Arthritis

Gregory C. Gardner

This chapter contains a discussion of the common causes of joint pain encountered in clinical practice. These include osteoarthritis (OA), rheumatoid arthritis, the spondyloarthropathies (ankylosing spondylitis, psoriatic arthritis, and reactive arthritis), and crystalline forms of arthritis (gout and pseudogout). In addition, there will be a brief discussion of two other rheumatologic conditions: septic arthritis and polymyalgia rheumatica.

Basic Considerations

PROBLEM IN PERSPECTIVE

In December 2012, a study on the Global Burden of Disease and the worldwide impact of all diseases and risk factors reported that musculoskeletal conditions, including arthritis and back pain, affect more than 1.7 billion people worldwide and are the second greatest cause of disability worldwide.¹ Musculoskeletal conditions have the fourth greatest impact on the overall health of the world population with regard to death and disability.

In the United States, the Bone and Joint Decade took place from 2002 to 2011, and data reported in 2012 found that 54% of adults (126 million) in the United States reported a chronic musculoskeletal condition that year. This is much higher than those reporting a circulatory problem (31%), respiratory problem (28%), diabetes (13%), or cancer (9%). Approximately 75 million Americans report neck or low back pain, 52 million arthritis, and 4.5 million Americans will have an activity-related musculoskeletal injury each year. In addition, it is expected that 1 in 2 women and 1 in 4 men over the age of 50 years will have an osteoporosis-related fracture during their remaining years. Rheumatoid arthritis, an autoimmune form of arthritis, affects over 1.5 million adults in the United States, whereas over 300,000 children are afflicted with juvenile inflammatory arthritis. Both of these conditions not only affect mobility and quality of life but can also shorten life expectancy.

The economic burden is significant with an estimated $874 billion being spent both for treatment of musculoskeletal condition and in lost wages of affected workers.

JOINT ANATOMY

Joints in the extremities are synovial (diarthrodial) joints that permit movement over a wide range (Fig. 34.1).² The joint is held together by a capsule of dense fibrous tissue and ligaments and gains further support from overlying muscle and tendons. The inner surface of the joint capsule is covered by synovium, which consists of an intimal layer of specialized cells called synoviocytes, and an outer layer of highly vascularized connective tissue. Synoviocytes comprise one to three cell layers and are of two basic types: A and B. Type A synoviocytes are active in phagocytosis, and type B cells synthesize hyaluronate, which is primarily responsible for the high viscosity of normal synovial fluid. Synovial fluid in a normal joint lubricates the surfaces of synovium and cartilage. The synovium is folded along the inside of the joint capsule and does not cover the load-bearing surface of articular cartilage. The connective tissue layer of synovium blends with periosteum, which does not cover the bone within the joint. The synovium has a rich network of capillaries, venules, and lymphatics, and it is innervated by sympathetic nerve fibers. The knee and the sternoclavicular and radiocarpal joints contain disks of fibrocartilage that help to stabilize these joints when they rotate. The fibrocartilage meniscus of the knee also helps improve joint congruity which is important in the normal distribution of weight with joint loading. The intervertebral facet joints are diarthrodial joints and are covered by synovium.

Amphiarthrodial joints are only slightly movable and include the symphysis pubis and the joints between vertebral bodies. The joint surfaces are separated by intervertebral disks. The sacroiliac joint has elements of both a diarthrodial and an amphiarthrodial joint.

FIGURE 34.1 Schematic diagram of the anatomic features of a typical synovial joint seen in a section cut across the middle of the joint. (Reprinted with pemission from Oatis CA. Kinesiology. The Mechanics and Pathomechanics of Human Movement. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2016. Figure 5-1.)

Articular cartilage is composed of type 2 collagen and proteoglycans. Type 2 collagen is unique to joints and provides cartilage with form and tensile strength. Proteoglycan molecules are linked noncovalently to a long chain of hyaluronic acid and are interwoven within the network of collagen fibers. Proteoglycan molecules bind most of the water present in cartilage, which represents approximately 70% of the total weight of articular cartilage. The proteoglycan molecules are constrained within the meshwork of collagen fibers and are responsible for the resiliency of cartilage. Chondrocytes secrete collagen, proteoglycans, and enzymes that degrade the cartilaginous matrix. The process of remodeling and degradation is kept in balance unless the microenvironment of these cells is altered. Joints normally contain a small amount of synovial fluid, which is viscous and clear and does not clot spontaneously. Normal synovial fluid contains fewer than 200 white blood cells per cubic millimeter; most of these cells are mononuclear.

