Section 3: Disorders of the Joints and Adjacent Tissues

INTRODUCTION

Musculoskeletal complaints account for >315 million outpatient visits per year and >20% of all outpatient visits in the United States. The Centers for Disease Control and Prevention estimate that 54.4 million, or 1 in 5 adults) of the U.S. population has physician-diagnosed arthritis. While many patients will have self-limited conditions requiring minimal evaluation, reassurance, and symptomatic therapy, specific musculoskeletal presentations or their persistence may herald a more serious condition that requires further evaluation or laboratory testing to establish a diagnosis. The goal of the musculoskeletal evaluation is to formulate a differential diagnosis that leads to an accurate diagnosis and timely therapy, while avoiding excessive diagnostic testing and unnecessary treatment (Table 363-1). There are several urgent conditions that must be diagnosed promptly to avoid significant morbid or mortal sequelae. These “red flag” diagnoses include septic arthritis, acute crystal-induced arthritis (e.g., gout), and fracture. Each may be suspected by its acute onset and monarticular or focal musculoskeletal pain.

The majority of individuals with musculoskeletal complaints can be diagnosed with a thorough history and a comprehensive physical and musculoskeletal examination. The initial encounter should determine whether the musculoskeletal complaint signals a red flag condition (septic arthritis, gout, or fracture) or not. The evaluation should ascertain if the complaint is (1) articular or nonarticular in origin, (2) inflammatory or noninflammatory in nature, (3) acute or chronic in duration, and (4) localized (monarticular) or widespread (polyarticular) in distribution.

With this approach, the musculoskeletal presentation can be characterized (e.g., acute inflammatory monarthritis or a chronic noninflammatory, nonarticular widespread pain) to narrow the diagnostic possibilities. However, some patients will not fit immediately into an established diagnostic category. Many musculoskeletal disorders resemble each other at the outset, and some may take weeks or months (but not years) to evolve into a recognizable diagnostic entity. This consideration should temper the desire to establish a definitive diagnosis at the first encounter.

ARTICULAR VERSUS NONARTICULAR

The musculoskeletal evaluation must discriminate the anatomic origin(s) of the patient’s complaint. For example, ankle pain can result from a variety of pathologic conditions involving disparate anatomic structures, including gouty arthritis, calcaneal fracture, Achilles tendinitis, plantar fasciitis, cellulitis, and peripheral or entrapment neuropathy. Distinguishing between articular and nonarticular conditions requires a careful and detailed examination. Articular structures include the synovium, synovial fluid, articular cartilage, intraarticular ligaments, joint capsule, and juxtaarticular bone. Nonarticular (or periarticular) structures, such as supportive extraarticular ligaments, tendons, bursae, muscle, fascia, bone, nerve, and overlying skin, may be involved in the pathologic process. Although musculoskeletal complaints are often ascribed to the joints, nonarticular disorders more frequently underlie such complaints. Distinguishing between these potential sources of pain may be challenging to the unskilled examiner. Articular disorders may be characterized by deep or diffuse pain, pain or limited range of motion on active and passive movement, and swelling (caused by synovial proliferation, effusion, or bony enlargement), crepitation, instability, “locking,” or deformity. By contrast, nonarticular disorders tend to be painful on active, but not passive (or assisted), range of motion. Periarticular conditions often demonstrate point or focal tenderness in regions adjacent to articular structures, may radiate or be elicited with a specific movement or position, and have physical findings remote from the joint capsule. Moreover, nonarticular disorders seldom demonstrate swelling, crepitus, instability, or deformity of the joint itself.

INFLAMMATORY VERSUS NONINFLAMMATORY DISORDERS

In the course of a musculoskeletal evaluation, the examiner should determine the nature of the underlying pathologic process and whether inflammatory or noninflammatory findings exist. Inflammatory disorders may be infectious (Neisseria gonorrhoeae or Mycobacterium tuberculosis), crystal-induced (gout, pseudogout), immune-related (rheumatoid arthritis [RA], systemic lupus erythematosus [SLE]), reactive (rheumatic fever, reactive arthritis), or idiopathic. Inflammatory disorders may be identified by any of the 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). Articular stiffness commonly accompanies chronic musculoskeletal disorders. The duration of stiffness may be prolonged (hours) with inflammatory disorders (such as RA or polymyalgia rheumatica) and improves with activity. By contrast, intermittent stiffness (also known as gel phenomenon) is typical of noninflammatory conditions (such as osteoarthritis [OA]), shorter in duration (<60 min), and is exacerbated by activity. Fatigue may be profound with inflammation (as seen in RA and polymyalgia rheumatica) but may also be a consequence of fibromyalgia (a noninflammatory disorder), chronic pain, poor sleep, depression, anemia, cardiac failure, endocrinopathy, or malnutrition.

Noninflammatory disorders may be related to trauma (rotator cuff tear), repetitive use (bursitis, tendinitis), degeneration or ineffective repair (OA), neoplasm (pigmented villonodular synovitis), or pain amplification (fibromyalgia). Noninflammatory disorders are often characterized by pain without synovial swelling or warmth, absence of inflammatory or systemic features, daytime, intermittent gel phenomena rather than prolonged morning stiffness, and normal (for age) or negative laboratory investigations.

Identification of the nature of the underlying process and the site of the complaint will enable the examiner to characterize the musculoskeletal presentation (e.g., acute inflammatory monarthritis, chronic noninflammatory, nonarticular widespread pain). By narrowing the diagnostic considerations, the examiner can assess the need for immediate diagnostic or therapeutic intervention or for continued observation. Figure 363-1 presents an algorithmic approach to the evaluation of patients with musculoskeletal complaints. This approach relies on clinical and historic features, rather than laboratory testing, to diagnose many common rheumatic disorders.

A simpler, alternative approach would consider the most commonly encountered complaints first, based on frequency in younger versus older populations. The most prevalent causes of musculoskeletal complaints are shown in Fig. 363-2. Because trauma, fracture, overuse syndromes, and fibromyalgia are among the most common causes of musculoskeletal pain, these should be considered during the initial encounter. If excluded, other frequently occurring disorders should be considered according to the patient’s age. Hence, those aged <60 years are commonly affected by repetitive use/strain disorders, gout (men only), RA, spondyloarthritis, and uncommonly, infectious arthritis. Patients aged >60 years are frequently affected by OA, crystal (gout and pseudogout) arthritis, polymyalgia rheumatica, osteoporotic fracture, and uncommonly, septic arthritis. These conditions are between 10 and 100 times more prevalent than other serious autoimmune conditions, such as SLE, scleroderma, polymyositis, and vasculitis.

CLINICAL HISTORY

Historic features may reveal important clues to the diagnosis. Aspects of the patient profile, complaint chronology, extent of joint involvement, and precipitating factors can provide important information. Certain diagnoses are more frequent in different age groups. SLE and reactive arthritis occur more frequently in the young, whereas fibromyalgia and RA are frequent in middle age, and OA and polymyalgia rheumatica are more prevalent among the elderly. Diagnostic clustering is also evident when sex and race are considered. Gout, spondyloarthritis, and ankylosing spondylitis are more common in men, whereas RA, fibromyalgia, osteoporosis and lupus are more frequent in women. Racial predilections may be evident. Thus, polymyalgia rheumatica, giant cell arteritis, and granulomatosis with polyangiitis (GPA; formerly called Wegener’s granulomatosis) commonly affect whites, whereas sarcoidosis and SLE more commonly affect African Americans. Familial aggregation is most common with ankylosing spondylitis, gout, and Heberden’s nodes of OA.

The chronology of the complaint is an important diagnostic feature and can be divided into the onset, evolution, and duration. The onset of disorders such as septic arthritis or gout tends to be abrupt, whereas OA, RA, and fibromyalgia may have more indolent presentations. The patients’ complaints may evolve differently and be classified as chronic (OA), intermittent (crystal or Lyme arthritis), migratory (rheumatic fever, gonococcal or viral arthritis), or additive (RA, psoriatic arthritis). Musculoskeletal disorders are typically classified as acute or chronic based on a symptom duration that is either <6 weeks or >6 weeks, respectively. Acute arthropathies tend to be infectious, crystal-induced, or reactive. Chronic conditions include noninflammatory or immunologic arthritides (e.g., OA, RA) and nonarticular disorders (e.g., fibromyalgia).

The extent or distribution of articular involvement is often informative. Articular disorders are classified based on the number of joints involved, as either monarticular (one joint), oligoarticular or pauciarticular (two or three joints), or polyarticular (four or more joints). Although crystal and infectious arthritis are often mono- or oligoarticular, OA and RA are polyarticular disorders. Nonarticular disorders may be classified as either focal or widespread. Complaints secondary to tendinitis or carpal tunnel syndrome are typically focal, whereas weakness and myalgia, caused by polymyositis or fibromyalgia, are more widespread in their presentation. Joint involvement in RA tends to be symmetric and polyarticular. By contrast, spondyloarthritis, reactive arthritis, gout, and sarcoid are often asymmetric and oligoarticular. OA and psoriatic arthritis may be either symmetric or asymmetric and oligo- or polyarticular. The upper extremities are frequently involved in RA and OA, whereas lower extremity arthritis is characteristic of reactive arthritis and gout at their onset. Involvement of the axial skeleton is common in OA and ankylosing spondylitis but is infrequent in RA, with the notable exception of the cervical spine.

The clinical history should also identify precipitating events, such as trauma (osteonecrosis, meniscal tear), drug administration (Table 363-2), antecedent or intercurrent infection (rheumatic fever, reactive arthritis, hepatitis), or illnesses that may have contributed to the patient’s complaint. Certain comorbidities may have musculoskeletal consequences. This is especially so for diabetes mellitus (carpal tunnel syndrome), renal insufficiency (gout), depression or insomnia (fibromyalgia), myeloma (low back pain), cancer (myositis), and osteoporosis (fracture) or when using certain drugs such as glucocorticoids (osteonecrosis, septic arthritis), diuretics or chemotherapy (gout) (Table 363-2).

Lastly, a thorough rheumatic review of systems may disclose useful diagnostic information. A variety of musculoskeletal disorders may be associated with systemic features such as fever (SLE, infection), rash (SLE, psoriatic arthritis), nail abnormalities (psoriatic or reactive arthritis), myalgias (fibromyalgia, statin- or drug-induced myopathy), or weakness (polymyositis, neuropathy). In addition, some conditions are associated with involvement of other organ systems including the eyes (Behçet’s disease, sarcoidosis, spondyloarthritis), gastrointestinal tract (scleroderma, inflammatory bowel disease), genitourinary tract (reactive arthritis, gonococcemia), or nervous system (Lyme disease, vasculitis).

FIBROMYALGIA

Historically, syphilis and tuberculosis were labeled as the “great masqueraders” as their protean symptoms and potential for multi-organ involvement may result in delays in diagnosis and treatment. In the modern era, other serious diagnoses (including lupus, sarcoidosis, vasculitis and lymphoma) have also been labeled as great masqueraders. All of these are either uncommon or rare, and are overshadowed by the most common masquerader with musculoskeletal complaints—fibromyalgia. Fibromyalgia (see Chap. 366) is a pain amplification disorder unified by sleep disturbance, exaggerated pain and sensitivity (owing to lowered pain thresholds), and a multiplicity of symptoms with a paucity of abnormalities on clinical examination or laboratory testing. Tender “trigger points” are often found and include tenderness over the epicondyles, trochanteric bursae, anserine bursae, and muscles (gluteal, trapezius, supraspinatus) that often are misdiagnosed as other nonarticular conditions. Although fibromyalgia classically manifests as widespread aches and pains, presenting symptoms tend to be less specific, and only on further evaluation will the widespread noninflammatory features be disclosed. Fibromyalgia has numerous comorbidities including irritable bowel syndrome, dysmenorrhea, migraine, depression, anxiety, memory loss, non-anatomic paresthesia or dysesthesia, fatigue, myalgias, temporomandibular joint pain, and multiple chemical sensitivities. Fibromyalgia patients often see multiple specialists, are twice as likely to be hospitalized, and are plagued by polypharmacy. Fibromyalgia affects nearly 5 million Americans. Yet, fibromyalgia is frequently underrecognized or misdiagnosed as arthritis, lupus, multiple sclerosis, autoimmune disease, etc. Hence, patients are often referred to multiple consultants and are subjected to multiple investigations and even surgical interventions. Early consideration of this very common disorder can avert needless investigation, therapy, and concern for those afflicted (Fig. 363-2).

RHEUMATOLOGIC EVALUATION OF THE ELDERLY

The incidence of rheumatic diseases rises with age, such that 58% of those >65 years will have joint complaints. Musculoskeletal disorders in elderly patients are often not diagnosed because the signs and symptoms may be insidious, overlooked, or overshadowed by comorbidities. These difficulties are compounded by the diminished reliability of laboratory testing in the elderly, who often manifest nonpathologic abnormal results. For example, the ESR may be misleadingly elevated, and low-titer positive tests for rheumatoid factor (RF) and antinuclear antibodies (ANAs) may be seen in up to 15% of elderly patients. Although nearly all rheumatic disorders afflict the elderly, geriatric patients are particularly prone to OA, osteoporosis, osteoporotic fractures, gout, pseudogout, polymyalgia rheumatica, vasculitis, and drug-induced disorders (Table 363-2). The elderly should be approached in the same manner as other patients with musculoskeletal complaints, but with an emphasis on identifying the potential rheumatic consequences of medical comorbidities and therapies. The physical examination should identify the nature of the musculoskeletal complaint as well as coexisting diseases that may influence diagnosis and choice of treatment.

RHEUMATOLOGIC EVALUATION OF THE HOSPITALIZED PATIENT

Evaluation of a hospitalized patient with rheumatic complaints is often more complex owing to greater symptom severity, more acute presentations, and greater interplay of comorbidities. In patients with rheumatic disorders tend to be admitted for one of several reasons: (1) acute onset of inflammatory arthritis (possibly gout or septic arthritis); (2) undiagnosed systemic or febrile illness; (3) musculoskeletal trauma; (4) exacerbation or deterioration of an existing autoimmune disorder (e.g., SLE); or (5) new medical comorbidities (e.g., thrombotic event, lymphoma, infection) arising in patients with an established rheumatic disorder. Notably, rheumatic patients are seldom if ever admitted because of widespread pain or serologic abnormalities or for the initiation of new therapies.

Acute monarticular inflammatory arthritis may be a “red flag” condition (e.g., septic arthritis, gout, pseudogout) that will require arthrocentesis and, on occasion, hospitalization if infection is suspected. However, new-onset inflammatory polyarthritis will have a wider differential diagnosis (e.g., RA, hepatitis-related arthritis, chikungunya arthritis, serum sickness, drug-induced lupus, polyarticular septic arthritis) and may require targeted laboratory investigations rather than synovial fluid analyses. Patients with febrile, multisystem disorders will require exclusion of crystal, infectious, or neoplastic etiologies and an evaluation driven by the dominant symptom/finding with the greatest specificity. Conditions worthy of consideration may include gout or pseudogout, vasculitis (giant cell arteritis in the elderly or polyarteritis nodosa in younger patients), adult-onset Still’s disease, SLE, antiphospholipid antibody syndrome, IgG4-related disease, and sarcoidosis. A preexisting rheumatic diagnosis (e.g., SLE, RA, ankylosing spondylitis) should be confirmed by careful history, examination and review of medical records, as this will influence the ensuing in-patient evaluation. It is important to note that when established rheumatic disease patients are admitted to the hospital, it is usually not for a medical problem related to their autoimmune disease, but rather because of either a comorbid condition or complication of drug therapy. Patients with chronic inflammatory disorders (e.g., RA, SLE, psoriasis) have an augmented risk of infection, cardiovascular events, and neoplasia.

Certain conditions, such as acute gout, can be precipitated in hospitalized patients by surgery, dehydration, or medications and should be considered when hospitalized patients are evaluated for the acute onset of a musculoskeletal condition. Lastly, overly aggressive and unfocused laboratory testing will often yield abnormal findings that are better explained by the patient’s preexisting condition (chronic lung, renal, or liver disease) rather than a new inflammatory or autoimmune disorder (lupus, vasculitis).

PHYSICAL EXAMINATION

The goal of the physical examination is to ascertain the structures involved, the nature of the underlying pathology, the functional consequences of the process, and the presence of systemic or extraarticular manifestations. A knowledge of topographic anatomy is necessary to identify the primary site(s) of involvement and differentiate articular from nonarticular disorders. The musculoskeletal examination depends largely on careful inspection, palpation, and a variety of specific physical maneuvers to elicit diagnostic signs (Table 363-3). Although most articulations of the appendicular skeleton can be examined in this manner, adequate inspection and palpation are not possible for many axial (e.g., zygapophyseal) and inaccessible (e.g., sacroiliac or hip) joints. For such joints, there is a greater reliance on specific maneuvers and imaging for assessment.

