Osteoarthritis

Joel A. Block, MD

Dr. Block or an immediate family member has received royalties from Agios, Inc., Daiichi Sankyo, Inc., and Omeros Inc.; serves as a paid consultant to or is an employee of GlaxoSmithKline, Medivir Inc.; has stock or stock options held in Gilead, Inc.; has received research or institutional support from AstraZeneca, Novartis, and Pfizer; and serves as a board member, owner, officer, or committee member of the American College of Rheumatology and the OsteoArthritis Research Society International.

INTRODUCTION

Osteoarthritis (OA) is a heterogeneous disease characterized by pain and functional loss. It is overwhelmingly the most common form of arthritis; adults have a 40%-50% lifetime risk of developing symptomatic OA.¹^,² In addition, OA causes vast societal cost and morbidity worldwide,¹^,³ consuming approximately 0.5% of the GDP of industrialized societies.⁴ It represents one of the largest sources of days lost from work and is the single greatest source of functional mobility limitation among the elderly.¹^,⁵ Finally, it predominantly affects the middle-aged and elderly and is exacerbated by obesity; hence, the societal burden is rising dramatically as the developed world ages and becomes more obese.

DEFINITION

OA was formerly considered to be a disease of degenerative cartilage, and throughout the 20th century, research directed at treating or delaying disease progression was focused largely on preserving or repairing cartilage. However, cartilage degeneration alone is both painless and a normal process of aging, suggesting it alone cannot be the sole source of the painful disease that is OA. It is now clear that OA is whole organ disease of the joint and not merely of cartilage. Hence, a modern definition is:

OA is a painful degenerative process that affects all joint structures and involves the progressive deterioration of articular cartilage and reactive alterations of subchondral bone and the surrounding joint structures. OA is not a systemic inflammatory process, but local inflammation is common and is thought to be reactive rather than a primary component of OA.

EPIDEMIOLOGY

A number of large longitudinal observational studies have reported the natural history of OA and collectively have provided a great deal of insight regarding its epidemiology. As noted, its prevalence has increased dramatically as the population of the developed world has aged. Approximately 27 million Americans had physician-diagnosed OA in 2005, which was a 30% increase from a decade earlier, and this is expected to reach at least 67 million by 2030.³ Historically, community-based epidemiology studies identified OA on the basis of radiographic disease—the presence of osteophytes, joint space narrowing, and subchondral sclerosis. Radiographic OA increases dramatically with aging, and while it is rare prior to
the age of 45 years, by the seventh decade, it is virtually universal. However, this structural definition overstates the number with clinical disease. A large number of asymptomatic individuals have radiographic involvement, but only approximately 7% to 17% of those older than 44 years actually have symptomatic OA. The prevalence is higher in women than men, and in African Americans relative to Caucasian Americans.¹

RISK FACTORS FOR OSTEOARTHRITIS

Risk factors for incident OA may be divided into those that are modifiable and those that are nonmodifiable. The strongest nonmodifiable factor is aging; this is true both for radiographic degeneration and for symptomatic OA. Other important nonmodifiable risks include genetics and female sex, especially after menopause. The most significant heritable component is for OA of the hand or hip and is estimated at between 48% and 65% for so-called “generalized OA” characterized by osteophytes of the distal interphalangeal (DIP) joints (Heberden nodes) or the proximal interphalangeal (PIP) joints (Bouchard nodes). In contrast to nonmodifiable risk factors, modifiable OA risk factors may provide potential targets for prevention. The most important of these is obesity, which alone confers approximately threefold increased risk of incident OA. Occupational and lifestyle activities that involve repeated trauma or excessive loading may be associated with increased risk of OA. These include chronic squatting, bending, and lifting such as by warehouse workers and laborers, who have increased knee involvement, and classically, pneumatic drill operators who develop OA of the wrist and elbow. Posttraumatic OA is recognized as a distinct syndrome, often with onset much earlier in life than primary OA.⁶ Major knee or ankle injury, for example, is strongly associated with the subsequent development of OA in the injured joint. Finally, progressive OA has been shown to be mediated by aberrant loading of joints,⁷ as well as by abnormal joint alignment.

