Osteoarthritis and Rheumatoid Arthritis

Defining and Classifying Osteoarthritis

In epidemiological studies, OA is most commonly defined by radiological criteria. The principal method for defining the presence and severity of OA is the Kellgren–Lawrence (KL) grading system, which scores the severity of OA on a scale of 0–4, with definite radiographic OA being defined as a KL grade of 2 or higher ( ). The Osteoarthritis Research Society International (OARSI) atlas also provides a means of scoring individual radiographic features, such as osteophytes, joint space narrowing, and sclerosis, in a semiquantitative manner; whereas other methods are available to quantify joint space width on radiographs. The KL grading system has been used for the hand, hip, and knee. Other grading systems are also used, such as Croft’s radiological grading system for the hip ( ). With the advent of magnetic resonance imaging (MRI), numerous joint structures can now be examined that were previously not visualized on radiographs. To date, no MRI definition of OA has been established, although individual structural lesions on MRI are well described, including cartilage lesions, osteophytes, bone marrow lesions, synovitis, effusion, and subchondral bone attrition.

Many persons with radiographic OA have few if any joint symptoms. Symptomatic OA is defined as the presence of radiographic features of OA in combination with knee symptoms attributable to OA. An individual may be considered to have generalized OA if several joint areas are involved, such as the hand (e.g., distal interphalangeal, proximal interphalangeal, or first carpometacarpal joints), knee, and/or hip. The American College of Rheumatology (ACR) has developed a set of classification criteria that are intended to be used in clinical studies ( Box 47-1 ) ( ). These criteria allow classification of OA to be based on the history, examination, and when available, laboratory or radiographic findings.

Clinical Features and Diagnosis of Osteoarthritis

The diagnosis of OA can usually be made clinically and confirmed by radiography if needed. The primary features suggestive of OA include pain, stiffness, and potentially decreased range of motion in the absence of systemic features (such as fever); bone enlargement, particularly of the hand joints, is also present, as is a common distribution of the joints involved ( Fig. 47-1 ). Specifically, the knees, hips, and first carpometacarpal or distal interphalangeal joints are most commonly involved, individually or in some combination. Intermittent swelling, crepitus, and at later stages, loss of range of motion may be present. Pain is the main manifestation and the primary reason for seeking medical care. In addition to joint pain, persons with OA often have functional limitations.

Pain in OA typically occurs with use of the joint. In knee OA, walking, prolonged standing, or stair climbing, in addition to more vigorous activity involving the lower extremity, can produce pain. However, at later stages of disease the pain can become more constant, even being present at rest, with periods of worsening that may be predictable (e.g., in conjunction with weight-bearing activities) or unpredictable (i.e., unrelated to weight-bearing activities). The pain may be localized to the knee. Additional symptoms of instability or buckling may be present. Hip OA also typically involves pain with weight bearing, is usually felt in the groin or medial aspect of the thigh, and can radiate to the thigh. Hand OA pain is generally felt in the area of the joint or joints involved and can lead to substantial limitations in function.

Examination of the affected joint can reveal joint line tenderness, palpable bone enlargement reflecting the presence of osteophytes, and local signs of inflammation, such as effusion in the knee. At later stages, joint movement may be restricted, ligamentous laxity may be elicited, and muscle wasting may be present.

The diagnosis is usually straightforward, although with acute flares, differentiating OA from an inflammatory condition may be difficult. If effusion is present, aspiration will typically reveal a non-inflammatory fluid. No specific laboratory tests are available for OA, but rather laboratory tests may help rule out other conditions. OA involvement outside the usual joints (see Fig. 47-1 ) suggests OA secondary to a systemic disorder or major trauma involving the affected joint and may warrant further investigation for an underlying cause.

For knee and hand OA especially, imaging is not needed to make a diagnosis if the typical symptoms and signs are present. Radiographic changes may not be present in early stages of the disease. For instances in which the diagnosis is not clear, imaging may be helpful. Typical findings include joint space narrowing, osteophytes, and at later stages, sclerosis and cysts ( Fig. 47-2 ). Other imaging modalities such as ultrasound or MRI may demonstrate changes earlier than detectable on radiographs. Although no accepted definition of OA by these modalities exists at present, a number of features noted on such imaging can be identified as being compatible with OA. For MRI, such features include cartilage lesions or loss, osteophytes, bone marrow lesions, synovitis, and effusion ( Fig. 47-3 ).