Examination of involved and uninvolved joints will determine whether pain, warmth, erythema, or swelling is present. The locale and level of pain elicited by palpation or movement should be quantified. One standard would be to count the number of tender joints on palpation of 28 easily examined joints (proximal interphalangeals [PIPs], metacarpophalangeals [MCPs], wrists, elbows, shoulders, and knees). Similarly, the number of swollen joints (0–28) can be counted and recorded. Careful examination should distinguish between true articular swelling (caused by bony hypertrophy, synovial effusion or proliferation), and nonarticular (or periarticular) involvement, which usually extends beyond the normal joint margins. Synovial effusion can be distinguished from synovial hypertrophy or bony hypertrophy by palpation or specific maneuvers. For example, small to moderate knee effusions may be identified by the “bulge sign” or “ballottement of the patellae.” Bursal effusions (e.g., effusions of the olecranon or prepatellar bursa) are often focal, periarticular, overlie bony prominences, and are fluctuant with defined borders. Joint stability can be assessed by stabilizing the proximal joint, by palpation, and by the application of manual stress to the distal appendage. Subluxation or dislocation, which may be secondary to traumatic, mechanical, or inflammatory causes, can be assessed by inspection and palpation. Joint swelling or volume can be assessed by palpation. Distention of the articular capsule usually causes pain and evident enlargement or fluctuance. The patient will attempt to minimize the pain by maintaining the joint in the position of least intraarticular pressure and greatest volume, usually partial flexion. For this reason, inflammatory effusions may give rise to flexion contractures. Clinically, this may be detected as fluctuant or “squishy” swelling in larger joints and grape-like compressibility in smaller joints. Inflammation may result in fixed flexion deformities or diminished range of motion—especially on extension, when intraarticular pressure is increased. Active and passive range of motion should be assessed in all planes, with contralateral comparison. A goniometer may be used to quantify the arc of movement. Each joint should be passively manipulated through its full range of motion (including, as appropriate, flexion, extension, rotation, abduction, adduction, lateral bending, inversion, eversion, supination, pronation, medial/lateral deviation, and plantar- or dorsiflexion). Extreme range of motion may be seen with hypermobility syndrome, with joint pain and connective tissue laxity, often associated with Ehlers-Danlos or Marfan’s syndrome. Limitation of motion is frequently caused by inflammation, effusion, pain, deformity, contracture, or restriction from neuromyopathic causes. If passive motion exceeds active motion, a periarticular process (e.g., tendinitis, tendon rupture, or myopathy) should be considered. Contractures may reflect antecedent synovial inflammation or trauma. Minor joint crepitus is common during joint palpation and maneuvers but may indicate significant cartilage degeneration as it becomes coarser (e.g., OA). Joint deformity usually indicates a long-standing or aggressive pathologic process. Deformities may result from ligamentous destruction, soft tissue contracture, bony enlargement, ankylosis, erosive disease, subluxation, trauma, or loss of proprioception. Examination of the musculature will document strength, atrophy, pain, or spasm. Appendicular muscle weakness should be characterized as proximal or distal. Muscle strength should be assessed by observing the patient’s performance (e.g., walking, rising from a chair, grasping, writing). Strength may also be graded on a 5-point scale: 0 for no movement; 1 for trace movement or twitch; 2 for movement with gravity eliminated; 3 for movement against gravity only; 4 for movement against gravity and resistance; and 5 for normal strength. The examiner should assess for often-overlooked nonarticular or periarticular involvement, especially when articular complaints are not supported by objective findings referable to the joint capsule. The identification of soft tissue/nonarticular pain will prevent unwarranted and often expensive additional evaluations. Specific maneuvers may reveal common nonarticular abnormalities, such as a carpal tunnel syndrome (which can be identified by Tinel’s or Phalen’s sign). Other examples of soft tissue abnormalities include olecranon bursitis, epicondylitis (e.g., tennis elbow), enthesitis (e.g., Achilles tendinitis), and tender trigger points associated with fibromyalgia.

APPROACH TO REGIONAL RHEUMATIC COMPLAINTS

Although all patients should be evaluated in a logical and thorough manner, many cases with focal musculoskeletal complaints are caused by commonly encountered disorders that exhibit a predictable pattern of onset, evolution, and localization; they can often be diagnosed immediately on the basis of limited historic information and selected maneuvers or tests. Although nearly every musculoskeletal complaint could be approached in this manner, the evaluation of four common involved anatomic regions—the hand, shoulder, hip, and knee—are reviewed here.

HAND PAIN

Focal or unilateral hand pain may result from trauma, overuse, infection, or a reactive or crystal-induced arthritis. By contrast, bilateral hand complaints commonly suggest a degenerative (e.g., OA), systemic, or inflammatory/immune (e.g., RA) etiology. The distribution or pattern of joint involvement is highly suggestive of certain disorders (Fig. 363-3). Thus, OA (or degenerative arthritis) may manifest as distal interphalangeal (DIP) and PIP joint pain with bony hypertrophy sufficient to produce Heberden’s and Bouchard’s nodes, respectively. Pain, with or without bony swelling, involving the base of the thumb (first carpometacarpal joint) is also highly suggestive of OA. By contrast, RA tends to cause symmetric, polyarticular involvement of the PIP, MCP, intercarpal, and carpometacarpal joints (wrist) with pain and palpable synovial tissue hypertrophy. Psoriatic arthritis may mimic the pattern of joint involvement seen in OA (DIP and PIP joints), but can be distinguished by the presence of inflammatory signs (erythema, warmth, synovial swelling), with or without carpal involvement, nail pitting, or onycholysis. Whereas lateral or medial subluxations at the PIP or DIP joints are most likely due to inflammatory OA or psoriatic arthritis, dorsal or ventral deformities (swan neck or boutonnière deformities) are typical of RA. Hemochromatosis should be considered when degenerative changes (bony hypertrophy) are seen at the second and third MCP joints with associated radiographic chondrocalcinosis or episodic, inflammatory wrist arthritis.

Dactylitis manifests as soft tissue swelling of the whole digit and may have a sausage-like appearance. Common causes of dactylitis include psoriatic arthritis, spondyloarthritis, juvenile spondylitis, mixed connective tissue disease, scleroderma, sarcoidosis, and sickle cell disease. Soft tissue swelling over the dorsum of the hand and wrist may suggest an inflammatory extensor tendon tenosynovitis possibly caused by gonococcal infection, gout, or inflammatory arthritis (e.g., RA). Tenosynovitis is suggested by localized warmth, swelling, or pitting edema and may be confirmed when the soft tissue swelling tracks with tendon movement during flexion and extension of fingers, or when pain is induced while stretching the extensor tendon sheaths (flexing the digits distal to the MCP joints and maintaining the wrist in a fixed, neutral position).

Focal wrist pain localized to the radial aspect may be caused by de Quervain’s tenosynovitis resulting from inflammation of the tendon sheath(s) involving the abductor pollicis longus or extensor pollicis brevis (Fig. 363-3). This commonly results from overuse or follows pregnancy and may be diagnosed with Finkelstein’s test. A positive result is present when radial wrist pain is induced after the thumb is flexed and placed inside a clenched fist and the patient actively deviates the hand downward with ulnar deviation at the wrist. Carpal tunnel syndrome is another common disorder of the upper extremity and results from compression of the median nerve within the carpal tunnel. Manifestations include pain in the wrist that may radiate with paresthesia to the thumb, second and third fingers, and radial half of the fourth finger and, at times, atrophy of thenar musculature. Carpal tunnel syndrome is commonly associated with pregnancy, edema, trauma, OA, inflammatory arthritis, and infiltrative disorders (e.g., amyloidosis). The diagnosis may be suggested by a positive Tinel’s or Phalen’s sign. With each test, paresthesia in a median nerve distribution is induced or increased by either “thumping” the volar aspect of the wrist (Tinel’s sign) or pressing the extensor surfaces of both flexed wrists against each other (Phalen’s sign). The low sensitivity and moderate specificity of these tests may require nerve conduction velocity testing to confirm a suspected diagnosis.

SHOULDER PAIN

During the evaluation of shoulder disorders, the examiner should carefully note any history of trauma, fibromyalgia, infection, inflammatory disease, occupational hazards, or previous cervical disease. In addition, the patient should be questioned as to the activities or movement(s) that elicit shoulder pain. While arthritis is suggested by pain on movement in all planes, pain with specific active motion suggests a periarticular (nonarticular) process. Shoulder pain may originate in the glenohumeral or acromioclavicular joints, subacromial (subdeltoid) bursa, periarticular soft tissues (e.g., fibromyalgia, rotator cuff tear/tendinitis), or cervical spine (Fig. 363-4). Shoulder pain is referred frequently from the cervical spine but may also be referred from intrathoracic lesions (e.g., a Pancoast tumor) or from gallbladder, hepatic, or diaphragmatic disease. These same visceral causes may also manifest as focal scapular pain. Fibromyalgia should be suspected when glenohumeral pain is accompanied by diffuse periarticular (i.e., subacromial, bicipital) pain, tender points (i.e., trapezius or supraspinatus), and a sleep disturbance. The shoulder should be put through its full range of motion both actively and passively (with examiner assistance): forward flexion, extension, abduction, adduction, and internal and external rotation. Manual inspection of the periarticular structures will often provide important diagnostic information. Glenohumeral involvement is best detected by placing the thumb over the glenohumeral joint just medial and inferior to the coracoid process and applying pressure anteriorly while internally and externally rotating the humeral head. Pain localized to this region is indicative of glenohumeral pathology. Synovial effusion or tissue is seldom palpable but, if present, may suggest infection, RA, amyloidosis, or an acute tear of the rotator cuff. The examiner should apply direct manual pressure over the subacromial bursa that lies lateral to and immediately beneath the acromion (Fig. 363-4). Subacromial bursitis is a frequent cause of shoulder pain. Anterior to the subacromial bursa, the bicipital tendon traverses the bicipital groove. This tendon is best identified by palpating it in its groove as the patient rotates the humerus internally and externally. Direct pressure over the tendon may reveal pain indicative of bicipital tendinitis. Palpation of the acromioclavicular joint may disclose local pain, bony hypertrophy, or, uncommonly, synovial swelling. Whereas OA and RA commonly affect the acromioclavicular joint, OA seldom involves the glenohumeral joint, unless there is a traumatic or occupational cause.

Rotator cuff tendinitis or tear is a very common cause of shoulder pain. Nearly 30% of the elderly will have shoulder pain, with rotator cuff tendinitis or tear as a primary cause. The rotator cuff is formed by four tendons that attach the scapula to the proximal humerus (supraspinatus, infraspinatus, teres minor, and subscapularis tendons). Of these, the supraspinatus muscle is the most commonly damaged. Rotator cuff tendinitis is suggested by pain on active abduction (but not passive abduction), pain over the lateral deltoid muscle, night pain, and evidence of the impingement signs (pain with overhead arm activities). The Neer test for impingement is performed by the examiner raising the patient’s arm into forced flexion while stabilizing and preventing rotation of the scapula. A positive sign is present if pain develops before 180° of forward flexion. Tear of the rotator cuff is common in the elderly and often results from trauma; it may manifest in the same manner as tendinitis. The drop arm test is abnormal with supraspinatus pathology and is demonstrated by passive abduction of the arm to 90° by the examiner. If the patient is unable to hold the arm up actively or unable to lower the arm slowly without dropping, the test is positive. Tendinitis or tear of the rotator cuff is best confirmed by magnetic resonance imaging (MRI) or ultrasound.

KNEE PAIN

Knee pain may result from intraarticular (OA, RA) or periarticular (anserine bursitis, collateral ligament strain) processes or be referred from hip pathology. A careful history should delineate the chronology of the knee complaint and whether there are predisposing conditions, trauma, or medications that might underlie the complaint. For example, patellofemoral disease (e.g., OA) may cause anterior knee pain that worsens with climbing stairs. Observation of the patient’s gait is also important. The knee should be carefully inspected in the upright (weight-bearing) and supine positions for swelling, erythema, malalignment, visible trauma, muscle wasting, and leg length discrepancy. The most common malalignment in the knee is genu varum (bowlegs) or genu valgum (knock-knees) resulting from asymmetric cartilage loss medially or laterally. Bony swelling of the knee joint commonly results from hypertrophic osseous changes seen with disorders such as OA and neuropathic arthropathy. Swelling caused by hypertrophy of the synovium or synovial effusion may manifest as a fluctuant, ballotable, or soft tissue enlargement in the suprapatellar pouch (suprapatellar reflection of the synovial cavity) or regions lateral and medial to the patella. Synovial effusions may also be detected by balloting the patella downward toward the femoral groove or by eliciting a “bulge sign.” With the knee extended, the examiner should manually compress, or “milk,” synovial fluid down from the suprapatellar pouch and lateral to the patellae. The application of manual pressure lateral to the patella may cause an observable shift in synovial fluid (bulge) to the medial aspect. The examiner should note that this maneuver is only effective in detecting small to moderate effusions (<100 mL). Inflammatory disorders such as RA, gout, pseudogout, and psoriatic arthritis may involve the knee joint and produce significant pain, stiffness, swelling, or warmth. A popliteal or Baker’s cyst may be palpated with the knee partially flexed and is best viewed posteriorly with the patient standing and knees fully extended to visualize isolated or unilateral popliteal swelling or fullness.

Anserine bursitis is an often missed periarticular cause of knee pain in adults. The pes anserine bursa underlies the insertion of the conjoined tendons (sartorius, gracilis, semitendinosus) on the anteromedial proximal tibia and may be painful following trauma, overuse, or inflammation. It is often tender in patients with fibromyalgia, obesity, and knee OA. Other forms of bursitis may also present as knee pain. The prepatellar bursa is superficial and is located over the inferior portion of the patella. The infrapatellar bursa is deeper and lies beneath the patellar ligament before its insertion on the tibial tubercle.

Internal derangement of the knee may result from trauma or degenerative processes. Damage to the meniscal cartilage (medial or lateral) frequently presents as chronic or intermittent knee pain. Such an injury should be suspected when there is a history of trauma, athletic activity, or chronic knee arthritis, and when the patient relates symptoms of “locking” or “giving way” of the knee. With the knee flexed 90° and the patient’s foot on the table, pain elicited during palpation over the joint line or when the knee is stressed laterally or medially may suggest a meniscal tear. A positive McMurray test may also indicate a meniscal tear. To perform this test, the knee is first flexed at 90°, and the leg is then extended while the lower extremity is simultaneously torqued medially or laterally. A painful click during inward rotation may indicate a lateral meniscus tear, and pain during outward rotation may indicate a tear in the medial meniscus. Lastly, damage to the cruciate ligaments should be suspected with acute onset of pain, possibly with swelling, a history of trauma, or a synovial fluid aspirate that is grossly bloody. Examination of the cruciate ligaments is best accomplished by eliciting a drawer sign. With the patient recumbent, the knee should be partially flexed and the foot stabilized on the examining surface. The examiner should manually attempt to displace the tibia anteriorly or posteriorly with respect to the femur. If anterior movement is detected, then anterior cruciate ligament damage is likely. Conversely, significant posterior movement may indicate posterior cruciate damage. Contralateral comparison will assist the examiner in detecting significant anterior or posterior movement.

HIP PAIN

The hip is best evaluated by observing the patient’s gait and assessing range of motion. The vast majority of patients reporting “hip pain” localize their pain unilaterally to the posterior gluteal musculature (Fig. 363-5). Such pain tends to radiate down the posterolateral aspect of the thigh and may or may not be associated with complaints of low back pain. This presentation frequently results from degenerative arthritis of the lumbosacral spine or disks and commonly follows a dermatomal distribution with involvement of nerve roots between L4 and S1. Sciatica is caused by impingement of the L4, L5, or S1 nerve (i.e., from a herniated disk) and manifests as unilateral neuropathic pain extending from the gluteal region down the posterolateral leg to the foot. Some individuals instead localize their “hip pain” laterally to the area overlying the trochanteric bursa. Because of the depth of this bursa, swelling and warmth are usually absent. Diagnosis of trochanteric bursitis or enthesitis can be confirmed by inducing point tenderness over the trochanteric bursa. Gluteal and trochanteric pain are common findings in fibromyalgia. Range of movement may be limited by pain. Pain in the hip joint is less common and tends to be located anteriorly, over the inguinal ligament; it may radiate medially to the groin. Uncommonly, iliopsoas bursitis may mimic true hip joint pain. Diagnosis of iliopsoas bursitis may be suggested by a history of trauma or inflammatory arthritis. Pain associated with iliopsoas bursitis is localized to the groin or anterior thigh and tends to worsen with hyperextension of the hip; many patients prefer to flex and externally rotate the hip to reduce the pain from a distended bursa.

LABORATORY INVESTIGATIONS

The vast majority of musculoskeletal disorders can be logically diagnosed by a complete history and physical examination. An additional objective of the initial encounter is to determine whether additional investigations or immediate therapy is required. Additional evaluation is indicated with: (1) monarticular conditions; (2) traumatic or inflammatory conditions; (3) the presence of neurologic findings; (4) systemic manifestations; or (5) chronic symptoms (>6 weeks) and a lack of response to symptomatic measures. The extent and nature of the additional investigation should be dictated by the clinical features and suspected pathologic process. Laboratory tests should be used to confirm a specific clinical diagnosis and not be used to screen or evaluate patients with vague rheumatic complaints. Indiscriminate use of broad batteries of diagnostic tests and radiographic procedures is rarely a useful or cost-effective means to establish a diagnosis.

Besides a complete blood count, including a white blood cell (WBC) and differential count, the routine evaluation should include a determination of an acute-phase reactant such as the ESR or CRP, which can be useful in discriminating inflammatory from noninflammatory disorders. Both are inexpensive, easily obtained, and may be elevated with infection, inflammation, autoimmune disorders, neoplasia, pregnancy, renal insufficiency, advanced age, or hyperlipidemia. Extreme elevation of the acute-phase reactants (CRP, ESR) is seldom seen without evidence of serious illness (e.g., sepsis, pleuropericarditis, polymyalgia rheumatica, giant cell arteritis, adult Still’s disease).

Serum uric acid determinations are useful in the diagnosis of gout and in monitoring the response to urate-lowering therapy. Uric acid, the end product of purine metabolism, is primarily excreted in the urine. Serum values range from 238 to 516 μmol/L (4.0–8.6 mg/dL) in men; the lower values (178–351 μmol/L [3.0–5.9 mg/dL]) seen in women are caused by the uricosuric effects of estrogen. Urinary uric acid levels are normally <750 mg per 24 h. Although hyperuricemia (especially levels >535 μmol/L [>9 mg/dL]) is associated with an increased incidence of gout and nephrolithiasis, levels may not correlate with the severity of articular disease. Uric acid levels (and the risk of gout) may be increased by inborn errors of metabolism (Lesch-Nyhan syndrome), disease states (renal insufficiency, myeloproliferative disease, psoriasis), or drugs (alcohol, cytotoxic therapy, thiazides). Although nearly all patients with gout will demonstrate hyperuricemia at some time during their illness, up to 50% of patients with an acute gouty attack will have normal serum uric acid levels. Monitoring serum uric acid is useful in assessing the response to urate-lowering therapy or chemotherapy, with the target goal being a serum urate <6 mg/dL.