Nerve and Blood Supply

Joints are supplied partly by articular nerves, which are branches of major peripheral nerves, and partly by branches of nerves supplying adjacent muscles as well as vasomotor sympathetic fibers. Nerve endings are distributed in the interstitial and perivascular tissue located in the subsynovium fibrous capsule, in the articular fat pads, and in the adventitial sheaths of arteries and arterioles supplying the joints. The periosteum is innervated, but articular cartilage and subchondral bones are not and thus not a direct source of pain in arthritis.

There are four types of receptors that supply joints.³ Type I receptors are ovoid corpuscles with a thin connective tissue capsule, and each is supplied by a small myelinated nerve fiber (5 to 8 mm in diameter) that arborizes within the capsule. The type I receptor occurs almost exclusively in the fibrous joint capsule, acts as a slowly adapting mechanoreceptor (stretch receptor), and resembles both structurally and functionally the Ruffini endings in the dermis. The type II receptor is approximately twice as large as the type I receptor and is supplied by a somewhat thicker myelinated fiber (8 to 12 mm in diameter) that usually ends as a single terminal within a rather thick laminated capsule. These receptors, which resemble the pacinian corpuscles, occur only in the fibrous joint capsule and have been shown to be rapidly adapting mechanoreceptors (acceleration receptors) that are sensitive to rapid movements. Type III receptors, which are the largest, are supplied by thick myelinated fibers that branch profusely. These receptors, which resemble the Golgi organs, are present in extrinsic and intrinsic ligaments (and not in the joint capsule) and adapt slowly and at high thresholds. Type IV receptors are represented by plexuses of fine unmyelinated fibers that occur in the fibrous joint capsules, ligaments, and subsynovial capsules and fat pads; they are considered to be the joint nociceptors.

An anastomotic plexus of blood vessels called the periarticular anastomosis, together with these nerves, surrounds the capsule, and its branches penetrate the capsule. The periarticular anastomosis is fed by branches of arteries passing the joint and is the source of blood to the capillary bed in the synovial membrane and also to the epiphysis.

Clinical Approach to Joint Pain

A variety of disorders, both systemic and local, can involve the joints. The process of arriving at a diagnosis begins with a thorough history which should initiate a differential diagnosis. The physical examination and subsequent laboratory and imaging testing continue the process of narrowing the differential.

HISTORY

The musculoskeletal history begins by determining the pattern or patterns of joint complaints. The rheumatologist often divides joint complaints into three different types: inflammatory, mechanical, and fibromyalgia-type discomfort. Inflammatory conditions, such as rheumatoid arthritis, are characterized by joint stiffness in the morning lasting at least 30 minutes but often several hours. Patients generally feel better after activity as the fluid accumulated during inactivity is pumped out of a swollen, stiff joint by the lymphatics, thus reducing the sensation of stiffness. The presence of inflammatory cytokines such as interleukin (IL)-1 or tumor necrosis factor (TNF) may cause fatigue, anorexia, or a loss of the sense of well-being. Joints may initially be stiff and painful but with time typically demonstrate swelling on examination. There is a subtype of inflammatory pain caused by the presence of microorganisms (usually bacteria), blood, or crystals. These conditions typically have an acute onset and cause severe joint pain. The affected person keeps the joint at 30 to 40 degrees of flexion and resists movement of the involved joint. This is the position of maximum joint volume and attempts to flex or extend the joint leads to decrease joint volume and thus an increase in joint fluid pressure leading to pain (Boyle’s law). Joint contractures form in part because of this principle as chronic immobility can lead to capsular contraction even when the fluid in no longer present.

Mechanical joint pain, typified by OA, generally causes only 5 to 10 minutes of morning stiffness, but affected joints become progressively more painful with activity. There may be discomfort for some period of time following use as well. Swelling may or may not be present or only present following stress. There are no systemic symptoms in patients with mechanical forms of arthritis.

Fibromyalgia-associated pain is characterized by all over morning stiffness or pain, a period of loosening up late morning or early afternoon, followed by fatigue and increased pain as the afternoon progresses. Sleep is poor, memory may be reported to be poor, and activity and exercise are poorly tolerated, and in fact, patients will report being in bed for 1 or 2 days following a strenuous physical or even emotional event. The diagnosis of fibromyalgia should be considered when a patient reports that they have one or two days of feeling severe fatigue and pain after an episode of significant physical activity or emotional distress. Even doing household chores may exacerbate the discomfort. Patients often describe their pain in dramatic terms such as the sensation of hot pokers or ice picks being driven into a particularly painful area. Patients with fibromyalgia often have other somatic complaints such as chronic low back pain, temporal mandibular jaw pain, or chronic headaches.

