Knee Arthritis: Pathology and Progression

John L. Hamilton, MD, PhD

Brett R. Levine, MD, MS

INTRODUCTION

Arthritis is a general term used to describe inflammation or degeneration of a particular joint. In general, osteoarthritis (OA) is a specific form of arthritis with an underlying pathological pathway and progressive pattern that is associated with a multifactorial degenerative process. Alternatively, other forms of arthritis, such as rheumatoid arthritis (RA) and associated conditions, are primarily mediated by an inflammatory condition that leads to degeneration of the afflicted joint; as a whole these conditions are grouped together using a catch-all phrase, termed inflammatory arthropathies. In the United States alone, over 50 million adults have some form of diagnosed arthritis, which is projected to increase 49% by 2040.¹ In the United States, arthritis is a leading cause of work disability.²

The knee is commonly involved in various types of arthritic conditions. The knee joint is a modified hinge joint that predominately allows flexion and extension but also permits slight internal and external rotation; it is composed of three compartments, which include the medial tibiofemoral, lateral tibiofemoral, and patellofemoral joint. In the context of arthritis within the knee joint, pathology at multiple tissues should be considered, including but not limited to the cartilage, bone, and synovium. Pathological changes at multiple tissue types contribute to the knee joint pain, dysfunction, and subsequent impaired mobility experienced by individuals with arthritis. There are over 100 forms of arthritis and related diseases; this chapter will discuss the pathologic pathways of progression and clinical presentation of the types of arthritis most commonly found within the knee.

OSTEOARTHRITIS

Epidemiology

Osteoarthritis (OA) is the most common form of arthritis, and the knee is the most commonly affected joint. In the United States, it is estimated that there is nearly a 50% chance of developing symptomatic knee OA in any given individual’s lifetime.³ There are a number of modifiable and nonmodifiable risk factors that contribute to the increased risk associated with the development and progression of OA. OA is predominately found in adults of older age, and the incidence of knee involvement increases with each decade as we age.⁴ Studies have investigated the role of aging in OA development and have found that aging can affect cellular processes at articular chondrocytes including elevated oxidative stress, reduced repair response, and increased catabolic matrix metalloproteinase activity.⁵,⁶ Furthermore, aging can affect all tissues at the joint including muscle and ligaments, which can further influence mechanical loading.

Younger adults who develop OA often have a history of a prior knee injury, and this type of OA is subclassified as posttraumatic OA (PTOA). Injuries can include acute damage to the cartilage, bone, ligament, and/or meniscus. In general, these injuries can result in the initiation of an inflammatory cascade, which can help facilitate OA development.⁷ Furthermore, trauma can cause acute and irreparable cartilage damage, and chondrocyte cell death can occur at the articular surface. Acute traumatic events can also lead to sustained upregulation of catabolic and inflammatory cytokine signaling.⁷ Damage that occurs at the knee as a result from the trauma can result in mechanical instability. Altered mechanical influences can lead to altered transduction of biochemical signaling molecules. These mechanically transduced signals can lead to increased expression of catabolic cytokines and mediators and stimulate cartilage degeneration, synovial inflammation, and bone remodeling, with subsequent joint degeneration over time.⁸

Individuals with obesity, defined as a BMI>30 kg/m², have an increased incidence of OA and develop OA earlier.⁹,¹⁰ Coggon et al. found that obesity can lead to a 6.8 times greater risk of developing knee OA.¹¹ Obesity can increase mechanical loading at the joint and will accentuate these abnormal forces in the setting of mechanical axis deviations. However, mechanical influences are not the only mechanism for increased OA risk. There is an increased risk of OA in non-weight bearing joints, such as the hands, with obesity.¹² Another potential mechanism through which obesity can contribute to OA pathogenesis is by facilitating low-grade chronic inflammation through secretion of adipose-derived cytokines, called adipokines.¹⁰

Hereditary influences can play a role in OA development. Rare genetic mutations encoding structural collagens found in articular cartilage can result in premature
OA; these rare mutations can cause OA in early adolescence and affect multiple joints.¹³,¹⁴ Twin studies have demonstrated that, even with adjustment for age, sex, and BMI, there is an association of genetic heritability in terms of knee structure, cartilage volume, and radiographic progression of OA.¹⁵ Genome-wide association studies have compared control and OA populations and have identified over 80 gene mutations or single nucleotide polymorphisms associated with OA; many of the genes encode important components of the cartilage matrix or are important signaling molecules for articular cartilage and joint maintenance.⁵

