Arthritis and Inflammatory Conditions of the Hip

Javad Mortazavi

Javad Parvizi

Joint disorders or arthritis affect 33% (69.9 million) of the US population according to recent surveys by the Centers for Disease Control and Prevention (1). Although most of these conditions are self-limiting and require minimal evaluation and intervention, in some patients, specific symptoms or their persistence may indicate the presence of a more serious condition that will require comprehensive evaluation to establish a diagnosis or the extent and nature of a pathologic process. Arthritis has been traditionally categorized as either inflammatory or noninflammatory, depending on the underlying pathologic processes. Inflammatory arthritis may be infectious (septic arthritis), crystal-induced (gout, pseudogout), immune-related (rheumatoid arthritis [RA]), or reactive (Reiter syndrome). Inflammatory disorders may be identified by any of four cardinal signs of inflammation (erythema, warmth, pain, or swelling), systemic symptoms (fatigue, fever, rash, weight loss), or laboratory evidence of inflammation (elevated erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP], thrombocytosis, anemia of chronic disease, or hypoalbuminemia). Osteoarthritis (OA) is considered the prototype for noninflammatory arthritis, although in recent years the noninflammatory nature of OA has been disputed. Noninflammatory conditions are often characterized by pain without synovial swelling or warmth, absence of inflammatory or systemic features, daytime gel phenomena rather than stiffness, and absence of serologic markers for inflammation.

The distinction between inflammatory and noninflammatory arthritis may at times be difficult. Further, not all inflammatory arthropathies present with the same or similar clinical and laboratory findings. Presentation of arthritic processes can be subtle and innocuous in some and florid in others such as those with septic arthritis. Another complexity is that crystalline deposition arthropathy may present in a very similar fashion to septic arthritis, yet the treatment for these two conditions is vastly different. Hence, orthopedic surgeons need to be aware of the modes in which these conditions present and to keep a high index of suspicion for emergent arthropathy conditions such as septic arthritis. The goal in the evaluation of a patient with arthritis is to establish an accurate diagnosis and deliver timely therapy, while avoiding excessive diagnostic testing and unnecessary treatment. As in other areas of medicine, a thorough history and a comprehensive physical examination are essential elements of the evaluation of a patient with arthritis, and laboratory tests should be more confirmatory than diagnostic. An orthopedic surgeon needs to be familiar with different types of arthritis, as accurate diagnosis is essential for the planning of an appropriate treatment strategy.

Hip Osteoarthritis

OA or degenerative joint disease is the most common form of arthritis and one of the leading causes of disability, especially in the elderly (2,3,4). In addition to the toll it takes on quality of life, OA also has a tremendous economic impact. It was found that 10% of all patients in rehabilitation, rheumatology and orthopedic departments, or receiving care at physiotherapy centers were composed of patients suffering from degenerative joint disease of the hip or knee joint (5). The direct and indirect cost of these patients has been shown to be greater if associated with poorer general quality of life and increased severity of OA (6,7). A report by the Centers for Disease Control and Prevention showed that from 1997 to 2005, total national expenditures among all US adults with arthritis increased by 100 billion dollars. Medical expenditures were $252 billion in 1997 and $353 billion in 2005 (8).

Hip OA is a relatively common disorder. The prevalence of hip OA has been reported to be 16% for men and 6% for women between the ages of 65 and 74 years (9). It has also been reported at 3% for women and 3.2% for men between the ages of 55 and 74 years according to the National Health and Nutrition Examination Survey (NHANES-I) and 15.1% for women and 14.1% for men older than 55 years according to the Rotterdam Study (10,11). The discrepant findings in prevalence studies of OA of the hip may be because of inconsistent relationship between radiographic changes and symptoms, as not all patients with radiographic evidence of OA have symptoms (12). In addition, the prevalence of hip OA is increasing with age, probably because of decrease in the ability of chondrocytes to respond to growth factor and to repair cartilage, leading to thinning of articular cartilage.
The burden of symptomatic hip OA is substantial with one in four people developing this condition by age 85 and it is not affected by race, sex, and body mass index (13).

The primary or idiopathic hip OA develops spontaneously with no previous injury or deformity, except for some evidence of genetic predisposition for primary hip OA (14). Secondary hip OA develops followings localized trauma to the hip such as fracture or a hip abnormality such as Perthes disease, developmental hip dysplasia, slipped capital femoral epiphysis, or Paget disease.