With experience, the clinician can with some ease categorize a patient’s joint complaints into one of these three major types. It is important to remember that Occam’s razor (the simplest explanation is usually correct) is usually best to follow, but it is not uncommon for patients with inflammatory disease to have one, two, or all three patterns simultaneously (Hickam’s dictum: the patients can have as many diseases as they darn well please). For example, a patient with rheumatoid arthritis can have active inflammatory arthritis (inflammatory pattern), have a rheumatoid arthritis associated damaged knee with secondary OA (mechanical pattern), and, because sleep and usual exercise activities may be disturbed by both former patterns, have fibromyalgia as well. With experience, a clinician can learn to distinguish the single-pattern from the multiple-pattern patient and help the patient understand that there is more than one cause to the pain. Patients generally adhere to Occam’s razor until taught otherwise.

Number of Joints Affected

The next step in developing a differential diagnosis is determining the number of joints involved. There are three categories in joint number as well and include monoarthritis, pauciarthritis (two to five joints affected), and finally polyarthritis (six or
more joints). Tables 34.1, 34.2, and 34.3 give a general differential diagnosis inflammatory or mechanical joint pain pattern and number of joints involved. It is important to recognize that these are general guidelines because a polyarticular condition such as rheumatoid arthritis might initially present with less than six affected joint but progress over time to be polyarticular in character. Once a disease has been established for several weeks/months, these patterns tend to be more fixed.

TABLE 34.1 Important Causes of Monoarthritis

Inflammatory		Mechanical
*Infection*		Osteoarthritis
Bacterial arthritis		Osteonecrosis
	Staphylococcus, Streptococcus, gram negatives, Neisseria gonorrhoeae	Trauma Tumor
Lyme arthritis
Mycobacterial arthritis
Fungal arthritis
*Crystals*
Monosodium urate
Calcium pyrophosphate
Hydroxyapatite
*Hemarthrosis*
Clotting disorder
Anticoagulation therapy
Trauma (ACL tear)
ACL, anterior cruciate ligament.

Pattern Recognition

A helpful historical and examination finding is the pattern of joint involvement. For example, OA affects the spine, the hands, hips, knees, and first metatarsophalangeal (MTP) joints. In the hand, the distal interphalangeal (DIP) joints, proximal interphalangeal (PIP) joints, and base of the thumb joint (first carpometacarpal [CMC]) are affected. The metacarpophalangeal (MCP) joints are spared in primary OA. For rheumatoid arthritis, the pattern of involvement is cervical spine only, shoulders, elbows, wrists, hands, hips, knees, ankles, and MTP joints. In the hand, the PIP joints and MCP joints are affected, but the DIP joints are spared. Noting the distribution of affected joints is very helpful in developing a differential diagnosis. This will be discussed further when the individual conditions are presented.

Systemic Features of Arthritis

A variety of systemic or demographic features of illness also provides clues to the underlying diagnosis and is discussed with the individual conditions.

TABLE 34.2 Important Causes of Pauciarthritis (Two to Five Joints)

Inflammatory	Mechanical
*Infection*	Osteoarthritis
Bacterial arthritis
*Crystals*
Monosodium urate
*Spondyloarthropathies*
Ankylosing spondylitis
Psoriatic arthritis
Reactive arthritis
*Miscellaneous*
Sarcoidosis

TABLE 34.3 Important Causes of Polyarthritis (Six or More Joints)

Inflammatory		Mechanical
*Infection*		Osteoarthritis
Poststreptococcal arthritis			Primary osteoarthritis
Viruses			Secondary osteoarthritis
	Parvovirus			Hemochromatosis
	Rubella			Acromegaly
	Hepatitis B and C			Calcium pyrophosphate deposition
*Autoimmune disease*
Rheumatoid arthritis
Systemic lupus erythematosus
Sjögren’s syndrome
Scleroderma
Miscellaneous
Serum sickness

PHYSICAL EXAMINATION

When a patient reports that he or she has “joint pain,” it may be the result of tendon, ligament, muscle, bone, joint, or nerve abnormalities. The clinician needs to keep this in mind during the examination. For example, “knee pain” may be caused by an L4 radiculopathy or hip pain may radiate to the area of the knee. Joints should be examined for evidence of synovial proliferation, fluid, and bony enlargement as well a range of motion. Tenderness, warmth, and any limitation of range of motion should be noted. Pain on passive motion of a joint suggests the possibility of inflammation or damage to the joint. Even though a patient may complain about a particular joint or joints, make sure to examine all joints. Milder abnormalities that may be present in nonpainful joints could add to the information on the number of joints involved and the pattern, thus helping with the differential diagnosis. Comparing an affected to a nonaffected joint often confirms the presence of swelling or deformity.