Serologic tests for RF, cyclic anticitrullinated peptide (CCP or ACPA) antibodies, ANAs, complement levels, Lyme and antineutrophil cytoplasmic antibodies (ANCA), or antistreptolysin O (ASO) titer should be carried out only when there is clinical evidence to specifically suggest an associated diagnosis because these have poor predictive value when used for screening, especially when the pretest probability is low. For most of these, there is no value to repeated or serial serologic testing. Although 4–5% of a healthy population will have positive tests for RF and ANAs, only 1% and <0.4% of the population will have RA or SLE, respectively. IgM RF (autoantibodies against the Fc portion of IgG) is found in 80% of patients with RA and may also be seen in low titers in patients with chronic infections (tuberculosis, leprosy, hepatitis); other autoimmune diseases (SLE, Sjögren’s syndrome); and chronic pulmonary, hepatic, or renal diseases. When considering RA, both serum RF and anti-CCP antibodies should be obtained as these are complementary. Both are comparably sensitive, but CCP antibodies are more specific than RF. In RA, the presence of anti-CCP and RF antibodies may indicate a greater risk for more severe, erosive polyarthritis. ANAs are found in nearly all patients with SLE and may also be seen in patients with other autoimmune diseases (polymyositis, scleroderma, antiphospholipid syndrome, Sjögren’s syndrome), drug-induced lupus (Table 363-2), chronic liver or renal disorders, and advanced age. Positive ANAs are found in 5% of adults and in up to 14% of elderly or chronically ill individuals. The ANA test is very sensitive but poorly specific for lupus, as only 1–2% of all positive results will be caused by lupus alone. The interpretation of a positive ANA test may depend on the magnitude of the titer and the pattern observed by immunofluorescence microscopy (Table 363-4). Diffuse and speckled patterns are least specific, whereas a peripheral, or rim, pattern (related to autoantibodies against double-strand [native] DNA) is highly specific and suggestive of lupus. Centromeric patterns are seen in patients with limited scleroderma (calcinosis, Raynaud’s phenomenon, esophageal involvement, sclerodactyly, telangiectasia [CREST] syndrome), primary biliary sclerosis, Sjögren’s syndrome or thyroiditis and nucleolar patterns may be seen in patients with diffuse systemic sclerosis or inflammatory myositis.

Aspiration and analysis of synovial fluid are always indicated in acute monarthritis or when an infectious or crystal-induced arthropathy is suspected. Synovial fluid may distinguish between noninflammatory and inflammatory processes by analysis of the appearance, viscosity, and cell count. Tests for synovial fluid glucose, protein, lactate dehydrogenase, lactic acid, or autoantibodies are not recommended because they have no diagnostic value. Normal synovial fluid is clear or a pale straw color and is viscous, primarily because of the high levels of hyaluronate. Noninflammatory synovial fluid is clear, viscous, and amber-colored, with a WBC count of <2000/μL and a predominance of mononuclear cells. The viscosity of synovial fluid is assessed by expressing fluid from the syringe one drop at a time. Normally, there is a stringing effect, with a long tail behind each synovial drop. Effusions caused by OA or trauma will have normal viscosity. Inflammatory fluid is turbid and yellow, with an increased WBC count (2000–50,000/μL) and a polymorphonuclear leukocyte predominance. Inflammatory fluid has reduced viscosity (no stringing), diminished hyaluronate, and little or no tail following each drop of synovial fluid. Such effusions are found in RA, gout, and other inflammatory arthritides. Septic fluid is opaque and purulent, with a WBC count usually >50,000/μL, a predominance of polymorphonuclear leukocytes (>75%), and low viscosity. Such effusions are typical of septic arthritis but may also occur with RA or gout. In addition, hemorrhagic synovial fluid may be seen with trauma, hemarthrosis, or neuropathic arthritis. An algorithm for synovial fluid aspiration and analysis is shown in Fig. 363-6. Synovial fluid should be analyzed immediately for appearance, viscosity, and cell count. Monosodium urate crystals (observed in gout) are seen by polarized microscopy and are long, needle-shaped, negatively birefringent, and usually intracellular. In chondrocalcinosis and pseudogout, calcium pyrophosphate dihydrate crystals are usually short, rhomboid-shaped, and positively birefringent. Whenever infection is suspected, synovial fluid should be Gram stained and cultured appropriately. If gonococcal arthritis is suspected, nucleic acid amplification tests should be used to detect either Chlamydia trachomatis or N. gonorrhoeae infection. Synovial fluid from patients with chronic monarthritis should also be cultured for M. tuberculosis and fungi. Last, it should be noted that crystal-induced arthritis and septic arthritis occasionally occur together in the same joint.

DIAGNOSTIC IMAGING IN JOINT DISEASES

Conventional radiography has been a valuable tool in the diagnosis and staging of articular disorders. Plain x-rays are most appropriate and cost effective when there is a history of trauma, suspected chronic infection, progressive disability, or monarticular involvement; when therapeutic alterations are considered; or when a baseline assessment is desired for what appears to be a chronic process. However, in acute inflammatory arthritis, early radiography is rarely helpful in establishing a diagnosis and may only reveal soft tissue swelling or juxtaarticular demineralization. As the disease progresses, calcification (of soft tissues, cartilage, or bone), joint space narrowing, erosions, bony ankylosis, new bone formation (sclerosis, osteophytes, or periostitis), or subchondral cysts may develop and suggest specific clinical entities. Consultation with a radiologist will help define the optimal imaging modality, technique, or positioning and prevent the need for further studies.

Additional imaging techniques may possess greater diagnostic sensitivity and facilitate early diagnosis in a limited number of articular disorders and in selected circumstances and are indicated when conventional radiography is inadequate or nondiagnostic (Table 363-5). Ultrasonography is useful in the detection of soft tissue abnormalities, such as tendinitis, tenosynovitis, enthesitis, bursitis, and entrapment neuropathies. Wider use, lower cost, better technology, and enhanced site-specific transducers now allow for wider use in outpatient care, especially for the evaluation of synovial (Baker’s) cysts, rotator cuff tears, tendinitis and tendon injury, and crystal deposition on cartilage. Use of power Doppler allows for early detection of synovitis and bony erosions. Radionuclide scintigraphy is a very sensitive, but poorly specific, means of detecting inflammatory or metabolic alterations in bone or periarticular soft tissue structures (Table 363-5). Scintigraphy is best suited for total-body assessment (extent and distribution) of skeletal involvement (neoplasia, Paget’s disease) and the assessment of patients with undiagnosed polyarthralgias, looking for occult arthritis. The use of scintigraphy has declined with greater use and declining cost of ultrasound and MRI. MRI has largely replaced scintigraphy in diagnosing osseous infection, neoplasia, inflammation, increased blood flow, bone remodeling, heterotopic bone formation, or avascular necrosis. Gallium scanning uses ⁶⁷Ga, which binds serum and cellular transferrin and lactoferrin and is preferentially taken up by neutrophils, macrophages, bacteria, and tumor tissue (e.g., lymphoma). As such, it is primarily used in the identification of occult infection or malignancy. Scanning with ¹¹¹In-labeled WBCs has been used to detect osteomyelitis and infectious or inflammatory arthritis. Despite their utility, ¹¹¹In-labeled WBC or ⁶⁷Ga scanning has largely been replaced by MRI, except when there is a suspicion of septic joint or prosthetic joint infections.

Computed tomography (CT) provides detailed visualization of the axial skeleton. Articulations previously considered difficult to visualize by radiography (e.g., zygapophyseal, sacroiliac, sternoclavicular, hip joints) can be effectively evaluated using CT. CT has been demonstrated to be useful in the diagnosis of low back pain syndromes (e.g., spinal stenosis vs herniated disk), sacroiliitis, osteoid osteoma, and stress fractures. Helical or spiral CT (with or without contrast angiography) is a novel technique that is rapid, cost effective, and sensitive in diagnosing pulmonary embolism or obscure fractures, often in the setting of initially equivocal findings. High-resolution CT can be advocated in the evaluation of suspected or established infiltrative lung disease (e.g., scleroderma or rheumatoid lung). The recent use of hybrid (positron emission tomography [PET] or single-photon emission CT [SPECT]) CT scans in metastatic evaluations has incorporated CT to provide better anatomic localization of scintigraphic abnormalities.

¹⁸F-Fluorodeoxyglucose (FDG) is the most commonly used radiopharmaceutical in PET scanning. FDG-PET/CT scans have been seldom used in the evaluation of septic or inflammatory arthritis, but have also been useful in the evaluation of patients with fever of unknown origin or suspected large vessel vasculitis. Dual-energy CT (DECT) scanning, developed in urology to identify urinary calculi, has been a highly sensitive and specific method used to identify and quantify uric acid deposition in tissues (Fig. 363-7).

MRI has significantly advanced the ability to image musculoskeletal structures. MRI has the advantages of providing multiplanar images with fine anatomic detail and contrast resolution (Fig. 363-8) that allows for the superior ability to visualize bone marrow and soft tissue periarticular structures. Although more costly with a longer procedural time than CT, the MRI has become the preferred technique when evaluating complex musculoskeletal disorders.

MRI can image fascia, vessels, nerve, muscle, cartilage, ligaments, tendons, pannus, synovial effusions, and bone marrow. Visualization of particular structures can be enhanced by altering the pulse sequence to produce either T1- or T2-weighted spin echo, gradient echo, or inversion recovery (including short tau inversion recovery [STIR]) images. Because of its sensitivity to changes in marrow fat, MRI is a sensitive but nonspecific means of detecting osteonecrosis, osteomyelitis, and marrow inflammation indicating overlying synovitis or osteitis (Fig. 363-8). Because of its enhanced soft tissue resolution, MRI is more sensitive than arthrography or CT in the diagnosis of soft tissue injuries (e.g., meniscal and rotator cuff tears); intraarticular derangements; marrow abnormalities (osteonecrosis, myeloma); and spinal cord or nerve root damage, synovitis, or cartilage damage or loss.

ACKNOWLEDGMENT

The author acknowledges the insightful contributions of Dr. Peter E. Lipsky to this chapter in previous editions.

FURTHER READING

INTRODUCTION

The use of polarizing light microscopy during synovial fluid analysis in 1961 by McCarty and Hollander and the subsequent application of other crystallographic techniques, such as electron microscopy, energy-dispersive elemental analysis, and x-ray diffraction, have allowed investigators to identify the roles of different microcrystals, including monosodium urate (MSU), calcium pyrophosphate (CPP), calcium apatite (apatite), and calcium oxalate (CaOx), in inducing acute or chronic arthritis or periarthritis. The clinical events that result from deposition of MSU, CPP, apatite, and CaOx have many similarities but also have important differences. Because of often similar clinical presentations, the need to perform synovial fluid analysis to distinguish the type of crystal involved must be emphasized. Polarized light microscopy alone can identify most typical crystals; apatite, however, is an exception. Aspiration and analysis of effusions are also important to assess the possibility of infection. Apart from the identification of specific microcrystalline materials or organisms, synovial fluid characteristics in crystal-associated diseases are nonspecific, and synovial fluid can be inflammatory or noninflammatory. Without crystal identification, these diseases can be confused with rheumatoid or other types of arthritis. A list of possible musculoskeletal manifestations of crystal-associated arthritis is shown in Table 365-1.

GOUT

Gout is a metabolic disease that most often affects middle-aged to elderly men and postmenopausal women. It results from an increased body pool of urate with hyperuricemia. It typically is characterized by episodic acute arthritis or chronic arthritis caused by deposition of MSU crystals in joints and connective tissue tophi and the risk for deposition in kidney interstitium or uric acid nephrolithiasis (Chap. 410).

ACUTE AND CHRONIC ARTHRITIS

Acute arthritis is the most common early clinical manifestation of gout. Usually, only one joint is affected initially, but polyarticular acute gout can occur in subsequent episodes. The metatarsophalangeal joint of the first toe often is involved, but tarsal joints, ankles, and knees also are affected commonly. Especially in elderly patients or in advanced disease, finger joints may be involved. Inflamed Heberden’s or Bouchard’s nodes may be a first manifestation of gouty arthritis. The first episode of acute gouty arthritis frequently begins at night with dramatic joint pain and swelling. Joints rapidly become warm, red, and tender, with a clinical appearance that often mimics that of cellulitis. Early attacks tend to subside spontaneously within 3–10 days, and most patients have intervals of varying length with no residual symptoms until the next episode. Several events may precipitate acute gouty arthritis: dietary excess, trauma, surgery, excessive ethanol ingestion, hypouricemic therapy, and serious medical illnesses such as myocardial infarction and stroke.

After many acute mono- or oligoarticular attacks, a proportion of gouty patients may present with a chronic nonsymmetric synovitis, causing potential confusion with rheumatoid arthritis (Chap. 351). Less commonly, chronic gouty arthritis will be the only manifestation, and, more rarely, the disease will manifest only as periarticular tophaceous deposits in the absence of synovitis. Women represent only 5–20% of all patients with gout. Most women with gouty arthritis are postmenopausal and elderly, have osteoarthritis and arterial hypertension that causes mild renal insufficiency, and usually are receiving diuretics. Premenopausal gout is rare. Kindreds of precocious gout in young women caused by decreased renal urate clearance and renal insufficiency have been described.

Laboratory Diagnosis

Even if the clinical appearance strongly suggests gout, the presumptive diagnosis ideally should be confirmed by needle aspiration of acutely or chronically involved joints or tophaceous deposits. Acute septic arthritis, several of the other crystalline- associated arthropathies, palindromic rheumatism, and psoriatic arthritis may present with similar clinical features. During acute gouty attacks, needle-shaped MSU crystals typically are seen both intracellularly and extracellularly (Fig. 365-1). With compensated polarized light, these crystals are brightly birefringent with negative elongation. Synovial fluid leukocyte counts are elevated from 2000 to 60,000/μL. Effusions appear cloudy due to the increased numbers of leukocytes. Large amounts of crystals occasionally produce a thick pasty or chalky joint fluid. Bacterial infection can coexist with urate crystals in synovial fluid; if there is any suspicion of septic arthritis, joint fluid must be cultured.

MSU crystals also can often be demonstrated in the first metatarsophalangeal joint and in knees not acutely involved with gout. Arthrocentesis of these joints is a useful technique to establish the diagnosis of gout between attacks.

Serum uric acid levels can be normal or low at the time of an acute attack, as inflammatory cytokines can be uricosuric and effective initiation of hypouricemic therapy can precipitate attacks. This limits the value of serum uric acid determinations for the diagnosis of gout. Nevertheless, serum urate levels are almost always elevated at some time and are important to use to follow the course of hypouricemic therapy. A 24-h urine collection for uric acid can, in some cases, be useful in assessing the risk of stones, elucidating overproduction or underexcretion of uric acid, and deciding whether it may be appropriate to use a uricosuric therapy (Chap. 410). Excretion of >800 mg of uric acid per 24 h on a regular diet suggests that causes of overproduction of purine should be considered. Urinalysis, serum creatinine, hemoglobin, white blood cell (WBC) count, liver function tests, and serum lipids should be obtained because of possible pathologic sequelae of gout and other associated diseases requiring treatment and as baselines because of possible adverse effects of gout treatment.

Radiographic Features

Cystic changes, well-defined erosions with sclerotic margins (often with overhanging bony edges), and soft tissue masses are characteristic radiographic features of advanced chronic tophaceous gout. Ultrasound may aid earlier diagnosis by showing a double contour sign overlying the articular cartilage. Dual-energy computed tomography (CT) can show specific features establishing the presence of urate crystals.

TREATMENT

CALCIUM PYROPHOSPHATE DEPOSITION (CPPD) DISEASE

PATHOGENESIS

The deposition of CPP crystals in articular tissues is most common in the elderly, occurring in 10–15% of persons age 65–75 years and 30–50% of those >85 years. In most cases, this process is asymptomatic, and the cause of CPPD is uncertain. Because >80% of patients are >60 years and 70% have preexisting joint damage from other conditions, it is likely that biochemical changes in aging or diseased cartilage favor crystal nucleation. In patients with CPPD arthritis, there is increased production of inorganic pyrophosphate and decreased levels of pyrophosphatases in cartilage extracts. Mutations in the ANKH gene, as described in both familial and sporadic cases, can increase elaboration and extracellular transport of pyrophosphate. The increase in pyrophosphate production appears to be related to enhanced activity of ATP pyrophosphohydrolase and 5′-nucleotidase, which catalyze the reaction of ATP to adenosine and pyrophosphate. This pyrophosphate could combine with calcium to form CPP crystals in matrix vesicles or on collagen fibers. There are decreased levels of cartilage glycosaminoglycans that normally inhibit and regulate crystal nucleation. High activities of transglutaminase enzymes also may contribute to the deposition of CPP crystals.

Release of CPP crystals into the joint space is followed by the phagocytosis of those crystals by monocyte-macrophages and neutrophils, which respond by releasing chemotactic and inflammatory substances and, as with MSU crystals, activating the inflammasome.

A minority of patients with CPPD arthropathy have metabolic abnormalities or hereditary CPP disease (Table 365-2). These associations suggest that a variety of different metabolic products may enhance CPP crystal deposition either by directly altering cartilage or by inhibiting inorganic pyrophosphatases. Included among these conditions are hyperparathyroidism, hemochromatosis, hypophosphatasia, and hypomagnesemia. The presence of CPPD arthritis in individuals aged <50 years should lead to consideration of these metabolic disorders (Table 365-2) and inherited forms of disease, including those identified in a variety of ethnic groups. Genomic DNA studies performed on different kindreds have shown a possible location of genetic defects on chromosome 8q or on chromosome 5p in a region that expresses the gene of the membrane pyrophosphate channel (ANKH gene). Investigation of younger patients with CPPD should include inquiry for evidence of familial aggregation and evaluation of serum calcium, phosphorus, alkaline phosphatase, magnesium, iron, and transferrin.