Gender seems to play a role in knee OA, with a greater prevalence found in women as compared to men.¹⁶ Women often present with more advanced stages of OA and have higher reported pain and disability.¹⁷,¹⁸ Isolated patellofemoral OA is also more prevalent in women as compared to men.¹⁸ Potential reasons for the gender difference in women include anatomic and kinematic differences and increased incidence of ACL injuries. Postmenopausal women have a particular increased risk of OA, which has been suggested to be related to decreased estrogen. Estrogen receptors have been identified at the articular cartilage.¹⁹,²⁰ However, assessment of what role and significance estrogen plays in OA pathology and progression is ongoing. Table 5-1 summarizes major influences on the development of OA.

The classification of OA can be primary or secondary. Primary OA implies an unknown or idiopathic attributable cause to OA development. Secondary OA signifies development of OA due to known injury or disease. Posttraumatic OA and obesity can be considered as secondary causes of OA. Congenital and developmental diseases, calcium deposition diseases, other bone and joint disorders, endocrine disorders, and other miscellaneous diseases such as neuropathic arthropathy can lead to the development of secondary OA.²¹ Table 5-2 summarizes secondary causes of OA. While there is an extensive list of secondary causes of OA, these pathologies can precipitate OA by previously characterized mechanism of OA development, such as altered biomechanical influences, inflammation and catabolic cytokines signaling, and altered remodeling and changes in the bone architecture.

TABLE 5-1 Major Influences on Knee Osteoarthritis Development

INFLUENCES

Aging
Previous trauma/injury
Obesity
Hereditary/genetic
Gender (women)

TABLE 5-2 Causes of Secondary Knee Osteoarthritis (OA)

SECONDARY KNEE OA
Posttraumatic OA		Bone and joint disorders
Obesity			Avascular necrosis
Congenital developmental diseases			Rheumatoid arthritis
	Unequal lower extremity length		Gouty arthritis
	Extreme valgus/varus deformity		Septic arthritis
	Bone dysplasia		Paget disease
Genetic and metabolic diseases		Endocrine diseases
	Hemochromatosis		Diabetes mellitus
	Ochronosis		Acromegaly
	Gaucher disease		Hypothyroidism
	Hemoglobinopathy		Hyperparathyroidism
	Ehlers-Danlos disease	Neuropathic arthropathy (Charcot joint)
	Calcium deposition disorders
	Calcium pyrophosphate deposition disease	Frostbite
		Kashin-Beck disease
	Apatite arthropathy	Caisson disease
Reproduced with permission from Altman R, et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum. 1986.

Symptoms

A primary complaint of individuals seeking knee OA treatment is pain. The pain is often described as exacerbated with activity and relieved with rest and characterized as a deep, dull ache. In certain cases the pain can be isolated to a single compartment of the knee but is more often diffuse in nature. With advanced disease, pain can occur at rest, resulting in difficulty falling and staying asleep. With chronic OA, pain-related psychological stress can occur.²² Symptoms of joint stiffness can occur in individuals with OA, and this is often described as short-lived stiffness that occurs after inactivity. Furthermore, degeneration of the joint can lead to a range of mechanical symptoms such as joint instability, buckling, or giving away. At the knee joint, reduced movement, deformity, contractures, effusion, and crepitus can occur.²²

There are number of different methods to quantify the severity of symptoms in knee OA, which are often used to assess responsiveness to surgical or nonsurgical interventions. The most commonly used patient-reported questionnaire for OA of the knee is the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index. In the WOMAC index, symptoms of OA are classified into three sections: pain, stiffness, and physical function.
The severity of pain is rated during various positions, times, and movements; these five-items include walking, stair climbing, sleeping at night, rest, and standing. Items of morning stiffness as well as stiffness occurring later in the day after sitting, lying, or resting are evaluated. There are 17 items related to impairments in physical function; these impairments include descending and ascending stairs; rising from sitting, standing, walking on a flat surface; getting in and out of car; going shopping; putting on and taking off socks; rising from bed; lying in bed; getting in and out of bath; sitting; getting on and off toilet; and heavy and light domestic duties. Each individual item is scored, and the severity of OA symptoms can be characterized using these 24 items and 3 sections. Higher scores overall or within individual sections can be used to quantify severity of OA symptoms.²³