Incidence and Prevalence of Osteoarthritis

One estimate of the lifetime risk for the development of symptomatic knee OA drawn from a rural population with high rates of disease was about 40% in men and 47% in women, with higher risk in those who were obese ( ). In a managed care setting, age- and sex-standardized incidence rates for symptomatic hand, hip, and knee OA have been estimated to be 100, 88, and 240 cases per 100,000 person-years, respectively, with incidence rates rising sharply after the age of 50 years and leveling off after 70 ( ).

Although prevalence estimates vary in different studies, probably related to underlying differences in study samples, as well as differing definitions of OA (e.g., clinically versus radiographically confirmed), recent estimates indicate a rise in the prevalence of OA, with an estimated 27 million U.S. adults 25 years and older having clinical OA of either the hand, knee, or hip joint, an increase from an estimate of 21 million in 1995 ( ). Such increases in the prevalence of OA are probably due to the aging of the population and the rising prevalence of obesity. Based on data from the Framingham Osteoarthritis Study, approximately 27% of adults 26 years or older have radiographic hand OA and 19% of adults 45 years or older have radiographic knee OA ( , ). The Johnston County Osteoarthritis Project found approximately 28% of adults 45 years or older to have radiographic knee OA and 28% to have radiographic hip OA ( , ). The latter estimate for hip OA is higher than the 7% estimate in women older than 65 years noted in the Study of Osteoporotic Fractures ( ).

Estimates of the prevalence of symptomatic OA are lower since its presence is defined by the combination of radiographic OA and pain, aching, or stiffness in the joint. The prevalence of symptomatic hand OA in adults 26 years or older was approximately 7%, but it increased to 26.2 and 13.4% in women and men, respectively, 71 years or older in the Framingham OA study. The prevalence of symptomatic knee OA in adults 45 years or older was about 7% in the Framingham OA study, whereas in the Johnston County Osteoarthritis Project it was approximately 17%. Symptomatic hip OA was present in around 10% of the Johnston County cohort. Not only do many persons with radiographically confirmed OA not have joint pain, but also many with joint pain do not have radiographically confirmed OA. In fact, persistent knee pain itself without regard to OA occurs in about 25% of people older than 55 years, with only about half of them having radiographic OA.

Racial and ethnic differences in the prevalence of OA have been noted. African American men had a higher prevalence of radiographic hip OA than did Caucasian men, whereas there were no differences between African American and Caucasian women in the Johnston County cohort ( ). In the Beijing Osteoarthritis Study, hand and hip OA was less prevalent in Chinese than in Caucasians in the Framingham OA study, but knee OA was more prevalent in Chinese women than in Caucasian women ( ).

Risk Factors for Osteoarthritis

OA can be thought of as the phenotypic manifestation of a series of different pathways leading to a common end-stage pathology. Hence the disease has a multifactorial etiology, with different sets of risk factors acting together to cause OA in any given individual. Generally, OA is thought to be driven largely by local mechanical factors within the context of a susceptible individual or joint. Systemic or person-level risk factors include age, sex, weight, and genetics. Age is one of the strongest risk factors for OA. Female sex is associated with higher prevalence and severity of OA ( ). However, there are conflicting findings regarding the effects of exogenous estrogen on OA and its symptoms. Obesity has long been identified as a risk factor for knee OA.

Those who are obese or overweight are reported to have at least three times the risk of new-onset knee OA as those with normal weight ( ). Decreasing the body mass index (BMI) by 2 units or more (≈5 kg) over a 10-year period was associated with a 50% lower risk of the development of symptomatic knee OA in women ( ). The Arthritis, Diet, and Activity Promotion Trial (ADAPT) demonstrated improved pain control and function in obese older adults with symptomatic knee OA who both lost weight and exercised ( ). However, the effects of BMI on progressive radiographic knee OA are conflicting. Greater weight has also been associated with new-onset hand OA, thus raising the possibility that obesity confers risk of OA not only through mechanical effects, such as might be expected at the knee, but also potentially through metabolic or inflammatory effects. The association between obesity and hip OA has been variable and, when noted, less strong than that for the knee or hand.

The heritable component of OA has been estimated to be between 40 and 65%, stronger for hand and hip OA than for knee OA. Polymorphisms of GDF5 , LRCH1 , and a locus on chromosome 7q22 have been associated with OA of different joints in recent meta-analytic studies. Further work linking genetic findings to potential mechanisms of the pathogenesis of OA is needed.