CLINICAL MANIFESTATIONS

CPPD arthropathy may be asymptomatic, acute, subacute, or chronic or may cause acute synovitis superimposed on chronically involved joints. Acute CPPD arthritis originally was termed pseudogout by McCarty and co-workers because of its striking similarity to gout. Other clinical manifestations of CPPD include (1) association with or enhancement of peculiar forms of osteoarthritis; (2) induction of severe destructive disease that may radiographically mimic neuropathic arthritis; (3) production of chronic symmetric synovitis that is clinically similar to rheumatoid arthritis; (4) intervertebral disk and ligament calcification with restriction of spine mobility, the crowned dens syndrome, or spinal stenosis (most commonly seen in the elderly); and (5) rarely periarticular tophus-like nodules.

The knee is the joint most frequently affected in CPPD arthropathy. Other sites include the wrist, shoulder, ankle, elbow, and hands. The temporomandibular joint may be involved. Clinical and radiographic evidence indicates that CPPD deposition is polyarticular in at least two-thirds of patients. When the clinical picture resembles that of slowly progressive osteoarthritis, diagnosis may be difficult. Joint distribution may provide important clues suggesting CPPD disease. For example, primary osteoarthritis less often involves metacarpophalangeal, wrist, elbow, shoulder, or ankle joints. If radiographs or ultrasound reveal punctate and/or linear radiodense deposits within fibrocartilaginous joint menisci or articular hyaline cartilage (chondrocalcinosis), the diagnostic likelihood of CPPD disease is further increased. Definitive diagnosis requires demonstration of typical rhomboid or rodlike crystals (generally weakly positively birefringent or nonbirefringent with polarized light) in synovial fluid or articular tissue (Fig. 365-2). In the absence of joint effusion or indications to obtain a synovial biopsy, chondrocalcinosis is presumptive of CPPD. One exception is chondrocalcinosis due to CaOx in some patients with chronic renal failure.

Acute attacks of CPPD arthritis may be precipitated by trauma. Rapid diminution of serum calcium concentration, as may occur in severe medical illness or after surgery (especially parathyroidectomy), can also lead to attacks.

In as many as 50% of cases, episodes of CPPD-induced inflammation are associated with low-grade fever and, on occasion, temperatures as high as 40°C (104°F). In such cases, synovial fluid analysis with microbial cultures is essential to rule out the possibility of infection. In fact, infection in a joint with any microcrystalline deposition process can lead to crystal shedding and subsequent synovitis from both crystals and microorganisms. The leukocyte count in synovial fluid in acute CPPD can range from several thousand cells to 100,000 cells/μL, with the mean being about 24,000 cells/μL and the predominant cell being the neutrophil. CPP crystals may be seen inside tissue fragments and fibrin clots and in neutrophils (Fig. 365-2). CPP crystals may coexist with MSU and apatite in some cases.

TREATMENT

CALCIUM APATITE DEPOSITION DISEASE

PATHOGENESIS

Apatite is the primary mineral of normal bone and teeth. Abnormal accumulation of basic calcium phosphates, largely carbonate substituted apatite, can occur in areas of tissue damage (dystrophic calcification), hypercalcemic or hyperparathyroid states (metastatic calcification), and certain conditions of unknown cause (Table 365-3). In chronic renal failure, hyperphosphatemia can contribute to extensive apatite deposition both in and around joints. Familial aggregation is rarely seen; no association with ANKH mutations has been described thus far. Apatite crystals are deposited primarily on matrix vessels. Incompletely understood alterations in matrix proteoglycans, phosphatases, hormones, and cytokines probably can influence crystal formation.

Apatite aggregates are commonly present in synovial fluid in an extremely destructive chronic arthropathy of the elderly that occurs most often in the shoulders (Milwaukee shoulder) and in a similar process in hips, knees, and erosive osteoarthritis of fingers. Joint destruction is associated with damage to cartilage and supporting structures, leading to instability and deformity. Progression tends to be indolent. Symptoms range from minimal to severe pain and disability that may lead to joint replacement surgery. Whether severely affected patients represent an extreme synovial tissue response to the apatite crystals that are so common in osteoarthritis is uncertain. Synovial lining cell or fibroblast cultures exposed to apatite (or CPP) crystals can undergo mitosis and markedly increase the release of prostaglandin E₂, various cytokines, and also collagenases and neutral proteases, underscoring the destructive potential of abnormally stimulated synovial lining cells.

CLINICAL MANIFESTATIONS

Periarticular or articular deposits may occur and may be associated with acute reversible inflammation and/or chronic damage to the joint capsule, tendons, bursa, or articular surfaces. The most common sites of apatite deposition include bursae and tendons in and/or around the knees, shoulders, hips, and fingers. Clinical manifestations include asymptomatic radiographic abnormalities, acute synovitis, bursitis, tendinitis, and chronic destructive arthropathy. Although the true incidence of apatite arthritis is not known, 30–50% of patients with osteoarthritis have apatite microcrystals in their synovial fluid. Such crystals frequently can be identified in clinically stable osteoarthritic joints, but they are more likely to come to attention in persons experiencing acute or subacute worsening of joint pain and swelling. The synovial fluid leukocyte count in apatite arthritis is usually low (<2000/μL) despite dramatic symptoms, with predominance of mononuclear cells.

DIAGNOSIS

Intra- and/or periarticular calcifications with or without erosive, destructive, or hypertrophic changes may be seen on radiographs (Fig. 365-3). They should be distinguished from the linear calcifications typical of CPPD.

Definitive diagnosis of apatite arthropathy, also called basic calcium phosphate disease, depends on identification of crystals from synovial fluid or tissue (Fig. 365-3). Individual crystals are very small and can be seen only by electron microscopy. Clumps of crystals may appear as 1- to 20-μm shiny intra- or extracellular nonbirefringent globules or aggregates that stain purplish with Wright’s stain and bright red with alizarin red S. Tetracycline binding and other investigative techniques are under consideration as labeling alternatives. Absolute identification depends on electron microscopy with energy-dispersive elemental analysis, x-ray diffraction, infrared spectroscopy, or Raman microspectroscopy, but these techniques usually are not required in clinical diagnosis.

TREATMENT

CaOx DEPOSITION DISEASE

PATHOGENESIS

Primary oxalosis is a rare hereditary metabolic disorder (Chap. 413). Enhanced production of oxalic acid may result from at least two different enzyme defects, leading to hyperoxalemia and deposition of CaOx crystals in tissues. Nephrocalcinosis and renal failure are typical results. Acute and/or chronic CaOx arthritis, periarthritis, and bone disease may complicate primary oxalosis during later years of illness.

Secondary oxalosis is more common than the primary disorder. In chronic renal disease, CaOx deposits have long been recognized in visceral organs, blood vessels, bones, and cartilage and are now known to be one of the causes of arthritis in chronic renal failure. Thus far, reported patients have been dependent on long-term hemodialysis or peritoneal dialysis (Chap. 306), and many had received ascorbic acid supplements. Ascorbic acid is metabolized to oxalate, which is inadequately cleared in uremia and by dialysis. Such supplements and foods high in oxalate content usually are avoided in dialysis programs because of the risk of enhancing hyperoxalosis and its sequelae.

CLINICAL MANIFESTATIONS AND DIAGNOSIS

CaOx aggregates can be found in bone, articular cartilage, synovium, and periarticular tissues. From these sites, crystals may be shed, causing acute synovitis. Persistent aggregates of CaOx can, like apatite and CPP, stimulate synovial cell proliferation and enzyme release, resulting in progressive articular destruction. Deposits have been documented in fingers, wrists, elbows, knees, ankles, and feet.

Clinical features of acute CaOx arthritis may not be distinguishable from those due to urate, CPP, or apatite. Radiographs may reveal chondrocalcinosis or soft tissue calcifications. CaOx-induced synovial effusions are usually noninflammatory, with <2000 leukocytes/μL, or mildly inflammatory. Neutrophils or mononuclear cells can predominate. CaOx crystals have a variable shape and variable birefringence to polarized light. The most easily recognized forms are bipyramidal, have strong birefringence (Fig. 365-4), and stain with alizarin red S.

TREATMENT

FURTHER READING

INTRODUCTION

Osteoarthritis (OA) is the most common type of arthritis. Its high prevalence, especially in the elderly, and its negative impact on physical function make it a leading cause of disability in the elderly. Because of the aging of Western populations and because obesity, a major risk factor, is increasing in prevalence, the occurrence of OA is on the rise.

OA affects certain joints, yet spares others (Fig. 364-1). Commonly affected joints include the hip, knee, and first metatarsal phalangeal joint (MTP) and cervical and lumbosacral spine. In the hands, the distal and proximal interphalangeal joints and the base of the thumb are often affected. Usually spared are the wrist, elbow, and ankle. Our joints were designed, in an evolutionary sense, for brachiating apes, animals that still walked on four limbs. We thus develop OA in joints that were ill designed for human tasks such as pincer grip (OA in the thumb base) and walking upright (OA in knees and hips). Some joints, like the ankles, may be spared because their articular cartilage may be uniquely resistant to loading stresses.

OA can be diagnosed based on structural abnormalities or on the symptoms these abnormalities evoke. According to cadaveric studies, by elderly years, structural changes of OA are nearly universal. These include cartilage loss (seen as joint space loss on x-rays) and osteophytes. Many persons with x-ray evidence of OA have no joint symptoms, and although the prevalence of structural abnormalities is of interest in understanding disease pathogenesis, what matters more from a clinical perspective is the prevalence of symptomatic OA. Symptoms, usually joint pain, determine disability, visits to clinicians, and disease costs.

Symptomatic OA of the knee (pain on most days of a recent month plus x-ray evidence of OA in that knee) occurs in ~12% of persons age ≥60 in the United States and 6% of all adults age ≥30. Symptomatic hip OA is roughly one-third as common as disease in the knee. Although radiographic hand OA and the appearance of bony enlargement in affected hand joints (Fig. 364-2) are extremely common in older persons, most cases are often not symptomatic. Even so, symptomatic hand OA occurs in ~10% of elderly individuals and often produces measurable limitation in function.

The prevalence of OA rises strikingly with age, being uncommon in adults aged <40 and highly prevalent in those aged >60. It is also a disease that, at least in middle-aged and elderly persons, is much more common in women than in men.

X-ray evidence of OA is common in the lower back and neck, but back pain and neck pain have not been tied to findings of OA on x-ray. Thus, back pain and neck pain are treated separately (Chap. 14).

DEFINITION

OA is joint failure, a disease in which all structures of the joint have undergone pathologic change, often in concert. The pathologic sine qua non of disease is hyaline articular cartilage loss, present in a focal and, initially, nonuniform manner. This is accompanied by increasing thickness and sclerosis of the subchondral bony plate, by outgrowth of osteophytes at the joint margin, by stretching of the articular capsule, by variable degrees of synovitis, and by weakness of muscles bridging the joint. In knees, meniscal degeneration is part of the disease. There are numerous pathways that lead to joint failure, but the initial step is often joint injury in the setting of a failure of protective mechanisms.

JOINT PROTECTIVE MECHANISMS AND THEIR FAILURE

Joint protectors include joint capsule and ligaments, muscle, sensory afferents, and underlying bone. Joint capsule and ligaments serve as joint protectors by providing a limit to excursion, thereby fixing the range of joint motion.

Synovial fluid reduces friction between articulating cartilage surfaces, thereby serving as a protector against friction-induced cartilage wear. This lubrication function depends on hyaluronic acid and on lubricin, a mucinous glycoprotein secreted by synovial fibroblasts whose concentration diminishes after joint injury and in the face of synovial inflammation.

The ligaments, along with overlying skin and tendons, contain mechanoreceptor sensory nerves. These mechanoreceptors fire at different frequencies throughout a joint’s range of motion, providing feedback by way of the spinal cord to muscles and tendons. As a consequence, these muscles and tendons can assume the right tension at appropriate points in joint excursion to act as optimal joint protectors, anticipating joint loading.

Muscles and tendons that bridge the joint are key joint protectors. Focal stress across the joint is minimized by muscle contraction that decelerates the joint before impact and assures that when joint impact arrives, it is distributed broadly across the joint surface.

Failure of these joint protectors increases the risk of joint injury and OA. For example, in animals, OA develops rapidly when a sensory nerve to the joint is sectioned and joint injury induced. Similarly, in humans, Charcot’s arthropathy, a severe and rapidly progressive OA, develops when minor joint injury occurs in the presence of posterior column peripheral neuropathy. Another example of joint protector failure is rupture of ligaments, a well-known cause of the early development of OA.

CARTILAGE AND ITS ROLE IN JOINT FAILURE

In addition to being a primary target tissue for disease, cartilage also functions as a joint protector. A thin rim of tissue at the ends of two opposing bones, cartilage is lubricated by synovial fluid to provide an almost frictionless surface across which these two bones move. The compressible stiffness of cartilage compared to bone provides the joint with impact-absorbing capacity.

The earliest changes of OA may occur in cartilage, and abnormalities there can accelerate disease development. The two major macromolecules in cartilage are type 2 collagen, which provides cartilage its tensile strength, and aggrecan, a proteoglycan macromolecule linked with hyaluronic acid, which consists of highly negatively charged glycosaminoglycans. In normal cartilage, type 2 collagen is woven tightly, constraining the aggrecan molecules in the interstices between collagen strands, forcing these highly negatively charged molecules into close proximity with one another. The aggrecan molecule, through electrostatic repulsion of its negative charges, gives cartilage its compressive stiffness. Chondrocytes, the cells within this avascular tissue, synthesize all elements of the matrix and produce enzymes that break down the matrix. Synovium and chondrocytes synthesize and release cytokines and growth factors, which provide feedback that modulates synthesis of matrix molecules (Fig. 364-3). Cartilage matrix synthesis and catabolism are in a dynamic equilibrium influenced by the cytokine and growth factor environment. Mechanical and osmotic stress on chondrocytes induces these cells to alter gene expression and increase production of inflammatory cytokines and matrix-degrading enzymes. While chondrocytes synthesize numerous enzymes, matrix metalloproteinases (MMP) (especially collagenases and ADAMTS-5) are critical enzymes in the breakdown of cartilage matrix. Both collagenase and aggrecanases act primarily in the territorial matrix surrounding chondrocytes; however, as the osteoarthritic process develops, their activities and effects spread throughout the matrix, especially in the superficial layers of cartilage.

The synovium, cartilage, and bone all influence disease development through cytokines, chemokines, and even complement activation (Fig. 364-3). These act on chondrocyte cell surface receptors and ultimately have transcriptional effects. Matrix fragments released from cartilage stimulate synovitis. Inflammatory cytokines such as interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) induce chondrocytes to synthesize prostaglandin E₂ and nitric oxide, which have complex effects on matrix synthesis and degradation. At early stages in the matrix response to injury the net effect of cytokine stimulation may be matrix synthesis, but ultimately, the combination of effects on chondrocytes triggers matrix degradation. Enzymes in the matrix are held in check by activation inhibitors, including tissue inhibitor of metalloproteinase (TIMP). Growth factors are also part of this complex network, with Bone Morphogenetic Protein 2 (BMP-2) and transforming growth factor β (TGF-β) playing prominent roles in stimulating the development of osteophytes. Whereas healthy articular cartilage is avascular in part due to angiogenesis inhibitors present in cartilage, disease is characterized by the invasion of blood vessels into cartilage from underlying bone. This is influenced by vascular endothelial growth factor (VEGF) synthesis in the cartilage and bone. With these blood vessels come nerves that may bring nociceptive innervation.

Probably as a result of chronic oxidative damage, articular chondrocytes exhibit an age-related decline in synthetic capacity while maintaining the ability to produce proinflammatory mediators and matrix-degrading enzymes, findings characteristic of a senescent secretory phenotype. These chondrocytes are unable to maintain tissue homeostasis (such as after insults of a mechanical or inflammatory nature). Thus, with age, cartilage is easily damaged by minor sometimes unnoticed injuries, including those that are part of daily activities.

OA cartilage is characterized by gradual depletion of aggrecan, an unfurling of the tightly woven collagen matrix, and loss of type 2 collagen. With these changes comes increasing vulnerability of cartilage, which loses its compressive stiffness.

RISK FACTORS

Joint vulnerability and joint loading are the two major factors contributing to the development of OA. On the one hand, a vulnerable joint whose protectors are dysfunctional can develop OA with minimal levels of loading, perhaps even levels encountered during everyday activities. On the other hand, in a young joint with competent protectors, a major acute injury or long-term overloading is necessary to precipitate disease. Risk factors for OA can be understood in terms of their effect either on joint vulnerability or on loading (Fig. 364-4).

SYSTEMIC RISK FACTORS

Age is the most potent risk factor for OA. Radiographic evidence of OA is rare in individuals aged <40; however, in some joints, such as the hands, OA occurs in >50% of persons aged >70. Aging increases joint vulnerability through several mechanisms. Whereas dynamic loading of joints stimulates cartilage matrix synthesis by chondrocytes in young cartilage, aged cartilage is less responsive to these stimuli. Partly because of this failure to synthesize matrix with loading, cartilage thins with age, and thinner cartilage experiences higher shear stress and is at greater risk of cartilage damage. Also, joint protectors fail more often with age. Muscles that bridge the joint become weaker with age and also respond less quickly to oncoming impulses. Sensory nerve input slows with age, retarding the feedback loop of mechanoreceptors to muscles and tendons related to their tension and position. Ligaments stretch with age, making them less able to absorb impulses. These factors work in concert to increase the vulnerability of older joints to OA.

Older women are at high risk of OA in all joints, a risk that emerges as women reach their sixth decade. Although hormone loss with menopause may contribute to this risk, there is little understanding of the unique vulnerability of older women versus men to OA.

HERITABILITY AND GENETICS

OA is a highly heritable disease, but its heritability is joint specific. Fifty percent of the hand and hip OA in the community is attributable to inheritance, that is, to disease present in other members of the family. However, the heritable proportion of knee OA is at most 30%, with some studies suggesting no heritability at all. Whereas many people with OA have disease in multiple joints, this “generalized OA” phenotype is rarely inherited and is more often a consequence of aging.