THE JOINT IN OSTEOARTHRITIS

OA is not one disease, but rather arises from a variety of different pathogenic mechanisms that collectively encompass the degeneration of joint structures with the development of pain. Although both processes occur concomitantly, there is well-described discordance between the severity of structural degeneration and the magnitude of pain felt by patients. The mechanisms of structural degeneration have been well studied for decades, but the biology of OA pain is less well understood.

Each of the joint tissues has been discussed separately in previous chapters; however, a functional joint must operate as an integrated organ encompassing the component tissues (Figure 1). These include the articular cartilage, fibrocartilaginous meniscus (in some joints), synovium, ligaments, subchondral bone, periarticular musculature, and innervation. An intact synovial joint efficiently bears loads and articulates smoothly. The articular cartilage is the best studied of the tissues in OA (Chapter 12), as OA was historically considered primarily a disease of degenerative cartilage. Its biomechanical function is to bear loads during joint function and to provide virtually frictionless articulation. The former is accomplished by its compressive stiffness combined with tensile strength (see Chapter 13); these physicochemical properties are endowed by the fibrillary collagen network entrapping highly hydrophilic and anionic aggregates of the proteoglycan aggrecan. In addition to load-bearing, the articular surface helps to maintain a virtually frictionless environment through a combination of fluid-film and boundary lubrication that is provided by a variety of macromolecular components of the synovial fluid, principally hyaluronan and lubricin, respectively.⁸ As a unit, the intact joint has among the lowest coefficients of friction known. The synovium is the source of the synovial fluid and is a highly vascularized structure consisting of few cell layers composed of synoviocytes which are either fibroblast- or macrophage-derived (Chapter 15). As articular cartilage is avascular, the synovial fluid provides much of the nutrition to the chondrocytes through passive diffusion. The ligaments, tendons, and periarticular musculature provide mechanical stability for the joint and of course are responsible for joint motion. Finally, whereas articular cartilage is aneural, the other joint structures are well innervated with nociceptors and a full array of somatosensory afferents, the most prominent of which are the proprioceptors. OA represents a failure of the synovial joint as an organ, and must be viewed holistically. Structurally, this includes degenerative changes in all tissues.

ARTICULAR CARTILAGE

Both aging and OA involve progressive loss of the articular cartilage. Early changes include enzymatic degradation of the extracellular matrix, now appreciated to involve the aggrecanases (principally ADAMTS-4 and -5) and the collagenases (principally MMP13), augmented by the production of catabolic cytokines, including interleukin (IL)-1 and tumor necrosis factor-α (TNF-α) (Figure 2). These serve to augment an imbalance between anabolic repair and catabolic degradation, further accelerating cartilage loss. Adult cartilage remains metabolically active throughout life; however, it is fundamentally a nonhealing tissue, and adult chondrocytes are unable to elaborate mechanically stable type 2 collagen fibers. Thus, early disruption of the collagen fibrillar network promotes swelling of the matrix, rendering the cartilage less able to resist compressive loads. As the degenerative process proceeds, chondrocytes themselves undergo apoptosis, which further jeopardizes the repair process.

MENISCUS

The knees and selected other joints contain fibrocartilaginous menisci that add to joint stability. These are innervated and vascularized and thus are often a source of articular pain. The
menisci are almost always degenerative in symptomatic knee OA. Moreover, degeneration and displacement of menisci represents a major source of radiographic joint space narrowing in knee OA.

FIGURE 1 Artist’s sketch of the Degenerative changes of osteoarthritis. A normal synovial joint integrates each of the articular tissues in a smooth and functional manner. As OA develops, the articular cartilage degenerates, resulting in significant joint space narrowing. Concomitantly, subchondral bony sclerosis develops underlying the diseased cartilage, and osteophytes form at the joint margins. Synovial hypertrophy is common, and menisci are frequently involved and displaced. Eventually, the joint becomes malaligned; varus deformity occurs when the medial compartment is most affected. A, A normal knee joint with intact joint structures and alignment. B, Advanced OA in a knee, with loss of articular cartilage, osteophyte formation, synovial hyptertrophy, and subchondral sclerosis. Because of the asymmetric cartilage loss, mainly in the medial compartment, varus alignment develops (shown by the mechanical angle outlined in black lines).