Physical Exam and Diagnosis

Physical exam of individuals with suspected knee OA should include the following: body height/weight and body mass index (BMI), joint range of motion, location of joint tenderness, skin integrity, adjacent joint assessment, muscle strength, ligament stability, gait pattern, and alignment of the lower limbs in standing and walking.²² Increased body weight and BMI are independent risk factors for OA. Restricted joint range of motion, crepitus with movement of the joint, or pain with active or passive movement of the joint can be seen in OA. Physical exam findings can show tenderness that is more classically located over the joint line. Along the joint line, bone deformity and osteophytes may be palpated. Visual deformity of the knees may be found—most often varus deformity. Patients may have instability at the knee joint and altered gait. Furthermore, muscle atrophy, weakness, contracture/lag, or joint effusions can be found.²²

Radiographs can be insensitive to the earliest pathologic features of OA, and absence of radiographic findings should not be used for definitive exclusion of the presence of OA.²² Furthermore, radiographic evidence of OA does not confirm pain at the knee is generated from the arthritic process rather than other pathology, such as for instance pes anserine bursitis.²²,²⁴ In general, the diagnosis of OA is made on history and physical exam, and radiography is used to confirm clinical suspicion and rule out alternative diagnoses. Plain radiographs are commonly used to aid in the diagnosis of OA and can show features including joint space narrowing, osteophytes, subchondral sclerosis, and cysts.

Laboratory findings are not used to aid in the diagnosis of OA, as they are generally expected to be relatively normal. Synovial fluid analysis at the knee in individuals with OA will predominately demonstrate that the fluid is classified as “noninflammatory,” which is designated to synovial fluid containing less than 2000 leukocytes per milliliter (ml). Normal synovial fluid is classified as a leukocyte count of less than 200 leukocytes per mL. Most individuals with OA at a joint will have synovial fluid with less than 500 leukocytes per mL.²⁵

Imaging

A common classification system used to describe the radiographic evidence and severity of OA is the Kellgren and Lawrence (KL) scale. Using this scale, radiography of the knee joint can be classified into five grades: 0 (none), 1 (doubtful OA), 2 (minimal OA), 3 (moderate OA), 4 (severe OA). A grade of 0 represents a normal knee joint; grade 1 demonstrates doubtful joint space narrowing and possible marginal osteophyte formation; grade 2 represents possible narrowing of the joint space with definite marginal osteophyte formation; grade 3 represents definite joint space narrowing, moderate marginal osteophyte formation, some sclerosis, and possible deformity of bony ends; grade 4 demonstrates large marginal osteophyte formation, severe joint space narrowing, marked subchondral bone sclerosis, and definite deformity of bone ends.²⁶,²⁷,²⁸ Fig. 5-1 demonstrates knee radiographic images corresponding to the KL classification scale.

When radiographically assessing the knee, there are three compartments to consider: medial tibiofemoral joint, lateral tibiofemoral joint, and patellofemoral joint. Often two or more of the compartments are affected. In some instances, patellofemoral or medial/lateral tibiofemoral joint OA can occur in isolation. With joint space narrowing, the narrowing is usually asymmetric, typically having greater effect on the medial tibiofemoral joint and/or patellofemoral joint. One criticism of classifications systems, such as the KL system, is often a lack of description and assessment of patellofemoral joint OA.²⁶ However, the KL system, for instance, can be used to assess patellofemoral joint OA alone.²⁹