EXAMINATION OF SYNOVIAL FLUID

Examination of the joint fluid is helpful in patients who have undiagnosed arthritis. Diagnosis of infectious or crystal-induced arthritis is established by analysis of joint fluid. Characteristics of the joint fluid in various rheumatic conditions are shown in Table 34.4. Normal joint fluid usually contains fewer than 200 white blood cells per cubic millimeter, and these cells are predominantly mononuclear. In inflammatory effusions, the white blood cell count is usually elevated
(typically over 2,000 white blood cells per cubic millimeter) with predominantly neutrophils present on cell count. Traditionally, cell counts greater than 75,000 per cubic millimeter suggest an infectious arthritis, but cell counts of this magnitude are also seen in noninfectious inflammatory joint diseases such as reactive arthritis or urate gout. Data suggested that a synovial fluid cell count over 25,000 cell per cubic millimeter should be evaluated for possible infection as the likelihood ratio of infection is greater than one; less than this level is unlikely to be related to a septic arthritis.

TABLE 34.4 Joint Fluid Characteristics in Various Forms of Arthritis

Diagnosis	Appearance	WBC/mm³	% PMNs
Normal	Clear/straw-colored	<200	<25
Osteoarthritis	Straw-colored	200-2,000	<25
Rheumatoid arthritis	Slightly opaque to cloudy	2,000-50,000	>50
Gout/pseudogout	Slightly opaque to cloudy	2,000-100,000	>75
Spondylo-arthropathies	Slightly opaque to cloudy	2,000-100,000	>50
Bacterial arthritis	Cloudy to purulent	25,000-100,000	>75
WBC, white blood cell; PMN, polymorphonuclear leukocytes.

Clinical Considerations

OSTEOARTHRITIS

OA is characterized by progressive loss of articular cartilage leading to joint pain and limitation of movement. Weight-bearing and frequently used joints are most often affected. The disease is divided into a primary (idiopathic) form, in which no predisposing factors are apparent, and a secondary form, which is associated with trauma, sequela of an inflammatory joint disease, a metabolic disease such as hemochromatosis, or a congenital structural abnormality. Primary OA is the more common form, but pathologically, the two forms are indistinguishable.

Epidemiology and Pathophysiology

OA is the most common form of arthritis worldwide and is the leading cause of disability in seniors.⁴^,⁵ The disease occurs in all races and geographic areas. Prevalence and severity increase with age. Under age 55 years, the frequency and joint distribution of OA in men and women are approximately the same. After age 55 years, OA of the knee is more common in women and OA of the hip in men.⁶ OA can be demonstrated radiographically in almost all persons over the age of 75 years. Weight-bearing joints such as the hips, knees, feet, and cervical and lumbosacral joints are most often affected. The DIP and PIP joints of the hands are also commonly involved. Certain occupations have been shown to predispose a person to OA. In coal miners, for example, OA of the shoulders and knees is more frequent, presumably because of the forces placed on these joints during work. Prizefighters are more likely to develop OA of their MCP joints, football players of their knees, and ballet dancers of their ankles. Hereditary factors also exist: Heberden’s nodes are twice as frequent in mothers of affected persons and 3 times more frequent in sisters.⁷ A single-point mutation in the complementary DNA (cDNA) coding for type II collagen was found in family members with an inherited form of OA associated with a mild chondrodysplasia.⁸^,⁹ Previous major trauma and repetitive use of a joint increase the risk of developing OA. Age alone is a risk factor, with the prevalence of OA increasing after age 45 years. Obesity has been shown to be a definite risk factor for developing OA of the hips and knees.⁵

The progressive change within the joint in OA is well known. The cartilage initially shows fissuring and pitting, which eventually progress to erosions and denuded areas. The proteoglycan content of cartilage and the number of chondrocytes decrease in proportion to the degree of disease. Subchondral bone becomes thickened and has an eburnated, or ivory-like, appearance. Cysts appear in the subchondral bone, and the formation of new bone at the joint margins produces osteophytes or spurs. The synovium is thickened and contains a modest infiltration of lymphocytes, plasma cells, and an occasional multinucleated giant cell. The joint capsule and ligaments are hypertrophied. Figure 34.2 shows the arthroscopic appearance progressive nature of OA in the knee.

Research in OA has identified a variety of factors associated with the development of OA. These include aging (older more at risk), gender (females have a higher prevalence and severity than males), joint trauma, inflammation (inflammatory cytokines such as IL-1 are thought to contribute to joint damage), mechanical factors (weight/alignment issues), genetics (may account for as much as 60% of hip OA), and obesity (via a variety of factors including adipokines such as leptin).⁵^,¹⁰ An interesting observation is that obesity leads to OA of the weight-bearing joints as might be expected but also to an increase risk of OA of the hand joints. In individual patients, all these factors may be contributing to a greater or lesser degree. Ultimately, prevention and treatment approaches will require that these factors be addressed in a more holistic fashion.