Pathogenesis

OA is essentially the failure of a joint as all structures of the joint including synovium, ligaments, subchondral bone, and the articular cartilage undergo pathologic changes (15). Each structure in the joint plays an important and unique role in the daily function of the joint. Articular cartilage with its compressive stiffness and smooth surface, synovial fluid providing a smooth and frictionless surface for movement, the joint capsule and the ligaments protecting the joint from excessive excursions, the periarticular muscles serving to minimize focal stresses across the joint by appropriate muscle contractions, sensory fibers providing feedback for muscles and tendons, and subchondral bone with its mechanical strength and shock-absorbing function all interact in an intricate manner to provide optimal function for the joint. Destruction of any of these structures or the disruption in the balance between them can and does lead to the process of arthritis.

OA will develop if there is an imbalance between joint protectors and joint loading. Major joint protectors are joint capsule and ligaments, synovial fluid, muscle and tendons, sensory afferents, and underlying bone. Muscles and tendons that bridge the joint are key joint protectors. Their contractions at appropriate time in joint movement provide the appropriate power and acceleration and deceleration to minimize focal stress at joint surface. The ligaments along with the overlying skin and tendons contain mechanoreceptor sensory afferent nerves which provide feedback to muscles and tendons. The bone underneath the cartilage works as shock absorber. Synovial fluid reduces friction between articulating cartilage, thereby serving as major protector against friction-induced cartilage wear. Joint becomes vulnerable when each of these protector mechanisms is defective and therefore even activity of daily living would develop OA. On the other hand, in a joint with functional protectors, and acute major injury or long-term overloading which would overcome the protectors would result in OA.

The earliest changes of OA usually appear in the hyaline articular cartilage. The cartilage matrix consists of two important macromolecules produced by chondrocytes: Type 2 collagen and aggrecan which is a proteoglycan macromolecule with highly negatively charged glycosaminoglycans. The highly negatively charged aggrecans create a strong electrostatic repulsion that is the source of the compressive stiffness of cartilage. Synthesis and catabolism of the matrix is a dynamic equilibrium controlled by cytokines and growth factors (produced by chondrocytes), and mechanical stresses (16) and other inflammatory mediators (including interleukins 6 and 8 [IL-6, IL-8], prostaglandin E2, nitric oxide, and bone morphogenic protein 2 [BMP 2]) (15). It is now clear that OA is also an inflammatory process initiated and propagated by inflammatory mediators that lead to the demise of the articular cartilage in the first instance and other structures in due process (17). The production of these mediators leads to an increase in the metabolic activity of articular cartilage, an otherwise low activity tissue. As OA progresses, the cartilage undergoes a gradual depletion of aggrecan and collagen type 2, and the tightly woven collagen type 2 begins to unfurl. As a result, the cartilage loses its compressive stiffness and becomes more vulnerable to further injury.

The classification of OA as a noninflammatory arthritis is, in part, because of the fact that the synovial fluid leukocyte count in OA patients is typically less than 2,000 cells per μL. The clinical presentation of OA, however, includes joint swelling, effusions, and stiffness, and there is no question that low-grade synovial inflammation does contribute to the pathogenesis of this disease. Histologic changes in the synovium include synovial hypertrophy and hyperplasia, which lead to an increase in the number of cells lining the joint. These changes are often accompanied by infiltration of the sublining tissue by scattered foci of lymphocytes. In contrast to RA, synovial inflammation in OA is mostly confined to the area adjacent to the affected cartilage and bone.

The initiation of the inflammation sets up a vicious cycle whereby further inflammatory mediators such as proteinases and cytokines are released from the synovium that can accelerate the destruction of the nearby cartilage. In turn, cartilage breakdown products, resulting from mechanical or enzymatic destruction, can provoke the release of collagenase and other hydrolytic enzymes from synovial cells and lead to vascular hyperplasia in synovial membranes. This cascade sequentially results in the induction of IL-1β and TNF-α, which enhance the inflammatory process. This “cytokine storm” is more likely to occur in earlier stages of OA (17).

The effect of these inflammatory mediators on cartilage and synovium is fairly well understood; less well understood, however, is the effect that these mediators have on subchondral bone. Nitric oxide is one inflammatory mediator which is known to affect bone cell function, which suggests that it might be responsible for affecting some of the pathologic processes occurring in the subchondral bone. It is known that the endothelial isoform of nitric oxide synthase (endothelial cell nitric oxide synthase [ecNOS]) is constitutively expressed in bone and that it likely regulates osteoblast activity and bone formation, and mediates the effects of mechanical loading on the skeleton. This enzyme also appears to act in conjunction with prostaglandins to promote bone formation and suppress bone resorption. In contrast, IL-1 and TNF induce the expression of inducible nitric oxide synthase (iNOS) in bone cells. Nitric oxide derived from this pathway, in contrast to that derived from the ecNOS pathway, participates in bone degradation pathways. Local production of anabolic growth factors like insulin-like growth factor-1 (IGF-1) and transforming growth factor beta (TGF-β), both of which are highly expressed in the osteophytes of the femoral head in OA patients, also contribute to osteophyte formation and subchondral remodeling (18). Production of reactive oxygen species (ROS), based on investigations at our center, was
found to play an important role for initiation and propagation of OA (19). The ROS by-products were detected during early OA and may be used as biomarkers for detection of this condition early in the process. Future directions for treatment of OA will likely be based on the discovery of new biomarkers for OA, further information about the enzymatic pathways active in the disease, and the development of disease-modifying OA drugs (DMOADs).