Emerging evidence has identified genetic mutations that confer a high risk of OA, the best replicated is a polymorphism within the growth differentiation factor 5 (GDF5) gene. This polymorphism diminishes the quantity of GDF5; GDF5 has its main influence on joint shape which is likely to be the mechanism by which genes predisposing to OA increase risk of disease.

GLOBAL CONSIDERATIONS

With the aging of the populations, both the prevalence of OA and the amount of disability worldwide related to OA have been increasing especially in developed countries where many are living into old age. Hip OA is rare in China and in immigrants from China to the United States. However, OA in the knees is at least as common, if not more so, in Chinese than in whites from the United States, and knee OA represents a major cause of disability in China, especially in rural areas. Anatomic differences between Chinese and white hips may account for much of the difference in hip OA prevalence, with white hips having a higher prevalence of anatomic predispositions to the development of OA.

RISK FACTORS IN THE JOINT ENVIRONMENT

Some risk factors increase vulnerability of the joint through local effects on the joint environment. With changes in joint anatomy, for example, load across the joint is no longer distributed evenly across the joint surface, but rather shows an increase in focal stress. In the hip, three uncommon developmental abnormalities occurring in utero or in childhood, congenital dysplasia, Legg-Perthes disease, and slipped capital femoral epiphysis, leave a child with distortions of hip joint anatomy that often lead to OA later in life. Girls are predominantly affected by acetabular dysplasia, a mild form of congenital dislocation, whereas the other abnormalities more often affect boys. Depending on the severity of the anatomic abnormalities, hip OA occurs either in young adulthood (severe abnormalities) or middle age (mild abnormalities). Femoroacetabular impingement can develop during adolescence. It is a clinical syndrome in which anatomic abnormalities of the femoral head and/or the acetabulum result in abnormal contact between the two bones especially during hip flexion and rotation, leading to cartilage and labral damage and hip pain and ultimately in later life to possible hip OA.

Major injuries to a joint also can produce anatomic abnormalities that leave the joint susceptible to OA. For example, a fracture through the joint surface often causes OA in joints in which the disease is otherwise rare such as the ankle and the wrist. Avascular necrosis can lead to collapse of dead bone at the articular surface, producing anatomic irregularities and subsequent OA.

Tears of ligamentous and fibrocartilaginous structures that protect the joints, such as the meniscus in the knee and the labrum in the hip, can lead to premature OA. Meniscal tears increase with age and when chronic are often asymptomatic but lead to adjacent cartilage damage and accelerated OA. Even injuries in which the affected person never received a diagnosis may increase risk of OA. For example, in the Framingham Study subjects, men with a history of major knee injury, but no surgery, had a 3.5-fold increased risk for subsequent knee OA.

Another source of anatomic abnormality is malalignment across the joint (Fig. 364-5). This factor has been best studied in the knee, which is the fulcrum of the longest lever arm in the body. Varus (bowlegged) knees with OA are at exceedingly high risk of cartilage loss in the medial or inner compartment of the knee, whereas valgus (knock-kneed) malalignment predisposes to rapid cartilage loss in the lateral compartment. Malalignment causes this effect by increasing stress on a focal area of cartilage, which then breaks down. There is evidence that malalignment in the knee not only causes cartilage loss but leads to underlying bone damage, producing bone marrow lesions seen on magnetic resonance imaging (MRI). Malalignment in the knee often produces such a substantial increase in focal stress within the knee (as evidenced by its destructive effects on subchondral bone) that severely malaligned knees may be destined to progress regardless of the status of other risk factors.

Weakness in the quadriceps muscles bridging the knee increases the risk of the development of painful OA in the knee.

The role of bone in serving as a shock absorber for impact load is not well understood, but persons with increased bone density are at high risk of OA, suggesting that the resistance of bone to impact during joint use may play a role in disease development.

LOADING FACTORS

Obesity

Three to six times body weight is transmitted across the knee during single-leg stance. Any increase in weight may be multiplied by this factor to reveal the excess force across the knee in overweight persons during walking. Obesity is a well-recognized and potent risk factor for the development of knee OA and, less so, for hip OA. Obesity precedes the development of disease and is not just a consequence of the inactivity present in those with disease. It is a stronger risk factor for disease in women than in men, and in women, the relationship of weight to the risk of disease is linear, so that with each pound increase in weight, there is a commensurate increase in risk. Weight loss in women lowers the risk of developing symptomatic disease. Not only is obesity a risk factor for OA in weight-bearing joints, but obese persons have more severe symptoms from the disease.

Obesity’s effect on the development and progression of disease is mediated mostly through the increased loading in weight-bearing joints that occurs in overweight persons. However, a modest association of obesity with an increased risk of hand OA suggests that systemic products of adipose tissue such as adipokines may affect disease risk also.

Repeated Use of Joint and Exercise

There are two categories of repetitive joint use, occupational use and leisure time physical activities. Workers performing repetitive tasks as part of their occupations for many years are at high risk of developing OA in the joints they use repeatedly. For example, farmers are at high risk for hip OA, and miners have high rates of OA in knees and spine. Workers whose jobs require regular knee bending or lifting or carrying heavy loads have a high rate of knee OA. One reason why workers may get disease is that during long days at work, their muscles may gradually become exhausted, no longer serving as effective joint protectors.

It is widely recommended for people to adopt an exercise-filled lifestyle, and long-term studies of exercise suggest no consistent association of exercise with OA risk in the majority of persons. However, persons who already have injured joints may put themselves at greater risk by engaging in certain types of exercise. For example, persons who have already sustained major knee injuries are at increased risk of progressive knee OA as a consequence of running. In addition, compared to nonrunners, elite runners (professional runners and those on Olympic teams) have high risks of both knee and hip OA. Lastly, although recreational runners are not at increased risk of knee OA, studies suggest that they have a modest increased risk of disease in the hip.

PATHOLOGY

The pathology of OA provides evidence of the involvement of many joint structures in disease. Cartilage initially shows surface fibrillation and irregularity. As disease progresses, focal erosions develop there, and these eventually extend down to the subjacent bone. With further progression, cartilage erosion down to bone expands to involve a larger proportion of the joint surface, even though OA remains a focal disease with nonuniform loss of cartilage (Fig. 364-6).

After an injury to cartilage, chondrocytes undergo mitosis and clustering. Although the metabolic activity of these chondrocyte clusters is high, the net effect of this activity is to promote proteoglycan depletion in the matrix surrounding the chondrocytes. This is because the catabolic activity is greater than the synthetic activity. As disease develops, collagen matrix becomes damaged, the negative charges of proteoglycans get exposed, and cartilage swells from ionic attraction to water molecules. Because in damaged cartilage proteoglycans are no longer forced into close proximity, cartilage does not bounce back after loading as it did when healthy, and cartilage becomes vulnerable to further injury. Chondrocytes at the basal level of cartilage undergo apoptosis.

With loss of cartilage comes alteration in subchondral bone. Stimulated by growth factors and cytokines, osteoclasts and osteoblasts in the subchondral bony plate, just underneath cartilage, become activated. Bone formation produces a thickening and stiffness of the subchondral plate that occurs even before cartilage ulcerates. Trauma to bone during joint loading may be the primary factor driving this bone response, with healing from injury (including microcracks) producing stiffness. Small areas of osteonecrosis usually exist in joints with advanced disease. Bone death may also be caused by bone trauma with shearing of microvasculature, leading to a cutoff of vascular supply to some bone areas.

At the margin of the joint, near areas of cartilage loss, osteophytes form. These start as outgrowths of new cartilage, and with neurovascular invasion from the bone, this cartilage ossifies. Osteophytes are an important radiographic hallmark of OA.

The synovium produces lubricating fluids that minimize shear stress during motion. In healthy joints, the synovium consists of a single discontinuous layer filled with fat and containing two types of cells, macrophages and fibroblasts, but in OA, it can sometimes become edematous and inflamed. There is a migration of macrophages from the periphery into the tissue, and cells lining the synovium proliferate. Inflammatory cytokines and alarmins secreted by the synovium activate chondrocytes to produce enzymes which accelerate destruction of matrix.

Additional pathologic changes occur in the capsule, which stretches, becomes edematous, and can become fibrotic.

The pathology of OA is not identical across joints. In hand joints with severe OA, for example, there are often cartilage erosions in the center of the joint probably produced by bony pressure from the opposite side of the joint.

Basic calcium phosphate and calcium pyrophosphate dihydrate crystals are present microscopically in most joints with end-stage OA. Their role in osteoarthritic cartilage is unclear, but their release from cartilage into the joint space and joint fluid likely triggers synovial inflammation, which can, in turn, produce release of cytokines and trigger nociceptive stimulation.

SOURCES OF PAIN

Because cartilage is aneural, cartilage loss in a joint is not accompanied by pain. Thus, pain in OA likely arises from structures outside the cartilage. Innervated structures in the joint include the synovium, ligaments, joint capsule, muscles, and subchondral bone. Most of these are not visualized by the x-ray, and the severity of x-ray changes in OA correlates poorly with pain severity. However, in later stages of OA, loss of cartilage integrity that is accompanied by neurovascular invasion may contribute to pain.

Based on MRI studies in osteoarthritic knees comparing those with and without pain and on studies mapping tenderness in unanesthetized joints, likely sources of pain include synovial inflammation, joint effusions, and bone marrow edema. Modest synovitis develops in many but not all osteoarthritic joints. The presence of synovitis on MRI is correlated with the presence and severity of knee pain. Capsular stretching from fluid in the joint stimulates nociceptive fibers there, inducing pain. Increased focal loading as part of the disease not only damages cartilage but probably also injures the underlying bone. As a consequence, bone marrow edema appears on the MRI; histologically, this edema signals the presence of microcracks and scar, which are the consequences of trauma. These lesions may stimulate bone nociceptive fibers.

Pain may arise from outside the joint also, including bursae near the joints. Common sources of pain near the knee are anserine bursitis and iliotibial band syndrome.

The pathologic changes of OA may eventually lead to alterations in nervous system signaling. Specifically, peripheral nociceptors can become more responsive to sensory input, known as peripheral sensitization, and there can also be an increase in central ascending nociceptive pathway activity, known as central sensitization. Individuals with OA may also have insufficient descending inhibitory modulation. Some individuals may be genetically predisposed to becoming sensitized; however, regardless of the etiology, these nervous system alterations are associated with more severe pain severity, and may contribute to the presence of allodynia and hyperalgesia in patients with OA.

CLINICAL FEATURES

Joint pain from OA is primarily activity-related in the early stages of the disease. Pain comes on either during or just after joint use and then gradually resolves. Examples include knee or hip pain with going up or down stairs, pain in weight-bearing joints when walking, and, for hand OA, pain when cooking. Early in disease, pain is episodic, triggered often by overactive use of a diseased joint, such as a person with knee OA taking a long run and noticing a few days of pain thereafter. As disease progresses, the pain becomes continuous and even begins to be bothersome at night. Stiffness of the affected joint may be prominent, but morning stiffness is usually brief (<30 min).

In knees, buckling may occur, in part, from weakness of muscles crossing the joint. Mechanical symptoms, such as buckling, catching, or locking, could also signify internal derangement, like an anterior cruciate ligament or meniscal tear; however, these symptoms, which are common in persons with knee OA need to be further evaluated only if they develop after an acute knee injury. In the knee, pain with activities requiring knee flexion, such as stair climbing and arising from a chair, often emanates from the patellofemoral compartment of the knee, which does not actively articulate until the knee is bent ~35°.

OA is the most common cause of chronic knee pain in persons aged >45, but the differential diagnosis is long. Inflammatory arthritis is likely if there is prolonged morning stiffness and many other joints are affected. Bursitis occurs commonly around knees and hips. A physical examination should focus on whether tenderness is over the joint line (at the junction of the two bones around which the joint is articulating) or outside of it. Anserine bursitis, medial and distal to the knee, is an extremely common cause of chronic knee pain that may respond to a glucocorticoid injection. Prominent nocturnal pain in the absence of end-stage OA merits a distinct workup. For hip pain, OA can be detected by loss of internal rotation on passive movement, and pain isolated to an area lateral to the hip joint usually reflects the presence of trochanteric bursitis.

No blood tests are routinely indicated for workup of patients with OA unless symptoms and signs suggest inflammatory arthritis. Examination of the synovial fluid is often more helpful diagnostically than an x-ray. If the synovial fluid white count is >1000/μL, inflammatory arthritis or gout or pseudogout is likely, the latter two being also identified by the presence of crystals.

X-rays are indicated to evaluate the possibility of OA only when joint pain and physical findings are not typical of OA or if pain persists after inauguration of treatment effective for OA. In OA, radiographic findings (Fig. 364-7) correlate poorly with the presence and severity of pain. Further, in both knees and hips, radiographs may be normal in early disease as they are insensitive to cartilage loss and other early findings.

Although MRI may reveal the extent of pathology in an osteoarthritic joint, it is not indicated as part of the diagnostic workup. Findings such as meniscal tears and cartilage and bone lesions occur not only in most patients with OA in the knee, but also in most older persons without joint pain. MRI findings almost never warrant a change in therapy.

TREATMENT

FURTHER READING

ARTHRITIS ASSOCIATED WITH SYSTEMIC DISEASE

ARTHROPATHY OF ACROMEGALY

Acromegaly is the result of excessive production of growth hormone by an adenoma in the anterior pituitary gland (Chap. 373). The excessive secretion of growth hormone along with insulin-like growth factor I stimulates proliferation of cartilage, periarticular connective tissue, and bone, resulting in several musculoskeletal problems, including osteoarthritis, back pain, muscle weakness, and carpal tunnel syndrome.

Osteoarthritis is a common feature, most often affecting the knees, shoulders, hips, and hands. Single or multiple joints may be affected. Hypertrophy of cartilage initially produces radiographic widening of the joint space. The newly synthesized cartilage is abnormally susceptible to fissuring, ulceration, and destruction. Ligamental laxity of joints further contributes to the development of osteoarthritis. Cartilage degrades, the joint space narrows, and subchondral sclerosis and osteophytes develop. Joint examination reveals crepitus and laxity. Joint fluid is noninflammatory. Calcium pyrophosphate dihydrate crystals are found in the cartilage in some cases of acromegaly arthropathy and, when shed into the joint, can elicit attacks of pseudogout. Chondrocalcinosis may be observed on radiographs. Back pain is extremely common, perhaps as a result of spine hypermobility. Spine radiographs show normal or widened intervertebral disk spaces, hypertrophic anterior osteophytes, and ligamental calcification. The latter changes are similar to those observed in patients with diffuse idiopathic skeletal hyperostosis. Dorsal kyphosis in conjunction with elongation of the ribs contributes to the development of the barrel chest seen in acromegalic patients. The hands and feet become enlarged as a result of soft tissue proliferation. The fingers are thickened and have spadelike distal tufts. One-third of patients have a thickened heel pad. Approximately 25% of patients exhibit Raynaud’s phenomenon. Carpal tunnel syndrome occurs in about half of patients. The median nerve is compressed by excess connective tissue in the carpal tunnel. Patients with acromegaly may develop proximal muscle weakness, which is thought to be caused by the effect of growth hormone on muscle. Serum muscle enzyme levels and electromyographic findings are normal. Muscle biopsy specimens contain muscle fibers of varying size without inflammation.

ARTHROPATHY OF HEMOCHROMATOSIS

Hemochromatosis is a disorder of iron storage. Absorption of excessive amounts of iron from the intestine leads to iron deposition in parenchymal cells, which results in impairment of organ function (Chap. 407). Symptoms of hemochromatosis usually begin between the ages of 40 and 60 but can appear earlier. Arthropathy, which occurs in 20–40% of patients, usually begins after the age of 50 and may be the first clinical feature of hemochromatosis. The arthropathy is an osteoarthritis-like disorder affecting the small joints of the hands and later the larger joints, such as knees, ankles, shoulders, and hips. The second and third metacarpophalangeal joints of both hands are often the first and most prominent joints affected; this clinical picture may provide an important clue to the possibility of hemochromatosis because these joints are not predominantly affected by “routine” osteoarthritis. Patients experience some morning stiffness and pain with use of involved joints. The affected joints are enlarged and mildly tender. Radiographs show narrowing of the joint space, subchondral sclerosis, subchondral cysts, and juxtaarticular proliferation of bone. Hooklike osteophytes are seen in up to 20% of patients; although they are regarded as a characteristic feature of hemochromatosis, they can also occur in osteoarthritis and are not disease specific. The synovial fluid is noninflammatory. The synovium shows mild to moderate proliferation of iron-containing lining cells, fibrosis, and some mononuclear cell infiltration. In approximately half of patients, there is evidence of calcium pyrophosphate deposition disease, and some patients late in the course of disease experience episodes of acute pseudogout (Chap. 365). An early diagnosis is suggested by high serum transferrin saturation, which is more sensitive than ferritin elevation.

Iron may damage the articular cartilage in several ways. Iron catalyzes superoxide-dependent lipid peroxidation, which may play a role in joint damage. In animal models, ferric iron has been shown to interfere with collagen formation and increase the release of lysosomal enzymes from cells in the synovial membrane. Iron inhibits synovial tissue pyrophosphatase in vitro and therefore may inhibit pyrophosphatase in vivo, resulting in chondrocalcinosis.

TREATMENT

HEMOPHILIC ARTHROPATHY

Hemophilia is a sex-linked recessive genetic disorder characterized by the absence or deficiency of factor VIII (hemophilia A, or classic hemophilia) or factor IX (hemophilia B, or Christmas disease) (Chap. 112). Hemophilia A constitutes 85% of cases. Spontaneous hemarthrosis is a common problem with both types of hemophilia and can lead to a deforming arthritis. The frequency and severity of hemarthrosis are related to the degree of clotting factor deficiency. Hemarthrosis is not common in other disorders of coagulation such as von Willebrand disease, factor V deficiency, warfarin therapy, or thrombocytopenia.