Conventional radiography (standard knee series includes an AP, lateral, Skiers, Merchant, and mechanical axis views of the affected limb) is the gold standard imaging approach used to assess and aid in the diagnosis of OA. However, MRI, while not necessary in the diagnosis of OA, can detect additional secondary changes in OA not seen on radiography. MRI can detect joint fluid changes, ligamentous and meniscal damage, cartilage morphology, bone marrow edema, effusion, and synovitis/synovial thickening.³⁰ Therefore, MRI can serve to provide greater understanding of OA within the knee, affording greater details on the mechanism and pathology of OA. The enhanced detail seen with an MRI may serve as an important investigative tool in regard to OA pathology and progression. MRI of the knee can also be used to rule out isolated causes of knee pain outside of OA including but not limited to ligamentous and meniscal damage, bursitis, iliotibial band syndrome, chondral and osteochondral defects, or avascular necrosis not seen on plain radiography.²²

FIGURE 5-1 Radiographic images of the knee representative of the Kellgren and Lawrence (KL) scale for classification of OA severity. KL = 0, normal-appearing knee joint (not shown in the image); A: KL = 1 (doubtful OA), doubtful joint space narrowing and possible marginal osteophyte formation; B: KL = 2 (minimal OA), possible narrowing of the joint space with definite marginal osteophyte formation; C: KL = 3 (moderate OA), definite joint space narrowing, moderate marginal osteophyte formation, some sclerosis, and possible deformity of bony ends; D: KL = 4 (severe OA), severe joint space narrowing, large marginal osteophyte formation, marked subchondral bone sclerosis, and definite deformity of bony ends. White arrows show osteophyte formation. Black arrows show joint space narrowing. (Reproduced with permission from Hayashi D, et al. Imaging for osteoarthritis. 2016.)

Pathophysiology and Progression

Greater emphasis is now placed in classifying OA as a “whole joint” disease; therefore, consideration of the cartilage, bone, synovium, ligaments, and surrounding soft tissues are packaged as part of the pathophysiology. In the early pathogenesis of OA, it has been debated whether changes in the cartilage occur before bone or changes in the bone occur before cartilage. Extensive evidence in both human and animal studies suggests that remodeling of the subchondral bone is evident at the preradiography stage of OA and can potentially influence worsening of cartilage loss.³¹ Early adaptations of the subchondral bone such as increased thickness and stiffness can result in increased load transfer to the overlying cartilage.³² The capacity of chondrocytes to respond to altered mechanical loads and their capacity for a repair response is rather limited in comparison to the underlying subchondral bone. During the course and progression of OA, it is likely that there are parallel and distinct changes in the cartilage and subchondral bone, which are responding to similar biomechanical signals.³³

An early change seen at the cartilage in OA is surface fibrillation. Hydrophilic proteoglycans within the collagen network of cartilage attract water and aid in the “shock absorbing” properties of cartilage. As the collagen network loosens and breaks down, there is an initial swelling of the cartilage matrix through these hydrophilic interactions. Chondrocytes are the only cell type present within cartilage; they are relatively quiescent but aid in homeostasis of the cartilage through anabolic and catabolic activities. Likely due to matrix loss during OA progression, chondrocytes respond by proliferating and forming clusters. Aiding in the cartilage degeneration at the chondrocyte level is an upregulation of catabolic proteinases and ultimately cell death. Proteolytic enzymes degrading the cartilage can also be produced from the synovium. Some of the chondrocytes undergo a shift to a hypertrophic phenotype that have increased cytoplasm area and characteristically express type X collagen and matrix metalloproteinase (MMP)-13 and can undergo apoptosis.³⁴

Endochondral ossification aids in the degeneration of the adult articular cartilage in OA. During OA development, a proportion of hyaline articular chondrocytes undergo a hypertrophic phenotype; these cells can aid in calcifying the surrounding matrix. During OA progression, there is expansion of the region of the calcified cartilage which is evidence by tidemark duplication. The tidemark is the boundary between the calcified and noncalcified cartilage. Blood vessels penetrate from the subchondral bone into the calcified cartilage and to some degree in OA the normally avascular noncalcified hyaline cartilage. These blood vessels carry osteo/chondroclasts, which resorb the surrounding calcified matrix and carry progenitor cells that lay down new bone into the calcified and hyaline cartilage, leading to cartilage thinning.³³,³⁵,³⁶,³⁷,³⁸ Fig. 5-2 demonstrates cartilage degeneration, tidemark duplication, and vascular invasion during the course of OA development.

Only gold members can continue reading. Log In or Register to continue