Symptoms and Signs

OA may be limited to one or two joints or may occur in a generalized form involving many joints. Involved joints are stiff for 30 minutes or less in the morning and after periods of inactivity. Pain typically develops with use. The involved joints also can ache at night affecting the quality of sleep. Night pain is caused in part by increased intraosseous venous pressure.¹¹ As the disease progresses, pain becomes a constant feature of physical activity and can persist for several hours afterward. Eventually, restricted motion and joint deformities develop.

Primary OA most frequently affects the DIP joints, the first CMC joint, the scaphotrapezoid joint, the hips, knees, first MTP joint, and the cervical and lumbar spine.

Heberden’s nodes usually develop after age 40 years and are associated with OA of the DIP joints. Similar nodes, called Bouchard’s nodes, appear at the PIP joints (Fig. 34.3). At times, these nodes become red and painful to touch. Bony enlargement, small effusions, restricted motion, and angulation can be seen on physical examination. Radial subluxation of the first CMC joint gives a square appearance to this joint (shelf sign). A form of OA, referred to as primary generalized OA, appears most often in middle-aged women and affects the DIP and PIP joints of the hand, the first CMC joint, knees, hips, and the first MTP joint. Episodes of inflammation are characterized by warmth, pain, and swelling of these joints.

OA of the hip is usually unilateral, but the opposite side is also affected in approximately 20% of patients.¹² Congenital or developmental abnormalities such as slipped capital femoral epiphysis, Legg-Calvé-Perthes syndrome, or hip dysplasia underlie many of the cases. OA follows avascular necrosis, which can be related to deep-water diving, glucocorticosteroid therapy, alcohol, or sickle cell disease. Hip pain is experienced in the groin, over the greater trochanter, in the buttock, or down the anterior and inner thigh. Pain might be referred to the distal thigh and upper knee because the obturator nerve and its branches supply both hip and knee. As noted earlier, hip disease can be mistaken for knee arthritis or trochanteric bursitis because hip pain can be referred to those locations. The pain of hip disease is often described as dull and aching and is initially experienced with physical activity. Later, night pain is also experienced. Patients might limp and have difficulty rising from a sitting position. Functional shortening of the leg caused by adduction and flexion contractures causes the patient to walk with a shuffling gait. Examination of the hip shows initially decreased internal rotation that is followed later by decreased extension, abduction, and flexion as well as a flexion contracture.

Previous injury such as a torn meniscus or ligament predisposes the knee to secondary OA. The presence of an alignment abnormality such as genu varum (bow legs) or genu valgum (knock knees) increases the force directed through either the medial or lateral side of the knee and can lead to OA. These deformities are also acquired in OA as a result of destruction of either the medial or lateral articular cartilage. Obesity predisposes the knees to OA by the additional weight and by the thigh thickness, which places the legs in a genu varus position and increases the pressure on the medial compartment.
In addition, obesity leads to the production of a variety of cytokines and adipokines that may affect the quality or quantity of cartilage.¹³ Pain also can be localized to either the medial or lateral aspect of the joint depending on which compartment is primarily involved. Atrophy and weakness of the quadriceps muscle develop with progression of the arthritis. Crepitus might be noted with bending of the knee as well as an effusion. With more severe disease, a contracture may be present which increases the energy required to stand upright. With loss of ligamentous and muscle support, the knee becomes unstable, and the patient may be hesitant to walk on uneven surfaces. The knee might suddenly give way because of a pain reflex. A loose cartilaginous fragment, sometimes referred to as a loose body, can prevent the joint from being fully extended.

FIGURE 34.2 Progression of osteoarthritis of the knee via arthroscopy. A: Normal appearing knee. Note the smoothness of the articular cartilage of the femur as well as the meniscus. B: Thickening and fissuring of the cartilage and meniscus. C: Advanced osteoarthritis of the knee with bare areas devoid of cartilage and loss of meniscal tissue.

FIGURE 34.3 Osteoarthritis of the hands. Note Heberden’s nodes (distal interphalangeal joints) and Bouchard’s nodes (proximal interphalangeal joints) in this patient with classic hand osteoarthritis.

Patellofemoral arthritis occurs alone or in conjunction with arthritis of the other knee compartments, especially in older patients. The term chondromalacia patellae is often used interchangeably with patellofemoral arthritis, although some restrict
this term to a self-limiting disorder occurring in adolescents and young adults. Patellofemoral arthritis is caused in some patients by improper tracking of the patella through the patellofemoral groove (trochlea). The patella is pulled to the lateral margin of the groove by a tight lateral patellar retinaculum or a relative weakness of the vastus medialis compared with the vastus lateralis of the quadriceps muscle. Lateral subluxation of the patella can also be caused by an increased Q angle resulting from rotational misalignment of the femur and tibia.