Hemarthrosis occurs after 1 year of age, when a child begins to walk and run. In order of frequency, the joints most commonly affected are the knees, ankles, elbows, shoulders, and hips. Small joints of the hands and feet are occasionally involved.

In the initial stage of arthropathy, hemarthrosis produces a warm, tensely swollen, and painful joint. The patient holds the affected joint in flexion and guards against any movement. Blood in the joint remains liquid because of the absence of intrinsic clotting factors and the absence of tissue thromboplastin in the synovium. The synovial blood is resorbed over a period of ≥1 week, with the precise interval depending on the size of the hemarthrosis. Joint function usually returns to normal or baseline in ~2 weeks. Low-grade temperature elevation may accompany hemarthrosis, but a fever >38.3°C (101°F) warrants concern about infection.

Recurrent hemarthrosis may result in chronic arthritis. The involved joints remain swollen, and flexion deformities develop. Joint motion may be restricted and function severely limited. Restricted joint motion or laxity with subluxation is a feature of end-stage disease.

Bleeding into muscle and soft tissue also causes musculoskeletal dysfunction. When bleeding into the iliopsoas muscle occurs, the hip is held in flexion because of the pain, resulting in a hip flexion contracture. Rotation of the hip is preserved, which distinguishes this problem from hemarthrosis or other causes of hip synovitis. Expansion of the hematoma may place pressure on the femoral nerve, resulting in femoral neuropathy. Hemorrhage into a closed compartment space, such as the calf or the volar compartment in the forearm, can result in muscle necrosis, neuropathy, and flexion deformities of the ankles, wrists, and fingers. When bleeding involves periosteum or bone, a painful pseudotumor forms. These pseudotumors occur distal to the elbows or knees in children and improve with treatment of hemophilia. Surgical removal is indicated if the pseudotumor continues to enlarge. In adults, pseudotumors develop in the femur and pelvis and are usually refractory to treatment. When bleeding occurs in muscle, cysts may develop within the muscle. Needle aspiration of a cyst is contraindicated because this procedure can induce further bleeding; however, if the cyst becomes secondarily infected, drainage may be necessary (after factor repletion).

Septic arthritis is rare in hemophilia and is difficult to distinguish from acute hemarthrosis on physical examination. If there is serious suspicion of an infected joint, the joint should be aspirated immediately, the fluid cultured, and treatment with broad-spectrum antibiotics administered, with coverage for microorganisms including Staphylococcus, until culture results become available. Clotting-factor deficiency should be corrected before arthrocentesis to minimize the risk of traumatic bleeding.

Radiographs of joints reflect the stage of disease. In early stages, there is only capsule distention; later, juxtaarticular osteopenia, marginal erosions, and subchondral cysts develop. Late in the disease, the joint space is narrowed and there is bony overgrowth similar to that in osteoarthritis.

TREATMENT

ARTHROPATHIES ASSOCIATED WITH HEMOGLOBINOPATHIES

Sickle Cell Disease

Sickle cell disease (Chap. 94) is associated with several musculoskeletal abnormalities (Table 367-1). Children aged <5 years may develop diffuse swelling, tenderness, and warmth of the hands and feet lasting 1–3 weeks. This condition, referred to as sickle cell dactylitis or hand-foot syndrome, has also been observed in sickle cell thalassemia. Dactylitis is believed to result from infarction of the bone marrow and cortical bone leading to periostitis and soft tissue swelling. Radiographs show periosteal elevation, subperiosteal new-bone formation, and areas of radiolucency and increased density involving the metacarpals, metatarsals, and proximal phalanges. These bone changes disappear after several months. The syndrome leaves little or no residual damage. Because hematopoiesis ceases in the small bones of the hands and feet with age, the syndrome is rarely seen after age 5.

Sickle cell crisis is associated with periarticular pain and occasionally with joint effusions. The joint and periarticular area are warm and tender. Knees and elbows are most often affected, but other joints can be involved. Joint effusions are usually noninflammatory. Acute synovial infarction can cause a sterile effusion with high neutrophil counts in synovial fluid. Synovial biopsies have shown mild lining-cell proliferation and microvascular thrombosis with infarctions. Scintigraphic studies have shown decreased marrow uptake adjacent to the involved joint. The treatment for sickle cell crisis is detailed in Chap. 94.

Patients with sickle cell disease seem predisposed to osteomyelitis, which commonly involves the long tubular bones (Chap. 126); Salmonella is a particularly common cause (Chap. 160). Radiographs of the involved site initially show periosteal elevation, with subsequent disruption of the cortex. Treatment of the infection results in healing of the bone lesion. In addition, sickle cell disease is associated with bone infarction resulting from vasoocclusion secondary to the sickling of red cells. Bone infarction also occurs in hemoglobin sickle cell disease and sickle cell thalassemia (Chap. 94). The bone pain in sickle cell crisis is due to infarction of bone and bone marrow. In children, infarction of the epiphyseal growth plate interferes with normal growth of the affected extremity. Radiographically, infarction of the bone cortex results in periosteal elevation and irregular thickening of the bone cortex. Infarction in the bone marrow leads to lysis, fibrosis, and new bone formation. Clinical distinction between osteomyelitis and bone infarctions can be difficult; imaging can be helpful.

Avascular necrosis of the head of the femur occurs in ~5% of patients. It also occurs in the humeral head and less commonly in the distal femur, tibial condyles, distal radius, vertebral bodies, and other juxtaarticular sites. Irregularity of the femoral head and other articular surfaces often results in degenerative joint disease. Radiography of the affected joint may show patchy radiolucency and density followed by flattening of the bone. MRI is a sensitive technique for detecting early avascular necrosis as well as bone infarction elsewhere. Total hip replacement and placement of prostheses in other joints may improve function and relieve joint pain in these patients.

Septic arthritis is occasionally encountered in sickle cell disease (Chap. 125). Multiple joints may be infected. Joint infection may result from bacteremia due to splenic dysfunction or from contiguous osteomyelitis. The more common microorganisms include Staphylococcus aureus, Streptococcus, and Salmonella. Salmonella does not cause septic arthritis as frequently as it causes osteomyelitis. Acute gouty arthritis is uncommon in sickle cell disease, even though 40% of patients are hyperuricemic. However, it may occur in patients generally not expected to get gout (young patients, female patients). Hyperuricemia is due to overproduction of uric acid secondary to increased red cell turnover as well as suboptimal renal excretion. Attacks may be polyarticular, and diagnostic arthrocentesis should be performed to distinguish infection from gout or synovial infarction.

The bone marrow hyperplasia in sickle cell disease results in widening of the medullary cavities, thinning of the cortices, and coarse trabeculations and central cupping of the vertebral bodies. These changes are also seen to a lesser degree in hemoglobin sickle cell disease and sickle cell thalassemia. In normal individuals red marrow is located mostly in the axial skeleton, but in sickle cell disease red marrow is found in the bones of the extremities and even in the tarsal and carpal bones. Vertebral compression may lead to dorsal kyphosis, and softening of the bone in the acetabulum may result in protrusio acetabuli.

Thalassemia

A congenital disorder of hemoglobin synthesis, β thalassemia is characterized by impaired production of β chains (Chap. 94). Bone and joint abnormalities occur in β thalassemia, being most common in the major and intermedia groups. In one study, ~50% of patients with β thalassemia had evidence of symmetric ankle arthropathy characterized by a dull aching pain that was aggravated by weight bearing. The onset came most often in the second or third decade of life. The degree of ankle pain in these patients varied. Some patients experienced self-limited ankle pain that occurred only after strenuous physical activity and lasted several days or weeks. Other patients had chronic ankle pain that became worse with walking. Symptoms eventually abated in a few patients. Compression of the ankle, calcaneus, or forefoot was painful in some patients. Synovial fluid from two patients was noninflammatory. Radiographs of the ankle showed osteopenia, widened medullary spaces, thin cortices, and coarse trabeculations—findings that are largely the result of bone marrow expansion. The joint space was preserved. Specimens of bone from three patients revealed osteomalacia, osteopenia, and microfractures. Increased numbers of osteoblasts as well as increased foci of bone resorption were present on the bone surface. Iron staining was found in the bone trabeculae, in osteoid, and in the cement line. Synovium showed hyperplasia of lining cells, which contained deposits of hemosiderin. This arthropathy was considered to be related to the underlying bone pathology. The role of iron overload or abnormal bone metabolism in the pathogenesis of this arthropathy is not known. The arthropathy was treated with analgesics and splints. Patients also received transfusions to decrease hematopoiesis and bone marrow expansion.

In patients with β-thalassemia major and β-thalassemia intermedia, other joints are also involved, including the knees, hips, and shoulders. Acquired hemochromatosis with arthropathy has been described in a patient with thalassemia. Gouty arthritis and septic arthritis can occur. Avascular necrosis is not a feature of thalassemia because there is no sickling of red cells leading to thrombosis and infarction.

β-Thalassemia minor (also known as β-thalassemia trait) is likewise associated with joint manifestations. Chronic seronegative oligoarthritis affecting predominantly ankles, wrists, and elbows has been described; the affected patients had mild persistent synovitis without large effusions or joint erosions. Recurrent episodes of acute asymmetric arthritis have also been reported; episodes last <1 week and may affect the knees, ankles, shoulders, elbows, wrists, and metacarpal phalangeal joints. The mechanism underlying this arthropathy is unknown. Treatment with NSAIDs is not particularly effective.

MUSCULOSKELETAL DISORDERS ASSOCIATED WITH HYPERLIPIDEMIA

(See also Chap. 400) Musculoskeletal or cutaneous manifestations may be the first clinical indication of a specific hereditary disorder of lipoprotein metabolism. Patients with familial hypercholesterolemia (previously referred to as type II hyperlipoproteinemia) may have recurrent migratory polyarthritis involving the knees and other large peripheral joints and, to a lesser degree, peripheral small joints. Pain ranges from moderate to incapacitating. The involved joints can be warm, erythematous, swollen, and tender. Arthritis usually has a sudden onset, lasts from a few days to 2 weeks, and does not cause joint damage. Episodes may suggest acute gout attacks. Several attacks occur per year. Synovial fluid from involved joints is not inflammatory and contains few white cells and no crystals. Joint involvement may actually represent inflammatory periarthritis or peritendinitis and not true arthritis. The recurrent, transient nature of the arthritis may suggest rheumatic fever, especially because patients with hyperlipoproteinemia may have an elevated erythrocyte sedimentation rate and elevated antistreptolysin O titers (the latter being quite common). Attacks of tendinitis, including the large Achilles and patellar tendons, may come on gradually and last only a few days or may be acute as described above. Patients may be asymptomatic between attacks. Achilles tendinitis and other joint manifestations often precede the appearance of xanthomas and may be the first clinical indication of hyperlipoproteinemia. Attacks of tendinitis may follow treatment with a lipid-lowering drug. Over time, patients may develop tendinous xanthomas in the Achilles, patellar, and extensor tendons of the hands and feet. Xanthomas have also been reported in the peroneal tendon, the plantar aponeurosis, and the periosteum overlying the distal tibia. These xanthomas are located within tendon fibers. Tuberous xanthomas are soft subcutaneous masses located over the extensor surfaces of the elbows, knees, and hands as well as on the buttocks. They appear during childhood in homozygous patients and after the age of 30 in heterozygous patients. Patients with elevated plasma levels of very-low-density lipoprotein (VLDL) and triglycerides (previously referred to as type IV hyperlipoproteinemia) may also have a mild inflammatory arthritis affecting large and small peripheral joints, usually in an asymmetric pattern, with only a few joints involved at a time. The onset of arthritis usually comes in middle age. Arthritis may be persistent or recurrent, with episodes lasting a few days or weeks. Some patients may experience severe joint pain or morning stiffness. Joint tenderness and periarticular hyperesthesia may also be present, as may synovial thickening. Joint fluid is usually noninflammatory and without crystals but may have increased white blood cell counts with predominantly mononuclear cells. Radiographs may show juxtaarticular osteopenia and cystic lesions. Large bone cysts have been noted in a few patients. Xanthoma and bone cysts are also observed in other lipoprotein disorders. The pathogenesis of arthritis in patients with familial hypercholesterolemia or with elevated levels of VLDL and triglycerides is not well understood. NSAIDs or analgesics usually provide adequate relief of symptoms when used on an as-needed basis.

Patients may improve clinically as they are treated with lipid-lowering agents; however, patients treated with an HMG-CoA reductase inhibitor may experience myalgias, and a few patients develop myopathy, myositis, or even rhabdomyolysis. Patients who develop myositis during statin therapy may be susceptible to this adverse effect because of an underlying muscle disorder and should be reevaluated after discontinuation of the drug. Testing for anti-HMGCR autoantibodies in patients with elevated muscle enzymes on treatment may identify patients with statin-induced necrotizing autoimmune myopathy. Myositis has also been reported with the use of niacin (Chap. 358) but is less common than myalgias.

Musculoskeletal syndromes have not clearly been associated with the more common mixed hyperlipidemias seen in general practice.

OTHER ARTHRITIDES

NEUROPATHIC JOINT DISEASE

Neuropathic joint disease (Charcot joint) is a progressive destructive arthritis associated with loss of pain sensation, proprioception, or both. Normal muscular reflexes that modulate joint movement are impaired. Without these protective mechanisms, joints are subjected to repeated trauma, resulting in progressive cartilage and bone damage. Today, diabetes mellitus is the most frequent cause of neuropathic joint disease (Fig. 367-1). A variety of other disorders are associated with neuropathic arthritis, including tabes dorsalis, leprosy, yaws, syringomyelia, meningomyelocele, congenital indifference to pain, peroneal muscular atrophy (Charcot-Marie-Tooth disease), and amyloidosis. An arthritis resembling neuropathic joint disease has been reported in patients who have received intraarticular glucocorticoid injections, but this is a rare complication and was not observed in one series of patients with knee osteoarthritis who received intraarticular glucocorticoid injections every 3 months for 2 years. The distribution of joint involvement depends on the underlying neurologic disorder (Table 367-2). In tabes dorsalis, the knees, hips, and ankles are most commonly affected; in syringomyelia, the glenohumeral joint, elbow, and wrist; and in diabetes mellitus, the tarsal and tarsometatarsal joints.

PATHOLOGY AND PATHOPHYSIOLOGY

The pathologic changes in the neuropathic joint are similar to those found in the severe osteoarthritic joint. There is fragmentation and eventual loss of articular cartilage with eburnation of the underlying bone. Osteophytes are found at the joint margins. With more advanced disease, erosions are present on the joint surface. Fractures, devitalized bone, intraarticular loose bodies, and microscopic fragments of cartilage and bone may be present.

At least two underlying mechanisms are believed to be involved in the pathogenesis of neuropathic arthritis. An abnormal autonomic nervous system is thought to be responsible for the dysregulated blood flow to the joint with subsequent resorption of bone. Loss of bone, particularly in the diabetic foot, may be the initial finding. With the loss of deep pain, proprioception, and protective neuromuscular reflexes, the joint is subjected to repeated microtrauma, resulting in ligamental tears and bone fractures. The injury that follows frequent intraarticular glucocorticoid injections is thought to be due to the analgesic effect of glucocorticoids, leading to overuse of an already damaged joint; the result is accelerated cartilage damage, although steroid-induced cartilage damage is more common in some other animal species than in humans. It is not understood why only a few patients with neuropathy develop clinically evident neuropathic arthritis.

CLINICAL MANIFESTATIONS

Neuropathic joint disease usually begins in a single joint and then becomes apparent in other joints, depending on the underlying neurologic disorder. The involved joint becomes progressively enlarged as a result of bony overgrowth and synovial effusion. Loose bodies may be palpated in the joint cavity. Joint instability, subluxation, and crepitus occur as the disease progresses. Neuropathic joints may develop rapidly, and a totally disorganized joint with multiple bony fragments may evolve within weeks or months. The amount of pain experienced by the patient is less than would be anticipated from the degree of joint damage. Patients may experience sudden joint pain from intraarticular fractures of osteophytes or condyles.

Neuropathic arthritis is encountered most often in patients with diabetes mellitus, with an incidence of ~0.5%. The onset of disease usually comes at an age of ≥50 years in a patient who has had diabetes for several years, but exceptions occur. The tarsal and tarsometatarsal joints are most often affected, with the metatarsophalangeal and talotibial joints next most commonly involved. The knees and spine are occasionally involved. Patients often attribute the onset of foot pain to antecedent trauma such as twisting of the foot. Neuropathic changes may develop rapidly after a foot fracture or dislocation. The foot and ankle are often swollen. Downward collapse of the tarsal bones leads to convexity of the sole, referred to as a “rocker foot.” Large osteophytes may protrude from the top of the foot. Calluses frequently form over the metatarsal heads and may lead to infected ulcers and osteomyelitis. The value of protective inserts and orthotics, as well as regular foot examination, cannot be overstated. Radiographs may show resorption and tapering of the distal metatarsal bones. The term Lisfranc fracture-dislocation is sometimes used to describe the destructive changes at the tarsometatarsal joints.

DIAGNOSIS

The diagnosis of neuropathic arthritis is based on the clinical features and characteristic radiographic findings in a patient with underlying sensory neuropathy. The differential diagnosis of neuropathic arthritis depends upon the severity of the process and includes osteomyelitis, avascular necrosis, advanced osteoarthritis, stress fractures, and calcium pyrophosphate deposition disease. Radiographs in neuropathic arthritis initially show changes of osteoarthritis with joint space narrowing, subchondral bone sclerosis, osteophytes, and joint effusions; marked destructive and hypertrophic changes follow later. The radiographic findings of neuropathic arthritis may be difficult to differentiate from those of osteomyelitis, especially in the diabetic foot. The joint margins in a neuropathic joint tend to be distinct, while in osteomyelitis they are blurred. Imaging studies may be helpful, but cultures of tissue from the joint are often required to exclude osteomyelitis. MRI and bone scans using indium 111–labeled white blood cells or indium 111–labeled immunoglobulin G, which will show increased uptake in osteomyelitis but not in a neuropathic joint, may be useful. A technetium bone scan will not distinguish osteomyelitis from neuropathic arthritis, as increased uptake is observed in both. The joint fluid in neuropathic arthritis is noninflammatory; it may be xanthochromic or even bloody and may contain fragments of synovium, cartilage, and bone. The finding of calcium pyrophosphate dihydrate crystals supports the diagnosis of crystal-associated arthropathy. In the absence of such crystals, an increased number of leukocytes may indicate osteomyelitis.