The material properties of bone may influence susceptibility to OA. Higher systemic bone mineral density (BMD) has been linked to an increased risk of new-onset OA, yet not necessarily progressive OA ( ). Low BMD has been associated cross-sectionally with reduced joint space width at the hip. Some evidence suggests that although the apparent density of bone in persons with OA may be increased, the bone itself is less mineralized, which results in lower material density.

The effects of readily modifiable dietary factors in humans have been inconclusive. Although observational studies of vitamin D and OA have been conflicting, a randomized controlled trial did not demonstrate a beneficial effect on cartilage loss in knee OA with MRI ( ). Anti-oxidant vitamins are thought to potentially play a role in OA. Low dietary intake of vitamin C, as well as low serum levels of vitamin C, have been associated with increased risk of progression of knee OA, but no clear association with new-onset disease has been noted ( ). In contrast, a randomized double-blind placebo-controlled trial showed that vitamin E failed to improve knee symptoms or prevent cartilage volume loss on MRI ( ). Plasma levels of vitamin K, which has potential effects on bone and cartilage, have been associated with hand and knee OA, new-onset MRI-based cartilage lesions, and potentially less hand OA in those who were deficient at baseline in a randomized trial, although the overall trial results were null ( ). Selenium and iodine deficiency has been linked to Kashin-Beck osteoarthropathy, an endemic form of arthritis occurring in regions of China. Both low and high levels of selenium have been associated with OA ( , ). Further studies are required to clarify the association between dietary factors and OA.

A number of joint-specific factors also contribute to risk for OA. Repetitive joint use may predispose to OA. For example, squatting was found to be associated with knee OA in Beijing Chinese, and jobs requiring kneeling or squatting are associated with increased risk of knee OA ( , ). Occupational lifting and prolonged standing have been associated with hip OA. Occupations involving manual dexterity, particularly repeated pincer grip, have been associated with features of hand OA ( , ). Repetitive joint use may also be relevant for physical activity. In studies focused on former athletes, the results have been conflicting ( , , , ). On the other hand, habitual levels of activity have not been associated with increased risk of OA in the general population, whereas more vigorous levels of activity appeared to increase the risk of OA ( , , ). Even after adjusting for major knee or hip injuries, elite-level (or equivalent) physical activity/sports may be associated with increased risk of knee or hip OA.

Much sports-related activity may cause OA because sports enthusiasts experience major joint injuries, which in turn causes OA. Knee injuries such as meniscal tears requiring meniscectomy or anterior cruciate ligament injury are an important risk factor for the onset of OA. Knee injury confers a four-fold increased risk of knee OA ( ). Meniscal abnormalities are also an important risk factor for OA. Meniscal damage in knees free of cartilage lesions conferred a 10-fold increased risk for the development of knee OA over the ensuing 30 months ( ). In addition to sports-related injuries, certain occupational activities may predispose to meniscal tears. Floor layers, who spend much time kneeling, were more likely to have degenerative meniscal tears than were graphic designers without any knee demands ( ). Although the meniscal abnormalities increase as the severity of knee OA increases, surgical intervention has not been shown to reduce these risks.

Poor muscle strength may contribute to a predisposition to knee injury. However, quadriceps muscle weakness has not been convincingly associated with increased risk of structural damage or its progression at the knee but instead has been associated with risk of new-onset symptomatic knee OA and knee symptoms. Muscle strength could play a role in hand OA, with greater grip strength being reported to increase risk for the development of radiographic hand OA, perhaps because higher strength has a vise-like effect that increases loading across the hand joints.

Knee alignment partially determines the load distribution within the knee. Previous studies of static alignment have had conflicting findings regarding the effects of alignment on new-onset OA, and a best-evidence synthesis concluded that evidence was insufficient to draw a conclusion ( ). However, varus malalignment assessed by full-limb radiographs was recently shown to be associated with an increased incidence of knee OA ( ). Although knee malalignment is one of the strongest predictors of progressive knee OA, no study to date has documented slowing of disease progression if alignment is corrected. Leg length inequality (LLI) is another abnormality that can affect lower limb biomechanics. Persons with LLI of at least 1 cm were approximately twice as likely to have co-existing radiographic knee OA in the shorter limb ( ). The anatomy or the shape of a joint may also affect biomechanical load and risk for OA. The two-dimensional shape of the hip has been associated with OA. Mild acetabular dysplasia has been linked to a mild increase in risk for new-onset hip OA. More recently, a pistol grip deformity, or cam-type femoral acetabular impingement (FAI) syndrome, as well as pincer-type FAI, has been associated with hip OA and hip pain ( ).