In the spine, intervertebral disks and apophyseal (facet) joints are sites for OA. Involvement of intervertebral disks is referred to as spondylosis, whereas disease in the apophyseal joints is considered true OA. OA also affects the joints of Luschka (uncovertebral joints), which are located in the cervical spine between the superior process of one vertebral body and the inferior process of the vertebral body above it.

Symptoms of spine involvement are localized pain and stiffness, referred or dermatomal pain, and radicular pain from nerve root compression. Nerve root involvement produces paresthesias, decreased sensation, loss of muscle strength, and diminished or absent deep tendon reflexes. OA of the cervical spine causes either localized pain or pain referred to the occiput, shoulder, interscapular area, or arm, depending on the level affected. With upper cervical disease, the pain tends to be referred to the occiput, and with lower cervical involvement, it is referred to the shoulder, upper arm, or interscapular area. Neurologic manifestations are also caused by compression of the spinal cord by posteriorly directed osteophytes and by occlusion of the anterior spinal artery by a herniated disk. Cervical spine diseases are discussed in Chapter 67, and lumbar spine in Chapters 72, 73, 74, 75, 76.

SECONDARY OSTEOARTHRITIS

OA can develop in joints that have been damaged. A torn knee meniscus or ligament can lead to incongruity of the joint surfaces resulting in OA. In addition, ligaments contribute to proprioceptive input and injury to these structures may increase the risk of developing OA.¹⁴ OA may follow joint damage produced by infectious arthritis or an inflammatory arthritis such as rheumatoid arthritis. Neuropathic joint disease is a severe form of OA resulting from the loss of pain sensation, proprioception, or both.¹⁴^,¹⁵ Without these protective mechanisms, joints are subjected to repeated trauma, leading to progressive cartilage damage. Diabetes is the most common cause of neuropathic joint disease. Other causes include tabes dorsalis, syringomyelia, amyloidosis, meningomyelocele in children, and leprosy.

OA occurs in patients with excessively hypermobile joints. Patients with Ehlers-Danlos syndrome, a hereditary disorder of connective tissue, develop OA of their hands, shoulders, knees, and ankles usually before age 40 years.¹⁶ Debate exists regarding whether patients with idiopathic joint hypermobility are at risk of developing premature OA.

Several metabolic disorders are associated with the development of OA. These include hemochromatosis, ochronosis, and acromegaly. Arthritis occurs in 20% to 50% of patients with hemochromatosis and may appear before other overt clinical manifestations.¹⁷^,¹⁸ Hands, knees, and hips are most commonly affected. A particularly characteristic finding is involvement of the second and third MCP joints, which are rarely affected in primary OA. A person, especially a male with early onset OA or OA in unusual locations such as the MCP joints or the shoulder should be investigated for a metabolic disorder especially hemochromatosis. Look for >60% saturation of total iron binding capacity or a markedly elevated ferritin. Ochronosis is a rare disorder caused by a hereditary deficiency of homogentisic acid oxidase, leading to accumulation of homogentisic acid in connective tissue. Deposits of homogentisic acid impart a blue-black hue to the sclerae and external cartilage of the ears. Arthritis appears in middle age and involves most often the knees, shoulders, hips, and spine.¹⁹ These patients frequently have calcified intervertebral disks. Approximately 60% of patients with acromegaly develop OA, which most often involves the spine, knees, hips, shoulders, and, occasionally, ankles.²⁰ The increased growth of articular cartilage causes joint surface incongruity and abnormal wear.

Laboratory Findings

Routine laboratory work is normal in patients with primary OA. The synovial fluid in OA is straw-colored and has good viscosity. The cell count is usually less than 2,000 white cells per cubic millimeter, and the cells are predominantly mononuclear. Radiographs in early OA are usually normal, but as the disease progresses joint space narrowing, subchondral bone sclerosis, subchondral cysts, and osteophytes are observed (Fig. 34.4). Erosive OA is characterized by erosions on the joint surface, sclerosis of subchondral bone, and later by bony ankylosis. Radiographic abnormalities do not always correlate with clinical symptoms.

Treatment

Think about the treatment of OA as a program especially when the weight-bearing joints are involved. Basically, the program consists of three parts: physical modalities, medications, and surgery. The goal in OA should not necessarily be 100% pain relief, as absence of pain in a biomechanically abnormal joint may not be a good thing. The goal should be to reduce pain to a level that promotes quality of life and activity.