TREATMENT

HYPERTROPHIC OSTEOARTHROPATHY AND CLUBBING

Hypertrophic osteoarthropathy (HOA) is characterized by clubbing of digits and, in more advanced stages, by periosteal new-bone formation and synovial effusions. HOA may be primary or familial and may begin in childhood. Secondary HOA is associated with intrathoracic malignancies, suppurative and some hypoxemic lung diseases, congenital heart disease, and a variety of other disorders. Clubbing is almost always a feature of HOA but can occur as an isolated manifestation (Fig. 367-2). The presence of clubbing in isolation may be congenital or represent either an early stage or one element in the spectrum of HOA. Isolated acquired clubbing has the same clinical significance as clubbing associated with periostitis.

Pathology and Pathophysiology of Acquired HOA

In HOA, bone changes in the distal extremities begin as periostitis followed by new bone formation. At this stage, a radiolucent area may be observed between the new periosteal bone and the subjacent cortex. As the process progresses, multiple layers of new bone are deposited and become contiguous with the cortex, with consequent cortical thickening. The outer portion of the bone is laminated in appearance, with an irregular surface. Initially, the process of periosteal new-bone formation involves the proximal and distal diaphyses of the tibia, fibula, radius, and ulna and, less frequently, the femur, humerus, metacarpals, metatarsals, and phalanges. Occasionally, scapulae, clavicles, ribs, and pelvic bones are also affected. The adjacent interosseous membranes may become ossified. The distribution of bone manifestations is usually bilateral and symmetric. The soft tissue overlying the distal third of the arms and legs may be thickened. Proliferation of connective tissue occurs in the nail bed and volar pad of digits, giving the distal phalanges a clubbed appearance. Small blood vessels in the clubbed digits are dilated and have thickened walls. In addition, the number of arteriovenous anastomoses is increased.

Several theories have been suggested for the pathogenesis of HOA, but many have been disproved or have not explained the condition’s development in all clinical disorders with which it is associated. Previously proposed neurogenic and humoral theories are no longer considered likely explanations for HOA. Studies have suggested a role for platelets in the development of HOA. It has been observed that megakaryocytes and large platelet particles present in the venous circulation are fragmented in their passage through normal lung. In patients with cyanotic congenital heart disease and in other disorders associated with right-to-left shunts, these large platelet particles bypass the lung and reach the distal extremities, where they can interact with endothelial cells. Platelet–endothelial cell activation in the distal portion of the extremities may result in the release of platelet-derived growth factor (PDGF) and other factors leading to the proliferation of connective tissue and periosteum. Stimulation of fibroblasts by PDGF and transforming growth factor β results in cell growth and collagen synthesis. Elevated plasma levels of von Willebrand factor antigen have been found in patients with both primary and secondary forms of HOA, indicating endothelial activation or damage. Abnormalities of collagen synthesis have been demonstrated in the involved skin of patients with primary HOA. Other factors are undoubtedly involved in the pathogenesis of HOA, and further studies are needed to elucidate this disorder.

Clinical Manifestations

Primary or familial HOA, also referred to as pachydermoperiostitis or Touraine-Solente-Golé syndrome, usually begins insidiously at puberty. In a smaller proportion of patients, the onset comes in the first year of life. The disorder is inherited as an autosomal dominant trait with variable expression and is nine times more common among boys than among girls. Approximately one-third of patients have a family history of primary HOA.

Primary HOA is characterized by clubbing, periostitis, and unusual skin features. A small number of patients with this syndrome do not express clubbing. The skin changes and periostitis are prominent features of this syndrome. The skin becomes thickened and coarse. Deep nasolabial folds develop, and the forehead may become furrowed. Patients may have heavy-appearing eyelids and ptosis. The skin is often greasy, and there may be excessive sweating of the hands and feet. Patients may also experience acne vulgaris, seborrhea, and folliculitis. In a few patients, the skin over the scalp becomes very thick and corrugated, a feature that has been descriptively termed cutis verticis gyrata. The distal extremities, particularly the legs, become thickened as a consequence of the proliferation of new bone and soft tissue; when the process is extensive, the distal lower extremities resemble those of an elephant. The periostitis usually is not painful, which it can be in secondary HOA. Clubbing of the fingers may be extensive, producing large, bulbous deformities, and clumsiness. Clubbing also affects the toes. Patients may experience articular and periarticular pain, especially in the ankles and knees, and joint motion may be mildly restricted by periarticular bone overgrowth. Noninflammatory effusions occur in the wrists, knees, and ankles. Synovial hypertrophy is not found. Associated abnormalities observed in patients with primary HOA include hypertrophic gastropathy, bone marrow failure, female escutcheon, gynecomastia, and cranial suture defects. In patients with primary HOA, the symptoms disappear when adulthood is reached.

HOA secondary to an underlying disease occurs more frequently than primary HOA. It accompanies a variety of disorders and may precede clinical features of the associated disorder by months. Clubbing is more frequent than the full syndrome of HOA in patients with associated illnesses. Because clubbing evolves over months and is usually asymptomatic, it is often recognized first by the physician and not the patient. Patients may experience a burning sensation in their fingertips. Clubbing is characterized by widening of the fingertips, enlargement of the distal volar pad, convexity of the nail contour, and the loss of the normal 15° angle between the proximal nail and cuticle. The thickness of the digit at the base of the nail is greater than the thickness at the distal interphalangeal joint. An objective measurement of finger clubbing can be made by determining the diameter at the base of the nail and at the distal interphalangeal joint of all 10 digits. Clubbing is present when the sum of the individual digit ratios is >10. At the bedside, clubbing can be appreciated by having the patient place the dorsal surface of the distal phalanges of the fourth fingers together with the nails opposing each other. Normally, an open area is visible between the bases of the opposing fingernails; when clubbing is present, this open space is no longer visible. The base of the nail feels spongy when compressed, and the nail can be easily rocked on its bed. When clubbing is advanced, the finger may have a drumstick appearance, and the distal interphalangeal joint can be hyperextended. Periosteal involvement in the distal extremities may produce a burning or deep-seated aching pain. The pain, which can be quite incapacitating, is aggravated by dependency and relieved by elevation of the affected limbs. Pressure applied over the distal forearms and legs or gentle percussion of distal long bones like the tibia may be quite painful.

Patients may experience joint pain, most often in the ankles, wrists, and knees. Joint effusions may be present; usually, they are small and noninflammatory. The small joints of the hands are rarely affected. Severe joint or long bone pain may be the presenting symptom of an underlying lung malignancy and may precede the appearance of clubbing. In addition, the progression of HOA tends to be more rapid when associated with malignancies, most notably bronchogenic carcinoma. Noninflammatory but variably painful knee effusions may occur prior to the appearance of clubbing and symptoms of distal periostitis. Unlike primary HOA, secondary HOA does not commonly include excessive sweating and oiliness of the skin or thickening of the facial skin.

HOA occurs in 5–10% of patients with intrathoracic malignancies, the most common being bronchogenic carcinoma and pleural tumors (Table 367-3). Lung metastases infrequently cause HOA. HOA is also seen in patients with intrathoracic infections, including lung abscesses, empyema, and bronchiectasis, but is uncommon in pulmonary tuberculosis. HOA may accompany chronic interstitial pneumonitis, sarcoidosis, and cystic fibrosis. In cystic fibrosis, clubbing is more common than the full syndrome of HOA. Other causes of clubbing include congenital heart disease with right-to-left shunts, bacterial endocarditis, Crohn’s disease, ulcerative colitis, sprue, and neoplasms of the esophagus, liver, and small and large bowel. In patients who have congenital heart disease with right-to-left shunts, clubbing alone occurs more often than the full syndrome of HOA.

Unilateral clubbing has been found in association with aneurysms of major extremity arteries, with infected arterial grafts, and with arteriovenous fistulas of brachial vessels. Clubbing of the toes but not the fingers has been associated with an infected abdominal aortic aneurysm and patent ductus arteriosus. Clubbing of a single digit may follow trauma and has been reported in tophaceous gout and sarcoidosis. While clubbing occurs more commonly than the full syndrome in most diseases, periostitis in the absence of clubbing has been observed in the affected limb of patients with infected arterial grafts.

Hyperthyroidism (Graves’ disease), treated or untreated, is occasionally associated with clubbing and periostitis of the bones of the hands and feet. This condition is referred to as thyroid acropachy. Periostitis may be asymptomatic and occurs in the midshaft and diaphyseal portion of the metacarpal and phalangeal bones. Significant hand-joint pain may occur; this pain may respond to successful therapy for thyroid dysfunction. The long bones of the extremities are seldom affected. Elevated levels of long-acting thyroid stimulator are found in the sera of these patients.

Laboratory Findings

The laboratory abnormalities reflect the underlying disorder. The synovial fluid of involved joints has <500 white cells/μL, and the cells are predominantly mononuclear. Radiographs show a faint radiolucent line beneath the new periosteal bone along the shaft of long bones at their distal end. These changes are observed most frequently at the ankles, wrists, and knees. The ends of the distal phalanges may show osseous resorption. Radionuclide studies show pericortical linear uptake along the cortical margins of long bones that may precede any radiographic changes.

TREATMENT

REFLEX SYMPATHETIC DYSTROPHY SYNDROME

The reflex sympathetic dystrophy syndrome is now referred to as complex regional pain syndrome, type 1, according to the new classification system of the International Association for the Study of Pain. This syndrome is characterized by pain and swelling, usually of a distal extremity, accompanied by vasomotor instability, trophic skin changes, and the rapid development of bony demineralization. Reflex sympathetic dystrophy syndrome, including its treatment, is covered in greater detail in Chap. 432.

TIETZE SYNDROME AND COSTOCHONDRITIS

Tietze syndrome is manifested by painful swelling of one or more costochondral articulations. The age of onset is usually before 40, and both sexes are affected equally. In most patients, only one joint is involved, usually the second or third costochondral joint. The onset of anterior chest pain may be sudden or gradual. The pain may radiate to the arms or shoulders and is aggravated by sneezing, coughing, deep inspirations, or twisting motions of the chest. The term costochondritis is often used interchangeably with Tietze syndrome, but some workers restrict the former term to pain of the costochondral articulations without swelling. Costochondritis is observed in patients aged >40 years; it tends to affect the third, fourth, and fifth costochondral joints, and occurs more often in women. Both syndromes may mimic cardiac or upper abdominal causes of pain. Rheumatoid arthritis, ankylosing spondylitis, and reactive arthritis may involve costochondral joints but are distinguished easily by their other clinical features. Other skeletal causes of anterior chest wall pain are xiphoidalgia and the slipping rib syndrome, which usually involves the tenth rib. Malignancies such as breast cancer, prostate cancer, plasma cell cytoma, and sarcoma can invade the ribs, thoracic spine, or chest wall and produce symptoms suggesting Tietze’s syndrome. Patients with osteomalacia may have significant rib pain, with or without documented microfractures. These conditions should be distinguishable by radiography, bone scanning, vitamin D measurement, or biopsy. Analgesics, anti-inflammatory drugs, and local glucocorticoid injections usually relieve symptoms of costochondritis/Tietze’s syndrome. Care should be taken to avoid overdiagnosing these syndromes in patients with acute chest pain syndromes; many patients will be tender to overly vigorous palpation of the costochondral joints.

MYOFASCIAL PAIN SYNDROME

Myofascial pain syndrome is characterized by multiple areas of localized musculoskeletal pain and tenderness in association with tender points. The pain is deep and aching and may be accompanied by a burning sensation. Myofascial pain may be regional and follow trauma, overuse, or prolonged static contraction of a muscle or muscle group, which may occur when an individual is reading or writing at a desk or working at a computer. In addition, this syndrome may be associated with underlying osteoarthritis of the neck or low back. Pain may be referred from tender points to defined areas distant from the area of original tenderness. Palpation of the tender point reproduces or accentuates the pain. The tender points are usually located in the center of a muscle belly, but they can occur at other sites such as costosternal junctions, the xiphoid process, ligamentous and tendinous insertions, fascia, and fatty areas. Tender point sites in muscle have been described as feeling indurated and taut, and palpation may cause the muscle to twitch. These findings, however, have been shown not to be unique to myofascial pain syndrome: in a controlled study, they were also present in some “normal” subjects. Myofascial pain most often involves the posterior neck, low back, shoulders, and chest. Chronic pain in the muscles of the posterior neck may involve referral of pain from a tender point in the erector neck muscle or upper trapezius to the head, leading to persistent headaches that may last for days. Tender points in the paraspinal muscles of the low back may refer pain to the buttock. Pain may be referred down the leg from a tender point in the gluteus medius and can mimic sciatica. A tender point in the infraspinatus muscle may produce local and referred pain over the lateral deltoid and down the outside of the arm into the hand. Injection of a local anesthetic such as 1% lidocaine into the tender point site often results in at least transient pain relief. Another useful technique is first to spray an agent such as ethyl chloride from the tender point toward the area of referred pain and then to stretch the muscle. This maneuver may need to be repeated several times. Massage and application of ultrasound to the affected area also may be beneficial. Patients should be instructed in methods to prevent muscle stresses related to work and recreation. Posture and resting positions are important in preventing muscle tension. The prognosis in most patients is good. In some patients, regionally localized myofascial pain syndrome may seem to evolve into more generalized fibromyalgia (Chap. 366). Abnormal or nonrestorative sleep is a common accompaniment in these patients and may need to be specifically addressed.

NEOPLASIAS AND ARTHRITIS

Primary tumors and tumor-like disorders of synovium are uncommon but should be considered in the differential diagnosis of monarticular joint disease. In addition, metastases to bone and primary bone tumors adjacent to a joint may produce joint symptoms.

Pigmented villonodular synovitis (PVNS) is characterized by the slowly progressive, exuberant, benign proliferation of synovial tissue, usually involving a single joint. The most common age of onset is in the third decade, and women are affected slightly more often than men. The cause of this disorder is unknown.

The synovium has a brownish color and numerous large, fingerlike villi that fuse to form pedunculated nodules. There is marked hyperplasia of synovial cells in the stroma of the villi. Hemosiderin granules and lipids are found in the cytoplasm of macrophages and in the interstitial tissue. Multinucleated giant cells may be present. The proliferative synovium grows into the subsynovial tissue and invades adjacent cartilage and bone.

The clinical picture of PVNS is characterized by the insidious onset of persistent swelling and pain in affected joints, most commonly the knee. Other joints affected include the hips, ankles, calcaneocuboid joints, elbows, and small joints of the fingers or toes. The disease may also involve the common flexor sheath of the hands or fingers. Less often, tendon sheaths in the wrist, ankle, or foot may be involved. Symptoms of pain, a catching sensation, or stiffness may initially be mild and intermittent and may be present for years before the patient seeks medical attention. Radiographs may show joint space narrowing, erosions, and subchondral cysts. The diagnosis of PVNS is strongly suggested by gradient echo MRI, which reveals a synovial mass lesion of low signal intensity typical of tissue containing hemosiderin (Fig. 367-3). The joint fluid contains blood and is dark red or almost black in color. Lipid-containing macrophages may be present in the fluid. The joint fluid may be clear if hemorrhage has not occurred. Some patients have polyarticular involvement.

The treatment for PVNS is complete synovectomy. With incomplete synovectomy, the villonodular synovitis recurs, and the rate of tissue growth may be faster than it was originally. Irradiation of the involved joint has been successful in some patients.

Synovial chondromatosis is a disorder characterized by multiple focal metaplastic growths of normal-appearing cartilage in the synovium or tendon sheath. Segments of cartilage break loose and continue to grow as loose bodies. When calcification and ossification of loose bodies occur, the disorder is referred to as synovial osteochondromatosis. The disorder is usually monarticular and affects young to middle-aged individuals. The knee is most often involved, followed by hip, elbow, and shoulder. Symptoms are pain, swelling, and decreased motion of the joint. Radiographs may show several rounded calcifications within the joint cavity. Treatment is synovectomy; however, as in PVNS, the tumor may recur.

Synovial sarcoma is a malignant neoplasm often found near a large joint of both upper and lower extremities, being more common in the lower extremity. It seldom arises within the joint itself. Synovial sarcomas constitute 10% of soft tissue sarcomas. The tumor is believed to arise from primitive mesenchymal tissue that differentiates into epithelial cells and/or spindle cells. Small foci of calcification may be present in the tumor mass. Synovial sarcoma occurs most often in young adults and is more common in men. The tumor presents as a slowly growing deep-seated mass near a joint, without much pain. The area of the knee is the most common site, followed by the foot, ankle, elbow, and shoulder. Other primary sites include the buttocks, abdominal wall, retroperitoneum, and mediastinum. The tumor spreads along tissue planes. The most common site of visceral metastasis is the lung. The diagnosis is made by biopsy. Treatment consists of wide resection of the tumor, including adjacent muscle and regional lymph nodes, followed by chemotherapy and radiation therapy. Amputation of the involved distal extremity may be required. Chemotherapy may be beneficial in some patients with metastatic disease. Isolated sites of pulmonary metastasis can be surgically removed. The 5-year survival rate with treatment is variable and depends on the staging of the tumor, ranging from ~25% to ≥60%. Synovial sarcomas tend to recur locally and metastasize to regional lymph nodes, lungs, and skeleton.