Risk Factors

Several risk factors for OA have been identified. The risk factors either result in disruption of the protective mechanism of the joint, rendering them dysfunctional, or those causing excessive forces across the joint resulting in overloading of otherwise competent structures. The risk factors can be categorized into two groups based on the location of their effect (systemic or local).

Systemic Risk Factors

Age.

Age is perhaps the most important risk factor for OA. However, it is important to note that OA is not an inevitable consequence of aging; it is not a simple wearing out of the joint and age-related changes in the joint can be distinguished from those caused by disease. The aging chondrocyte’s ability to produce and repair the extracellular matrix is compromised because of a decline in growth factor activity (20). Aging increases the joint’s vulnerability through several mechanisms (21). With age, cartilage becomes thin and therefore more sensitive to shear stresses at basal layers and is at greater risk of damage. At the same time, other joint protectors become dysfunctional: muscles become weaker, ligaments stretch and are less able to absorb stresses, and sensory input is slower in elderly people.

Gender.

A variety of studies have reported that women are more at risk for developing OA and have a greater number of joints involved. While under the age 50, OA is more prevalent in men; over 50, OA in most joints is more prevalent in women, and the sex difference increases with age. While estrogen loss with menopause may have a role; the exact reason for the vulnerability of older women’s joints to OA is unknown. Nonetheless, hip OA has been shown to be more prevalent in men across the whole age spectrum (22).

Genetics.

The role of genetic factors in the development of OA is well-known (21,23). Numerous studies have confirmed the inherited element for this disease, particularly for OA of the hip and hand joints. In one study 50% of cases of hand and hip OA were attributed to inherited factors. In addition, recent studies have identified genetic mutations that place patients at a high risk of developing OA (21,23). Specifically, a mutation in the FRZB gene is believed to put women at high risk of hip OA. This gene encodes a Frizzle protein, whose role is to antagonize an extracellular Wnt ligand. Since the Wnt signaling pathway plays a critical role in matrix synthesis and joint development, it makes sense that a mutated Frizzle protein would be associated with increased incidence of OA (24). In addition, anatomical abnormalities of the joints in patients with skeletal dysplasia are a known cause of early OA. There are known genetic bases for many of these dysplasias (25). Recently, based on a study at our institution, a 4 MB region on chromosome 17q21 was identified that linked to developmental dysplasia of the hip (26). Finally, it has been shown that primary OA of the hip occurs at a rate of 3% to 6% in populations of the world with European ancestry. Family, sibling, and twin studies have proved 50% heritability of primary OA caused by European genetic variants (27).

Race.

There have been many studies done across different ethnicities and nationalities, showing that hip OA, according to the rate of hip arthroplasty, is much lower in the Asian population than in the White population (28). Hip OA is rare in Chinese and Chinese American populations, but knee OA is at least as common, if not more so, in Chinese than in Caucasian populations (29). In addition, Africans (although not African Americans) appear to have much lower rates of hip OA than do Caucasians.

Hormonal Factors.

Estrogen has a well-known critical role in bone homeostasis; however, its role in the homeostasis of joint tissue is not well understood (30). The effect of estrogen replacement therapy in protection against OA is also controversial. While some studies showed decreased cartilage thickness with estrogen supplementation (31), others have shown lower risk of OA in women under estrogen replacement therapy (32,33).

Nutritional Factors.

Nutritional factors such as vitamins may play an important role in joint health. Vitamin C is working as an antioxidant against ROS and serves as a cofactor for collagen II synthesis in the cartilage. The Framingham Heart Study showed low vitamin C intake was associated with progression of OA but did not affect the incidence of the disease. The same study showed that vitamin D, which is necessary for bone turnover, may play a role in hip OA (34).

Bone Density.

The role of bone as a shock absorber for the load of impact in not well understood, but it has been shown that people with increased bone density are at higher risk for OA (35,36). The association of osteoporosis with OA is controversial. While some studies showed that women with osteoporosis have lower-than-expected prevalence of OA (37), other studies have shown the opposite or no association (38,39,40).