BONE

The subchondral bone becomes sclerotic and develops pathological microfractures. It is controversial whether this process is a result of the diminished cushioning provided by degenerative cartilage, or if the bony changes precede and influence cartilage degeneration. In any case, these changes are matched with the degenerative processes in the overlying cartilage. The interface between the subchondral bone and the cartilage is a zone of calcified cartilage, which in OA has been shown to develop sensory neurovascular infiltration via osteochondral channels into areas that are normally poorly innervated and that connect the subchondral bone with overlying cartilage, and which may contribute to the pain of OA⁹^,¹⁰ (Figure 2). Beyond the subchondral bone, the periarticular bone undergoes OA-related changes, such as with osteophyte growth; these pathological bony formations develop from endochondral calcification at the joint margins and are cardinal manifestations of OA (Figure 1). Their function remains unknown, but it has been hypothesized that they may provide mechanical stability as struts supporting the joint.

SYNOVIUM

Whereas OA is primarily a degenerative rather than an inflammatory arthritis, it is frequently accompanied by local inflammation, characterized by mild synovitis. Histologically, the findings are similar to the synovitis of rheumatoid arthritis, with hyperplasia, vascularization, and infiltration of immune cells. The presence of local synovitis in OA has been associated with painful flares, and modern imaging has revealed it to be common in OA joints.¹¹ Synovial effusions are also common in OA and may cause pain by distension of the synovial capsule; while they are characteristically noninflammatory, with less than 2000 WBC/mm³, they nevertheless contain a variety of inflammatory mediators, which may exacerbate both the pain and the catabolic processes of OA.

FIGURE 2 Sketch illustrating the intra-articular tissues affected by the osteoarthritis (OA) process. A, The intra-articular mileu of a normal joint. B, An osteoarthritic joint. Note the degradation of the articular cartilage, local synovitis, osteophyte formation, and the subchondral bony reaction. Nociceptors penetrate the subchondral plate via neurovascular channels and connect the subchondral bone with the overlying cartilage. (Redrawn with permission from Glyn-Jones S, Palmer AJR, Agricola R, et al: Osteoarthritis. Lancet 2015;386[9991]:376-387.)

PERIARTICULAR MUSCULATURE

OA patients tend to have weak periarticular musculature. Although disuse and deconditioning may explain part of this, weakness has been observed in people with structural OA who have not yet developed symptomatic disease, as well as in more distal muscles. These observations raise the question of whether weakness itself may be pathogenically important rather than a simple consequence of the disease process.¹² Moreover, there are biomechanical consequences to muscle weakness, where this may result in altered joint loading during gait and subsequent progression of OA.

INNERVATION

OA is associated with a variety of somatosensory deficits, including diminished proprioception, altered allodynia, and widespread vibratory diminution.¹²^,¹³^,¹⁴ These are largely systemic and not restricted to the involved joint(s), suggesting that OA may be a systemic disease, even if symptomatic in only a few joints. It remains unclear whether somatosensory dysfunction antedates the onset of OA, suggesting a pathogenic role, or if it is a consequence of the degenerative structural changes in OA. In addition, peripheral and central nervous system sensitization in the form of hyperalgesia and allodynia are characteristic of OA,¹³ which may have implications for the treatment of OA pain.

PATHOGENIC MECHANISMS

OA is a multifactorial syndrome that comprises multiple etiologies, many unidentified. It is typically referred to as “primary” when no underlying etiology is identifiable and “secondary” when a specific etiology is known. Multiple factors are clearly involved in OA onset and progression.

AGING

Aging results in a variety of well described alterations at the molecular, cellular, and tissue levels across all parts of the joint. Many of these are normal degenerative events and are associated with the chronic low-grade inflammation of aging, termed “inflammaging,”¹⁵ and occur in the cells of each of the connective tissues. For example, as chondrocytes senesce, they undergo a secretory phenotype associated with increased production of proinflammatory cytokines, such as IL-1 and IL-6, growth factors, including transforming growth factor-β (TGF-β), and matrix metalloproteinases, including MMP-13, which all result in altered cartilage matrix and loss of mechanical function.¹⁶ In addition, carboxylation associated with oxidative stress occurs with advancing age and can alter protein folding, weaken tissues, and increase susceptibility to proteolytic cleavage. Finally, DNA methylation, histone acetylation and methylation, and micro-RNAs are important means of epigenetic regulation of changes in gene expression associated with aging in the cells of joint tissues.¹⁷