Physical modalities include education, weight loss if needed, joint protective aerobic exercises, range of motion exercises especially focusing on reduction of contractures, musclestrengthening exercises, assistive devices such as a cane, and attempts to affect alignment with off-loading knee braces or patellar taping, if needed. The Arthritis, Diet, and Activity Promotion Trial demonstrated the benefit of promoting both exercise and weight loss in an 18-month-long program that examined both together versus either one alone.²¹ The control group was healthy lifestyle. The combination group lost more weight than the weight loss group alone (5.7% of body weight vs. 4.9%), and the combination group had a 24% improvement in physical functioning and a 30% decrease in knee pain over the study period. The exercise group only showed improvement in walk time while the weight loss group showed no significant improvement in any of the variables related to the arthritis. Correct use of a cane can off-load a joint by up to 24% and has been shown to reduce pain in OA of the hip
or knee. There is evidence for a modest benefit with the use of an off-loading knee brace designed to realign either a varus or valgus knee misalignment.²²

FIGURE 34.4 Osteoarthritis of the hip. The features of osteoarthritis are well illustrated in this x-ray including joint space narrowing, subchondral cysts, osteophytes, and subchondral sclerosis (thickening of the bone where cartilage has been lost).

The first-line pharmacologic therapy for OA is over-thecounter analgesics (e.g., acetaminophen, 1,000 mg four times a day or even less if it is effective). If the patient remains symptomatic after 2 to 4 weeks, low-dose ibuprofen or nonacetylated salicylates are indicated. If the response is still inadequate after 2 to 4 weeks, the patient should be placed on a full dose of a nonsteroidal drug. In the patient with risk factors for upper gastrointestinal bleeding or ulcer disease, a proton pump inhibitor should also be provided. There is one cyclooxygenase-2 (COX-2) inhibitor currently on the market, celecoxib, which could be used for patients as significant risk of gastrointestinal bleeding if other options do not work. Because of a concern for cardiac toxicity from the COX-2 agents, use the recommended dose of no more than 200 mg per day. There was for a time some excitement about glucosamine based on a European trial (sponsored trial) published in the Lancet in 2001.²³ The data suggested not only a clinical benefit over placebo but also a possible disease modification of OA. A publicly funded U.S. five-arm trial (glucosamine, chondroitin, combination, nonsteroidal anti-inflammatory drug [NSAID], and placebo) did not demonstrate an impressive effect of either nutraceutical in OA, although the placebo response was impressive.²⁴^,²⁵ In the 2012, American College of Rheumatology (ACR) treatment guidelines for OA includes a recommendation that these not be used.²⁶

Intra-articular corticosteroid injections are effective in OA and can be used as part of the overall program. How often can injections be given? For many years, these were limited due to the concern about the development of Charcot joints. Again, the comments about not being too effective in controlling pain should be remembered. Data suggested that corticosteroid injections can be given every 3 months for at least 2 years with clinic benefit without structural change. In the absence of data, injections should probably not be given more frequently than this.²⁷ Injectable hyaluronic acid is approved for use on OA of the knee. A meta-analysis of data on hyaluronic acid injections in knee OA suggests a small benefit especially for the higher molecular weight compounds.²⁸ Treatment with hyaluronic acid requires three to five injections and can be used in patients who fail more conservative therapy. Other options in the 2012 ACR guidelines include use of topical NSAIDs for hands and knees such as diclofenac and tramadol.

When a joint is severely damaged and painful, joint replacement should be considered. Total hip replacement has provided dramatic relief of pain and improvement of function. Placement of a knee or shoulder can also be quite helpful. Correction of a valgus or varus deformity by osteotomy of the knee improves weight distribution and extends the functional life of the joint. Rebuilding the first CMC joint and replacement of the PIP joint with a prothesis are now possible. Surgery is generally suggested for patients with a level of pain that is not controlled with physical modalities or medications and the patient is willing to endure a period of hospitalization and physical therapy.

RHEUMATOID ARTHRITIS

Rheumatoid arthritis is an inflammatory polyarthritis of unknown etiology that involves peripheral joints in a symmetric distribution. The worldwide prevalence varies from 0.097 to 2.900 per 1,000.²⁹^,³⁰ In the United States, the prevalence is 1% to 2%. Women are more commonly affected: The average ratio is 3:1. Certain Native American populations in the United States can have prevalence rates as high as 7%.³¹