Local Risk Factors

Anatomy.

An abnormal joint anatomy that results in an uneven distribution of load across the joint and an increase in focal stresses can be a risk factor for OA. In the hip, developmental dysplasia, Perthes disease, and slipped capital femoral epiphysis are the most common reasons for early distortions in hip anatomy that can lead to OA later in life. The severity of the anatomic deformity determines whether OA will occur in young adulthood (seen most commonly in cases of severe abnormality) or later in life (more common in cases of mild abnormality). Recently it was shown that subtle developmental abnormalities in the hip
joint could lead to the femoroacetabular impingement and secondary OA (41). Anatomic distortion following intra-articular fractures also increases the susceptibility of a joint to early OA. Avascular necrosis secondary to a variety of different etiologies, particularly if it leads to the collapse of subchondral bone, can also produce joint irregularities that lead to OA. In addition, increased contact stress on the joint caused by incongruities on the articular surface may lead to early development of OA (42).

Obesity.

The relative risk of developing OA increases with obesity (43). Also, obese people have more severe symptoms of OA and are more likely to experience the disease in its progressive form. Obesity has been shown to be a strong risk factor for the development of knee OA and, less so, for hip OA. Interestingly, obesity has been shown to be a strong risk factor for the disease in women than men: In women, the relationship of weight to the risk of OA is linear, and weight loss in women lowers the risk of symptomatic disease (44).

Occupation.

Workers who perform repetitive tasks for many years (i.e., as part of their occupations) are at an increased risk of developing OA in the joints they repeatedly use. For example, a high incidence of hip OA has been reported in farmers because of repetitive activities such as bending, moving heavy objects, and walking on rough grounds (45). In addition, certain types of exercises may increase the risk of OA. Although there are studies that suggest that professional running increases the risk of hip and knee OA, there are other studies that indicate long-distance running does not increase the risk of OA of the hips and knees for healthy people (46).

Clinical Features

The initial stage of the OA disease process is silent, which explains the high prevalence of radiographic and pathologic signs of OA in clinically asymptomatic patients. Interestingly, even in later stages of OA, there is a poor correlation between clinical symptoms and the degree of change in bone or cartilage detected directly by arthroscopy or indirectly by radiographs or MRI.

Pain generated by OA is usually described as exacerbated by activity and relieved by rest. Early in the disease, the pain is episodic, triggered often by a day or two of overactive use of the involved joint (i.e., as a person with hip OA might notice a few days of pain after a long run). More advanced OA can cause pain at rest and night pain severe enough to awaken patients. Pain from OA is usually described as deep, aching, and poorly localized, and it may radiate or be referred to surrounding structures. Pain secondary to hip pathology classically presents in the groin, thigh (anterior more than lateral and posterior), and buttock. On rare occasions it can radiate to the knee or foot. In making a diagnosis of OA, it is also helpful to know the location of the pain and to perform a careful physical examination to identify particular motions that aggravate the pain. Groin pain usually indicates hip joint problem. Some patients with hip OA, though, may complain of knee rather than hip pain: For these patients, the key to a correct diagnosis of hip OA is the finding (through physical examination) that hip rotation increases pain. It is also important to know how the pain has affected the patient’s function at home, work, and in recreational activities, and how the patient is coping with the pain.

There is a wide range of additional symptoms that tend to be present alongside pain from OA. Many patients complain of a short-lived stiffness after inactivity. OA may also be associated with joint instability or giving way. Patients may also complain of a reduced range of motion, deformity, swelling, and crepitus. There are certain clinical features such as fever, weight loss, anemia, and elevated ESR that are not normally present in patients with OA. In the process of taking a history, the physician should also look for signs of psychological distress, (e.g., signs of anxiety, excessive pain-avoidant posturing, or sleep-onset insomnia) or depression (e.g., early morning wakening, weight loss, irritability, or a marked increase in memory/concentration problems).

The physical examination should include an assessment of body mass index, joint range of motion, location of tenderness, muscle strength, ligament stability, and limb alignment. Patients with advanced disease may exhibit deformities, with subluxation of the involved joint. OA is thought to be a uniformly progressive disease that invariably leads to joint replacement; however, the disease appears to stabilize in many patients, with no worsening of symptoms or signs. In specific subgroups, the prognosis was either worse or better, as both risk factors and protective factors were identified. Prognostic factors included a variety of biomechanical, psychological, clinical factors, as well as different treatment modalities.