Independent of cellular action, advanced glycation end-products (AGEs) accumulate in a nonenzymatic manner on all long-lasting matrix components; in the cartilage, this primarily affects the fibrillar type 2 collagen network. However, chondrocytes express AGE receptors (RAGE),¹⁸ which, when activated by AGE binding, further stimulate release of proinflammatory cytokines such as IL-6 and IL-8. Similar changes occur in the menisci and ligaments, and these aging-related responses diminish chondrocytes’ ability to respond to injury and render the joint more vulnerable to aberrant loads with diminished capacity to adapt that leads to cartilage degeneration. Nonetheless, the link between these alterations and symptomatic OA remains poorly understood.

BIOMECHANICS

It has been appreciated for decades that aberrant loading of joints mediates the evolution of structural joint degeneration and, in many cases, may contribute to the initiation of the process. For example, abnormal loading of the contralateral joints during unilateral lower extremity OA, such as with limping, has been shown to markedly increase the risk of severe OA in the overloaded joint.¹⁹ In addition, malalignment at the knee markedly increases the likelihood of subsequent OA in that knee. Abnormal joint loading precipitated by joint instability, malalignment, trauma, or congenital or inherited connective tissue diseases may be transmitted through the cartilage matrix, pathologically activating chondrocytes as well as inducing remodeling of the subchondral bone. Similarly, abnormal neuromuscular signaling, such as in cases of deficient somatosensory perception, may result in abnormal loading that can drive the OA process.

OBESITY

Obesity has long been recognized as a major risk factor for OA, and the association of the metabolic syndrome with OA has been well documented. The risk was generally ascribed to excessive loading across weight-bearing joints (eg, Ref. 20). However, obesity and the metabolic syndrome increase the OA risk in non-weight-bearing joints as well, such as in the hands.²¹^,²² As the hormonal and inflammatory influences of adipose tissue have been elucidated, obesity has been appreciated to play a direct role in OA pathogenesis, independent of mechanical overloading. Obesity, with or without the metabolic syndrome, is a state of chronic low intensity inflammation; it influences the innate immune system, stimulating transition of macrophages to the proinflammatory M1 macrophage phenotype, and altering T cell populations.²³^,²⁴ The inflammatory milieu is procatabolic and antianabolic and thereby contributes to degeneration of articular cartilage and the joint tissues and may predispose them to excess damage from otherwise minor insults. In addition, adipose tissue is a rich source of adipokines (adipose-derived cytokines) which form the metabolic link between obesity and OA. The adipokines, principally leptin, adiponectin, visfatin, and resistin, stimulate production of proinflammatory cytokines such as IL-1, TNF-α, and IL-6, which in turn can augment joint damage.²³^,²⁴^,²⁵

INFLAMMATION

OA is conventionally considered a degenerative rather than an inflammatory arthritis, and the local inflammatory component of synovial effusion formerly was thought to be merely an epiphenomenon. As understanding of the innate immune system has evolved, it has become clear that while OA is truly not a systemic inflammatory process, local inflammation may be a central component of the pain and structural degeneration inherent in the disease process.

SYNOVITIS

Cool synovial effusions are a hallmark of large joint OA. While the cell count is formally “noninflammatory” in OA, <2,000 cells/µL, the presence of the effusion and the leukocytes suggests a low-grade inflammation. Moreover, sensitive imaging techniques such as ultrasonography or MRI have demonstrated the presence of synovial hypertrophy in a large percentage of knee OA patients,²⁶^,²⁷ and the presence of synovitis is associated with OA pain and progression.²⁸ Moreover, the presence of ultrasonography-or MRI-detectable synovitis has been found to be predictive of the development of incident OA.¹¹^,²⁹ Pathologically, the synovitis found in OA joints appears histologically similar to rheumatoid synovitis, with infiltrating lymphocytes and macrophages, synovial lining hyperplasia, and increased vascularity.³⁰ Moreover, the presence of activated macrophages in the joint capsule has been associated with structural OA progression and pain, again suggesting a pathogenic role.²⁹

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