Pathogenesis of Osteoarthritis

OA is characterized by cartilage lesions and loss, bone remodeling, and intermittent inflammation. Certain features, such as bone marrow lesions, can be present even in the preradiographic stage, probably a reflection of the bone’s attempt at remodeling in response to excessive loads in those areas. A prevailing theory is that abnormal force through the joint, either from a single traumatic event or from repeated microtrauma over time, can lead to damage to the articular structures of the joint and initiate a cascade of events resulting in the pathological changes recognized as “OA.” Less commonly, primary cartilage defects, such as chondrodysplasia or a type II collagen defect, can predispose the joint to fail under normal loading conditions. The end result of these inciting events is breakdown of articular cartilage, osteophyte formation, bone remodeling with sclerosis, bone marrow lesions and subchondral bone attrition, and alterations of the synovium leading to synovial hyperplasia and inflammation.

There is an imbalance of anabolic and catabolic activity in OA that leads to eventual degeneration of the joint. This process is driven by cytokines, such as anti–tumor necrosis factor-α (anti–TNF-α) and interleukin-1β (IL-1β), which in turn lead to a decrease in collagen synthesis and an increase in catabolic mediators, including metalloproteinases, and inflammatory mediators such as IL-8, IL-6, prostaglandin E ₂ , and nitric oxide ( ). Mechanical stress leads to up-regulation of a number of effector molecules that parallel the changes seen in response to IL-1β stimulation. Reactive oxygen species are also implicated in chondrocyte apoptosis and catabolic processes. Indeed, premature apoptosis and senescence are characteristics of OA chondrocytes. This premature senescence and accelerated apoptosis may be a reflection of oxidative stress in OA.

The designation of OA as “non-inflammatory” is misleading because it is well recognized that low-grade inflammation is present in the OA joint, with synovial hypertrophy and inflammatory changes being noted within the synovium, as well as the presence of intermittent effusions. The synovial changes are thought to occur primarily in areas adjacent to damaged cartilage and bone and therefore may reflect a reaction to debris within the joint. Synovial activation can lead to release of the proteinases and cytokines implicated in cartilage loss.

OA is thought to be a high–bone turnover state that leads to relative hypomineralization and weaker bone, which is more easily deformed. Despite these inferior material properties, subchondral bone in OA has increased thickness and volume, and therefore OA bone may have increased stiffness overall. These altered properties of the articular surface of OA bone can have implications for how loads are distributed in the joint, thereby potentially adversely affecting the adjacent cartilage. Although cartilage may be able to compensate for some of the insults that it experiences from injury or overloading, at some point the capacity for chondrocytes to respond in a reparative fashion is exceeded by the destructive processes, and an inability to compensate and subsequent damage and tissue loss result.

Pain in Osteoarthritis

Pain is the primary symptom of OA ascertained in clinical studies, in addition to measures of function. Pain is typically assessed with questionnaires inquiring about the presence and severity of pain, as well as pain with certain activities. The most common instrument used to assess pain in OA is the Western Ontario and McMaster Universities (WOMAC) questionnaire ( ).

Clinically, symptoms related to knee OA are known to be associated with activity in the early stages, with progression to more persistent symptoms in late stages of the disease punctuated with intermittently increased pain ( ). A long-held concept in OA is the so-called structure–symptom discordance. That is, individuals may have substantial joint pain but little or no changes on radiographs of that joint, whereas others may have no or only mild pain with clearly abnormal joint radiographs. It was therefore thought that pathological structures have little to do with the symptoms experienced in OA. It has long been recognized that a number of factors influence the perception of pain, such as depressive symptoms, poor coping, and catastrophizing. Indeed, numerous factors contribute to differences between individuals in the pain experience, such as genetics, sociocultural environment, and medications, among others, in addition to psychological factors. These interindividual differences probably contribute to the apparent structure–symptom discordance.