Diagnosis

Classic findings of OA on plain radiographs are osteophytes, joint space narrowing, subchondral sclerosis, and, in more advanced disease, bone cysts. Radiographs are insensitive to the earliest pathologic features of OA, however, the absence of positive radiographic findings in a patient with symptoms of OA should not be interpreted as the complete absence of disease. In clinical practice, the diagnosis of OA should be made on the basis of the history and physical examination; the role of radiography is to confirm clinical suspicions and rule out other conditions rather than to make an independent diagnosis (47,48). This role is more distinct in patients with chronic hip pain, as the diagnosis can often be unclear without confirming radiographs. In addition, it was demonstrated both in cross-sectional and longitudinal studies that there was no or only weak association between radiographic changes and functioning in patients with OA (49). MRI can be used to diagnose other causes of hip pain (e.g., osteochondritis dissecans or avascular necrosis) that may otherwise be confused with OA in patients with joint pain.

No blood tests are routinely indicated for workup of patients with OA unless symptoms and signs suggest inflammatory arthritis. The synovial fluid analysis in patients with noninflammatory arthritis should usually demonstrate no evidence of inflammatory reaction with few leukocytes (<1,000 per μL) and good viscosity. The presence of more
than 1,000 leukocytes per μL usually is indicative of inflammatory arthritis.

Treatment

Goals in the treatment of patients with hip OA are pain relief and improvement of physical function. Treatment of patients with OA should be comprehensive and follow the stepwise formula recommended by the American College of Rheumatology (ACR). International guidelines advocate nonpharmacologic treatment as first line in the management for patients with OA (50,51). Nonpharmacologic treatments currently considered to have a sufficient level of scientific evidence are education, exercise, assistive devices (canes, insoles), weight reduction, and nutritional counseling and supplements.

In view of the chronic nature of OA, effective management of disease requires that patient understand the natural history of the OA and modalities that will alter the progression of disease. Patient education programs aim to impart a thorough understanding of the disease process and provide knowledge and skills to individuals so that they may better manage their arthritis. A variety of self-management programs have been developed for patients with OA (12,52,53,54), such as the Arthritis Self-Management Program that is sponsored in the United States by the Arthritis Foundation.

Muscle weakness often accompanies OA, and increased muscle strength helps reduce load on cartilage. Therapeutic exercise has been recommended in several treatment guidelines for patients with OA of the hip (55). Strengthening exercises of periarticular muscles are very important as they play a major role in protecting the articular cartilage from stress and progression of OA of the hip (55). Improved muscle strength in patients with OA is correlated with patient’s functional level and improves their psychological status (56).

Perhaps weight reduction, activity modification, implementation of periodic rest of the joint, and the use of assistive walking devices to off-load affected joints of the lower extremity are important in the treatment of hip OA. Obesity is an important factor for lower extremity joint deterioration and disability caused by knee and hip OA (57). Use of cushioned shoes also may reduce lower extremity joint symptoms, as they reduce the vertical impact, increase shock absorption, and improve the balance (58). Assistive devices such as canes reduce loading on the hip joint by 20% to 30% if used appropriately (59). For those patients with intermittent and mild symptoms, reassurance and nonpharmacologic therapies usually suffice; however, patients with ongoing, disabling pain may also need pharmacotherapy.

Currently, there are no disease-modifying drugs for OA and all available pharmacologic agents aim to provide symptomatic relief. The first-line medication for symptomatic pain relief is a simple analgesic such as acetaminophen. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely used for the management of pain associated with OA. For patients with inflammation (as seen in erosive OA) and for those whose symptoms cannot be well controlled with simple analgesics, NSAIDs are more effective. Selective NSAIDs (the COX-2 inhibitors) have been found to be more effective than placebo and comparable in efficacy to nonselective NSAIDs in patients with hip or knee OA (60,61). Although selective NSAIDs are associated with lower risk of gastrointestinal toxicity and less effect on platelet aggregation; they are not completely without risk. They must be administered with cautions in patients with mild or moderate renal insufficiency. There continues to be serious concerns regarding COX-2 inhibitor’s cardiovascular effects and patients need to be informed about these risks before prescription.

Nutriceuticals such as oral glucosamine and chondroitin have been shown to reduce pain in patients with knee OA, but further research is needed to confirm the effectiveness of this treatment.

Although there is no place for the systemic use of steroids in the treatment of OA, intra-articular cortisone injections to reduce synovial inflammation may have a role in relieving pain from OA. In general, there is still a lack of RCTs studying the effectiveness and safety of intra-articular steroid injection for the treatment of hip OA (62,63,64). However, current data demonstrate evidence that steroid injection can provide a short-term reduction in pain for patients with hip OA, especially in those with refractory pain to nonpharmacologic or analgesic and NSAID therapy (63

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