Etiology and Pathophysiology

Even though the etiology of rheumatoid arthritis remains unknown, significant advancements have been made in the understanding of the inflammatory events leading to joint injury and extra-articular manifestations. It is a disease process where genes and environment interact in pathologic dance that leads to autoimmune disease. The genetic contribution is polygenic, and currently, there are 100 or so risk genes identified. It is estimated that 40% to 65% of the risk in rheumatoid arthritis is associated with genetic factors.²⁹ The strongest genetic association exists with the HLA-DR4 antigen that is present on the surface of cells of the immune system. The so-called shared epitope (SE), which is carried by the vast majority of people with rheumatoid arthritis, is a five-amino acid sequence found on the third allelic hypervariable region of the HLA-DRβ chain of the HLA DR4 molecule. The presence of the SE confers not only disease risk but also severity. One of the earliest events in the development of rheumatoid arthritis is the appearance of anti-citrullinated antibodies. These antibodies appear as a result of inflammation causing the deamination of the amino acid arginine and the formation of the amino acid citrulline. Citrulline is not a normally occurring amino acid in the human body and its appearance in human proteins constitutes neoantigen formation to which the immune system responds. The HLA-DR4 molecule with its HLA-DRβ on T cells interacts with processed antigen (i.e., proteins that contain citrulline) from antigen-presenting cells, and if the HLA-DRβ happens to contain the SE, it is perfectly shaped or charged to interact with citrullinated peptides. The active T cells then produce inflammatory cytokines and also interact with B cells to produce antibodies against the citrulline-containing peptides (anti-CCP antibodies). There is typically a period of time when only the anti-CCP antibodies are present with no articular symptoms. This may be as long as 14 years.³² Then, at some point, the anti-CCP antibodies, joined often by rheumatoid factor, gain access to the joint and lead to inflammation. Rheumatoid factor is produced in the setting of immune complex disease and may serve as a protective mechanism to remove these from circulation. The hallmark of rheumatoid arthritis is the proliferation of synovium, which spreads over the articular surface as a pannus and damages cartilage, bone, and joint capsule. This process leads to eventual joint damage/destruction with the classic changes on examination.

The environmental exposure that may lead to lung inflammation and production of citrullinated peptides is smoking. An interesting piece of evidence in this light is the fact that rheumatoid arthritis was rare in the Old World before European exploration of the New World and seems to have appeared in Europe after this period.³³ Rheumatoid arthritis has been diagnosed via skeletal remains in certain Native American population antedating the age of exploration, leading some to speculate that the disease is a New World phenomenon that was transmitted back to the Old World. One of the New World products taken back to Europe was tobacco. There is a very strong relationship between smoking and the development of and severity of rheumatoid arthritis.³⁴

Symptoms and Signs

The typical patient with rheumatoid arthritis is a young to middle-aged woman who presents to her physician with a history of 2 to 3 months of joint pain and stiffness in her hands. Constitutional symptoms of fatigue, weight loss, and low-grade fever might also be present. The hands and other involved joints are stiff on arising in the morning. Stiffness might last from 30 minutes to 2 hours or longer. In severe disease, the patient might remain stiff most of the day.

Patients with involvement of the hands and wrists might have difficulty performing tasks such as lifting pots, washing their hair, and opening jars or doors. A firm handshake can be quite painful. Tingling and numbness of the thumb and index and middle fingers, which often occur at night, indicate
compression of the median nerve by synovial tissue in the carpal tunnel (carpal tunnel syndrome). At times, the carpal tunnel syndrome produces pain radiating up the forearm and down into the hand. Rheumatoid arthritis can begin in the feet in the MTP joints. It is not unusual for a patient to attribute metatarsalgia to improperly fitting shoes before seeking medical attention.

FIGURE 34.5 Example of rheumatoid arthritis of the hands. Distal interphalangeal joints are spared, whereas the metacarpophalangeal and proximal interphalangeal joints are swollen. There is beginning to be some early ulnar deviation on the left hand.

On physical examination, the joints are swollen, tender to palpation, and warm but not hot. The combination of synovial proliferation and fluid gives the joint a boggy sensation on palpation (Fig. 34.5). Synovial proliferation in the flexor tendons of the fingers fills in the palm, giving it a flat appearance. The skin over the small joints often has a bluish discoloration resulting from venous engorgement. The hands may be cool and clammy. The range of joint motion is initially limited by pain and later by contractures. Ulnar deviation of the fingers at the MCP joint is a common deformity in established disease and results from radial deviation of the wrist and slippage of the extensor tendons to the ulnar side of the MCP joints. Another common deformity of the hand that develops in chronic disease is the swan-neck deformity. This appearance results from flexion of the DIP joint and MCP joint with hyperextension of the PIP joint. The boutonniere deformity is caused by avulsion of the extensor hood over the PIP joint, leading to a flexion deformity of this joint and hyperextension of the DIP joint. In advanced disease, subluxation and flexion deformities are common and involve the knees, ankles, elbows, wrists, shoulders, hands, and feet.

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