When such between-person variability was accounted for by using a within-person knee-matched study design (in which one knee has pain but the other does not), a strong association between radiographic severity and the presence and severity of knee pain was noted, even at the earliest stages of radiographic knee OA ( Fig. 47-4 ) ( ). Such findings indicate that certain structural lesions within the knee may be a cause of knee pain. Furthermore, specific MRI features of OA that can change over time (bone marrow lesions, synovitis, and effusions) have been associated with fluctuations in knee pain ( ). As the structural lesions worsened, the likelihood that the knee would be painful increased. Similarly, a decrease in structural abnormalities of a knee was associated with subsidence of pain in that knee. A systematic review of 22 studies indicated that the preponderance of evidence favors an association of MRI-detected bone marrow lesions and synovitis with the pain experience of OA ( ), thus supporting further study of these abnormalities for rational therapeutic targeting.

A number of mechanisms related to pathological tissues in OA are thought to contribute to pain. Pain from subchondral bone pathology may be due to medullary hypertension and microfractures, osteophytes may stretch the periosteum, the joint capsule may undergo distention and inflammation, and inflammation of the synovium also contributes to elaboration of mediators that contribute to pain. With cartilage being largely aneural, it is unlikely to be a primary source of pain in OA.

There are also potential genetic contributions to pain that may be of relevance in OA. Studies of twins suggest that genetic factors contribute to risk for low back and neck pain ( , ). COMT polymorphisms have been associated with hip and knee OA-related pain, as well as temporomandibular pain ( ).

Sensitization in Osteoarthritis

Pain can be broadly categorized as adaptive or maladaptive ( ). Adaptive pain is necessary to protect from injury or to aid in healing when injury has occurred. Nociceptive pain and inflammatory pain fall under this category. For example, nociception is necessary to avoid overloading a joint. Without it, joint destruction can occur, such as seen with the often hyposensate Charcot joint. Inflammatory pain is necessary to promote healing of injured (inflamed) tissue, such as might be seen in OA or RA. With inflammatory pain, stimuli that would not normally cause pain now do so and lead to reduced contact or movement of that injured or inflamed part until it has healed, thereby minimizing further damage.

Maladaptive pain is pathological functioning of the nervous system in which the pain serves no useful function; the pain is unrelated to a noxious stimulus or injured or inflamed tissue in need of repair. Neuropathic pain and functional pain fall into this category. With neuropathic pain, there is damage to the nervous system, such as might be seen with diabetic or post-herpetic neuralgia, peripheral lesions, or central nervous system lesions such as stroke. With functional pain, there is abnormal operation of the nervous system with no specific pathology detectable, such as occurs with fibromyalgia, but it is probably related to abnormal responsiveness (heightened sensitivity) or function (insufficient inhibition).

Tissue injury and inflammation lead to a decrease in the excitation threshold and an increase in responsiveness to suprathreshold stimuli of nociceptors, which is peripheral sensitization. Noxious stimuli then begin to evoke exaggerated responses at the “injury” site, in this case the OA joint. Previously non-noxious stimuli, such as normally innocuous joint movement, can now provoke pain. Changes in the central nervous system are primarily responsible for the enhanced sensitivity to mechanical stimuli that develops outside the area of injury. Intense nociceptor activity after tissue injury or inflammation promotes a number of changes that eventually lead to sensitization of transmission neurons in the spinal cord; that is, these neurons become increasingly responsive to peripheral input (central sensitization). Once established, central sensitization can be maintained by low-level noxious or non-noxious input from the periphery ( ). One manifestation of central sensitization is temporal summation, which is a progressive increase in dorsal horn neuron discharges in response to repetitive afferent stimulation. Another manifestation is spatial summation, which is expansion of the receptive field of the dorsal horn neurons.

Thus, early in OA, the activity-related pain in the affected joint probably represents appropriate nociceptive and inflammatory pain. The analgesic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) also supports the involvement of inflammatory pain mechanisms. Later in disease, as the pain becomes more persistent, is present at rest and at night, is punctuated by spontaneous pain, and involves areas beyond the joint itself, the pain probably no longer reflects the presence of a noxious stimulus. Peripheral sensitization most likely contributes to the pain provoked by normally innocuous movements within the normal range of the joint (allodynia), whereas radiating pain suggests spatial summation, a feature of central sensitization. Central sensitization may also account for the reduced pain thresholds in unaffected joints and muscles. One study has pointed to the possibility that abnormal diffuse noxious inhibitory control (DNIC), or impaired conditioned pain modulation, may be responsible for these alterations ( ). These generalized somatosensory abnormalities are relieved by local treatment of the affected joint in some patients ( , ). A number of animal models also support the role of sensitization in the pain of OA.

Management of Osteoarthritis