to have certain genetic features, including an important genetic locus in HLA genes.Increased risk of RA is associated with the presence of a specific set of HLA-DR alleles.

These alleles share a pentapeptide sequence of AA's that forms the rheumatoid pocket on the HLA molecule.


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Humoral Immunity

The synovium of RA patients shows certain abnormalities. Ig's are produced in the synovium due to anaccumulation of lymphoctes and plasma cells. Immune complex deposits are present in the synovium and

articular cartilage.

Serum levels of certain immunoglobulins (IgM, IgA, IgG) are increased in RA patients. Rheumatoid factor (RF) isand IgM which is present in 70%-80% of patients with classic RA. The presence of RF is associated with moresevere disease, though RF is also found in some people who do not have RA.

Cellular Immunity

Activated, helper-type T lymphocytes infliltrate the rheumatoid synovium. These T cells interact withmacrophages directly or indirectly to produce an excess of pro-inflammatory cytokines, such as TNF and IL-1.These contribute to inflammation in the synovium and subsequent joint destruction.

Infectious Agents

Structures resembling viruses have been reported early in the course of the disease. High incidence of B cells andantibodies to Ebstein-Barr Virus (EBV) in RA patients suggests EBV may play a role in inciting RA. EBV is a

polyclonal B-cell activator that stimulates production of rheumatoid factor.

Pathology of Rheumatoid Arthritis

The joint pain and inflammation in RA the result of synovitis and synovial pannus within the joint. This eventually

leads to changes in the peri-articular bone and soft tissue in the area of the joint.

Changes in synovial membrane Changes in peri-articular bone Changes in soft tissue Synovial fluid

Changes in synovial membrane

Early changes in the synovium include:

edema, lymphocytes, plasma cells, macrophages increased vascularity exudation fibrin in joint space (formation of rice bodies)

Hyperplasia and hypertrophy of synovial lining cells causes these cells to creep over adjacent structures,including articular cartilage. This creeping synovial lining is called pannus. It fills the periphery of the joint,

cutting off the articular cartilage from the nourishment of the surrounding synovial fluid.

Eventually the joint is destroyed and ankylosis occurs, fusing the fibrous tissues in the joint. This is eventuallyfollowed by bony ankylosis, where apposing bones acutally fuse in the destroyed joint.


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Changes in peri-articular bone

As articular cartilage becomes completely degraded, the bone at the sides of the joint begins to erode, probably

due to a factor elaborated locally by rheumatoid synovium.

Progressively worsening bone erosion. From the ACR High Impact Rheumatology slide collection.

Changes in soft tissues

Rheumatoid nodules may form in subcutaneous tissue. Macroscopically, zones of fibrinoid necrosis can beidentified in these nodules. Microscopically, zones of necrobiosis are seen, surrounded by pallisading histiocytes.

Gross view of a rheumatoid nodule on lung tissue. PEIR

Pathology Library.

Rheumatoid nodule under the microscope, in the heart.

PEIR Pathology Library.

Synovial fluid

Aspirated rheumatoid synovial fluid has increased turbidity and decreased viscosity compared to normal synovialfluid. Inflammation causes the volume of fluid to increase, with increased content of both polymorphonuclear

lymphocytes (PMNL's) and proteins.

Review Exercise and Summary

Review what you have been learning about the pathogenesis and pathology of OA and RA. If you are not sure ofyour answers, follow the links to go back to the relevant part of the module.

Use the Back button on your browser to return to this page.

Identify factors that are involved in the development of idiopathic OA. Contrast changes in osteoarthritic articular cartilage with those seen in cartilage that is aging normally. Describe the degradation of an osteoarthritic joint, identifying the chronology in which various

structures are affected.

List factors that are thought to contribute to the development of RA. Describe the changes in the synovium of a joint affected by RA.

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Pathology and Pa Tho Genesis of Arthritis