In addition to the rare direct metastases of solid cell tumors to the highly vascular synovium, neoplasia arising from nonarticular organ sites can affect joints in other ways. Acute leukemias in children can mimic juvenile inflammatory arthritis with severe joint pain and fever. In adults, chronic and acute myeloid leukemia can infiltrate the synovium in rare instances. The rarely occurring hairy cell leukemia has a peculiar tendency to cause episodic inflammatory oligoarthritis and tenosynovitis; these episodes are dramatic and mimic acute gout attacks. They respond to potent anti-inflammatory therapy with glucocorticoids; with remission of the leukemia, they may abate. Carcinomas can be associated with several paraneoplastic articular syndromes, including HOA (discussed above). Acute palmar fasciitis with polyarthritis is a well-described but rare condition associated with certain cancers, mainly adenocarcinomas. Clinically, this syndrome is fairly abrupt in onset, with pain in the metacarpophalangeal and proximal interphalangeal joints of the hands and rapidly evolving contractures of the fingers due to thickening of the palmar (flexor) tendons. A similar syndrome can be seen in diabetics. Paraneoplastic arthritis has been described and may occur in several patterns: asymmetric disease predominantly affecting the lower extremity joints and symmetric polyarthritis with hand joint involvement. Tumors are often found after the onset of the arthritis, and many patients have a preceding period of malaise or weight loss. The onset is often acute, and patients tend to be older men. These features should raise the specter of an underlying malignancy (or a viral infection such as hepatitis C) as the cause of the arthritis. In one series, the symptoms resolved with successful therapy for the malignancy and did not recur with relapse of the malignancy. Dermatomyositis has a well-described association with neoplasms and may include joint pain and arthritis. Malignancy-associated arthritis may be responsive to NSAIDs and to treatment of the primary neoplasm.

ACKNOWLEDGMENT

This chapter represents a revised version of the chapter authored by Dr. Bruce C. Gilliland that appeared in previous editions of Harrison’s. Dr. Gilliland passed away on February 17, 2007. He had been a contributor to Harrison’s Principles of Internal Medicine since the 11th edition.

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DEFINITION

Fibromyalgia (FM) is characterized by chronic widespread musculoskeletal pain and tenderness. Although FM is defined primarily as a pain syndrome, patients also commonly report associated neuro-psychological symptoms of fatigue, unrefreshing sleep, cognitive dysfunction, anxiety, and depression. Patients with FM have an increased prevalence of other syndromes associated with pain and fatigue, including chronic fatigue syndrome (Chap. 442), temporomandibular disorder, chronic headaches, irritable bowel syndrome, interstitial cystitis/painful bladder syndrome, and other pelvic pain syndromes. Available evidence implicates the central nervous system as key to maintaining pain and other core symptoms of FM and related conditions. The presence of FM is associated with substantial negative consequences for physical and social functioning.

EPIDEMIOLOGY

In clinical settings, a diagnosis of FM is made in ~2% of the population and is far more common in women than in men, with a ratio of ~9:1. However, in population-based survey studies worldwide, the prevalence rate is ~2–5%, with a female-to-male ratio of only 2–3:1 and with some variability depending on the method of ascertainment. The prevalence data are similar across socioeconomic classes. Cultural factors may play a role in determining whether patients with FM symptoms seek medical attention; however, even in cultures in which secondary gain is not expected to play a significant role, the prevalence of FM remains in this range.

CLINICAL MANIFESTATIONS

Pain and Tenderness

At presentation, patients with FM most commonly report “pain all over.” These patients have pain that is typically both above and below the waist on both sides of the body and involves the axial skeleton (neck, back, or chest). The pain attributable to FM is poorly localized, difficult to ignore, severe in its intensity, and associated with a reduced functional capacity. For a diagnosis of FM, pain should have been present most of the day on most days for at least 3 months.

The pain of FM is associated with tenderness and increased evoked pain sensitivity. In clinical practice, this elevated sensitivity may be identified by pain induced by the pressure of a blood pressure cuff or skin roll tenderness. More formally, an examiner may complete a tender-point examination in which the examiner uses the thumbnail to exert pressure of ~4 kg/m² (or the amount of pressure leading to blanching of the tip of the thumbnail) on well-defined musculotendinous sites (Fig. 366-1). Previously, the classification criteria of the American College of Rheumatology required that 11 of 18 sites be perceived as painful for a diagnosis of FM. In practice, tenderness is a continuous variable, and strict application of a categorical threshold for diagnostic specifics is not necessary. Newer criteria eliminate the need for identification of tender points and focus instead on clinical symptoms of widespread or multi-site pain and neuropsychological symptoms. The newer criteria perform well in a clinical setting in comparison to the older, tender-point criteria. However, it appears that when the new criteria are applied to populations, the result is an increase in prevalence of FM and a change in the sex ratio (see “Epidemiology,” earlier).

Patients with FM often have peripheral pain generators that are thought to serve as triggers for the more widespread pain attributed to central nervous system factors. Potential pain generators such as arthritis, bursitis, tendinitis, neuropathies, and other inflammatory or degenerative conditions should be identified by history and physical examination. More subtle pain generators may include joint hypermobility and scoliosis. In addition, patients may have chronic myalgias triggered by infectious, metabolic, or psychiatric conditions that can serve as triggers for the development of FM. These conditions are often identified in the differential diagnosis of patients with FM, and a major challenge is to distinguish the ongoing activity of a triggering condition from FM that is occurring as a consequence of a comorbid condition and that should itself be treated.

Neuropsychological Symptoms

In addition to widespread pain, FM patients typically report fatigue, stiffness, sleep disturbance, cognitive dysfunction, anxiety, and depression. These symptoms are present to varying degrees in most FM patients but are not present in every patient or at all times in a given patient. Relative to pain, such symptoms may, however, have an equal or even greater impact on function and quality of life. Fatigue is highly prevalent in patients under primary care who ultimately are diagnosed with FM. Pain, stiffness, and fatigue often are worsened by exercise or unaccustomed activity (postexertional malaise). The sleep complaints include difficulty falling asleep, difficulty staying asleep, and early-morning awakening. Regardless of the specific complaint, patients awake feeling unrefreshed. Patients with FM may meet criteria for restless legs syndrome and sleep-disordered breathing; frank sleep apnea can also be documented. Cognitive issues are characterized as difficulties with attention or concentration, problems with word retrieval, and short-term memory loss. Studies have demonstrated altered cognitive function in these domains in patients with FM, though speed of processing is age-appropriate. Symptoms of anxiety and depression are common, and the lifetime prevalence of mood disorders in patients with FM approaches 80%. Although depression is neither necessary nor sufficient for the diagnosis of FM, it is important to screen for major depressive disorders by querying for depressed mood and anhedonia. Analysis of genetic factors that are likely to predispose to FM reveals shared neurobiologic pathways with mood disorders, providing the basis for comorbidity (see later in this chapter).

Overlapping Syndromes

Because FM can overlap in presentation with other chronic pain conditions, review of systems often reveals headaches, facial/jaw pain, regional myofascial pain particularly involving the neck or back, and arthritis. Visceral pain involving the gastrointestinal tract, bladder, and pelvic or perineal region is often present as well. Patients may or may not meet defined criteria for specific syndromes. It is important for patients to understand that shared pathways may mediate symptoms and treatment strategies effective for one condition may help with global symptom management.

Comorbid Conditions

FM is often comorbid with chronic musculoskeletal, infectious, metabolic, or psychiatric conditions. Whereas FM affects only 2–5% of the general population, it occurs in ≥20% of patients with degenerative or inflammatory rheumatic disorders, likely because these conditions serve as peripheral pain generators to alter central pain-processing pathways. Similarly, chronic infectious, metabolic, or psychiatric diseases associated with musculoskeletal pain can mimic FM and/or serve as a trigger for the development of FM. It is particularly important for clinicians to be sensitive to pain management of these comorbid conditions so that when FM emerges—characterized by pain outside the boundaries of what could reasonably be explained by the triggering condition, development of neuropsychological symptoms, or tenderness on physical examination—treatment of central pain processes will be undertaken as opposed to a continued focus on treatment of peripheral or inflammatory causes of pain.

Psychosocial Considerations

Symptoms of FM often have their onset and are exacerbated during periods of perceived stress. This pattern may reflect an interaction among central stress physiology, vigilance or anxiety, and central pain-processing pathways. An understanding of current psychosocial stressors will aid in patient management, as many factors that exacerbate symptoms cannot be addressed by pharmacologic approaches. Furthermore, there is a high prevalence of exposure to previous interpersonal and other forms of violence in patients with FM and related conditions. If posttraumatic stress disorder is an issue, the clinician should be aware of it and consider treatment options.

Functional Impairment

It is crucial to evaluate the impact of FM symptoms on function and role fulfillment. In defining the success of a management strategy, improved function is a key measure. Functional assessment should include physical, mental, and social domains. Recognition of the ways in which role functioning falls short will be helpful in the establishing treatment goals.

DIFFERENTIAL DIAGNOSIS

Because musculoskeletal pain is such a common complaint, the differential diagnosis of FM is broad. Table 366-1 lists some of the more common conditions that should be considered. Patients with inflammatory causes for widespread pain should be identifiable on the basis of specific history, physical findings, and laboratory or radiographic tests.

LABORATORY OR RADIOGRAPHIC TESTING

Routine laboratory and radiographic tests yield normal results in FM. Thus diagnostic testing is focused on exclusion of other diagnoses and evaluation for pain generators or comorbid conditions (Table 366-2). Most patients with new chronic widespread pain should be assessed for the most common entities in the differential diagnosis. Radiographic testing should be used sparingly and only for diagnosis of inflammatory arthritis. After the patient has been evaluated thoroughly, repeat testing is discouraged unless the symptom complex changes. Particularly to be discouraged is magnetic resonance imaging (MRI) of the spine unless there are features suggesting inflammatory spine disease or neurologic symptoms.

GENETICS AND PHYSIOLOGY

As in most complex diseases, it is likely that a number of genes contribute to vulnerability to the development of FM. To date, these genes appear to be in pathways controlling pain and stress responses. Some of the genetic underpinnings of FM are shared across other chronic pain conditions. Genes associated with metabolism, transport, and receptors of serotonin and other monoamines have been implicated in FM and overlapping conditions. Genes associated with other pathways involved in pain transmission have also been described as vulnerability factors for FM. Taken together, the pathways in which polymorphisms have been identified in FM patients further implicate central factors in mediation of the physiology that leads to the clinical manifestations of FM.

Psychophysical testing of patients with FM has demonstrated altered sensory afferent pain processing and impaired descending noxious inhibitory control leading to hyperalgesia and allodynia. Functional MRI and other research imaging procedures clearly demonstrate activation of the brain regions involved in the experience of pain in response to stimuli that are innocuous in study participants without FM. Pain perception in FM patients is influenced by the emotional and cognitive dimensions, such as catastrophizing and perceptions of control, providing a solid basis for recommendations for cognitive and behavioral treatment strategies.

Studies have indicated that some patients meeting criteria for FM may have a small fiber neuropathy. Other studies have identified alterations in expressed gene signatures in peripheral blood. These early studies raise the possibility that confirmatory diagnostic testing could be developed to assist in the diagnosis of FM.

APPROACH TO THE PATIENT

TREATMENT

PHARMACOLOGIC APPROACHES

It is essential for the clinician to treat any comorbid triggering condition and to clearly delineate for the patient the treatment goals for each medication. For example, glucocorticoids or nonsteroidal anti-inflammatory drugs may be useful for management of inflammatory triggers but are not effective against FM-related symptoms. At present, the treatment approaches that have proved most successful in FM patients target afferent or descending pain pathways. Table 366-3 lists the drugs with demonstrated effectiveness. It should be emphasized that strong opioid analgesics are to be avoided in patients with FM. These agents have no demonstrated efficacy in FM and are associated with adverse effects that can worsen both symptoms and function. Tramadol, an opioid with mild serotonin-noradrenaline reuptake inhibitor activity has been studied in this population with indication of efficacy. Use of single agents to treat multiple symptom domains is strongly encouraged. For example, if a patient’s symptom complex is dominated by pain and sleep disturbance, use of an agent that exerts both analgesic and sleep-promoting effects is desirable. These agents include cyclobenzaprine, sedating antidepressants such as amitriptyline, and alpha-2-delta ligands such as gabapentin and pregabalin. For patients whose pain is associated with fatigue, anxiety, or depression, drugs that have both analgesic and antidepressant/anxiolytic effects, such as duloxetine or milnacipran, may be the best first choice.

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INTRODUCTION

Periarticular disorders are common musculoskeletal abnormalities that can affect people throughout a wide range of ages. This chapter discusses some of the more common periarticular disorders.

BURSITIS

Bursitis is inflammation of a bursa, which is a thin-walled sac lined with synovial tissue. The function of the bursa is to facilitate movement of tendons and muscles over bony prominences. Excessive frictional forces from overuse, trauma, systemic disease (e.g., rheumatoid arthritis, gout), or infection may cause bursitis. Subacromial bursitis (subdeltoid bursitis) is the most common form of bursitis. The subacromial bursa, which is contiguous with the subdeltoid bursa, is located between the undersurface of the acromion and the humeral head and is covered by the deltoid muscle. Bursitis often accompanies rotator cuff tendinitis. Another frequently encountered form is trochanteric bursitis, which involves the bursa around the insertion of the gluteus medius onto the greater trochanter of the femur. Patients experience pain over the lateral aspect of the hip and upper thigh and have tenderness over the posterior aspect of the greater trochanter. External rotation and resisted abduction of the hip elicit pain as will direct pressure applied to the bursa. Olecranon bursitis occurs over the posterior elbow, and when the area is acutely inflamed, infection or gout should be excluded by aspirating the bursa and performing a Gram stain and culture on the fluid as well as examining the fluid for urate crystals. Achilles bursitis involves the bursa located above the insertion of the tendon to the calcaneus and results from overuse and wearing tight shoes. Retrocalcaneal bursitis involves the bursa that is located between the calcaneus and posterior surface of the Achilles tendon. The pain is experienced at the back of the heel, and swelling appears on the medial and/or lateral side of the tendon. It occurs in association with spondyloarthritides, rheumatoid arthritis, gout, or trauma. Ischial bursitis affects the bursa separating the gluteus medius from the ischial tuberosity and develops from prolonged sitting and pivoting on hard surfaces. Iliopsoas bursitis affects the bursa that lies between the iliopsoas muscle and hip joint and is lateral to the femoral vessels. Pain is experienced over this area and is made worse by hip extension and flexion. Anserine bursitis is an inflammation of the sartorius bursa located over the medial side of the tibia just below the knee and under the conjoint tendon and is manifested by pain on climbing stairs. Tenderness is present over the insertion of the conjoint tendon of the sartorius, gracilis, and semitendinosus. Prepatellar bursitis occurs in the bursa situated between the patella and overlying skin and is caused by kneeling on hard surfaces. Gout or infection may also occur at this site. Bursitis is typically diagnosed by history and physical examination, but visualization by ultrasound may play a useful role in selected instances for diagnosis and directed guidance of glucocorticoid injection. Treatment of bursitis consists of prevention of any aggravating situation, rest of the involved part, administration of a nonsteroidal anti-inflammatory drug (NSAID) where appropriate for an individual patient, or local glucocorticoid injection.

ROTATOR CUFF TENDINITIS AND IMPINGEMENT SYNDROME

Tendinitis of the rotator cuff is the major cause of a painful shoulder and is currently thought to be caused by inflammation of the tendon(s). The rotator cuff consists of the tendons of the supraspinatus, infraspinatus, subscapularis, and teres minor muscles, and inserts on the humeral tuberosities. Of the tendons forming the rotator cuff, the supraspinatus tendon is the most often affected, probably because of its repeated impingement (impingement syndrome) between the humeral head and the undersurface of the anterior third of the acromion and coracoacromial ligament above as well as the reduction in its blood supply that occurs with abduction of the arm (Fig. 368-1). The tendon of the infraspinatus and that of the long head of the biceps are less commonly involved. Subacromial bursitis also accompanies this syndrome. Symptoms can appear without a triggering cause or after injury or overuse, especially with activities involving elevation of the arm with some degree of forward flexion. Impingement syndrome occurs in persons participating in baseball, tennis, swimming, or occupations that require repeated elevation of the arm. Those aged >40 years are particularly susceptible. Patients complain of a dull aching in the shoulder, which may interfere with sleep. Severe pain is experienced when the arm is actively abducted into an overhead position. The arc between 60° and 120° is especially painful. Tenderness is present over the lateral aspect of the humeral head just below the acromion. NSAIDs, local glucocorticoid injection, and physical therapy may relieve symptoms. Surgical decompression of the subacromial space may be necessary in patients refractory to conservative treatment.

Patients may tear the supraspinatus tendon acutely by falling on an outstretched arm or lifting a heavy object. Symptoms are pain along with weakness of abduction and external rotation of the shoulder. Atrophy of the supraspinatus muscles develops. The diagnosis is established by ultrasound, magnetic resonance imaging (MRI), or arthrogram. Surgical repair may be necessary in patients who fail to respond to conservative measures. In patients with moderate-to-severe tears and functional loss, surgery is indicated.

CALCIFIC TENDINITIS

This condition is characterized by deposition of calcium salts, primarily hydroxyapatite, within a tendon. The exact mechanism of calcification is not known but may be initiated by ischemia or degeneration of the tendon. The supraspinatus tendon is most often affected because it is frequently impinged on and has a reduced blood supply when the arm is abducted. The condition usually develops after age 40. Calcification within the tendon may evoke acute inflammation, producing sudden and severe pain in the shoulder. However, it may be asymptomatic or not related to the patient’s symptoms. Diagnosis of calcific tendonitis can be made by ultrasound or radiograph. Most cases are self-limited and respond to conservative therapy with physical therapy and/or NSAIDs. A subset of patients is refractory and requires ultrasound-guided percutaneous needle aspiration and lavage or surgery.

BICIPITAL TENDINITIS AND RUPTURE

Bicipital tendinitis, or tenosynovitis, is produced by friction on the tendon of the long head of the biceps as it passes through the bicipital groove. When the inflammation is acute, patients experience anterior shoulder pain that radiates down the biceps into the forearm. Abduction and external rotation of the arm are painful and limited. The bicipital groove is very tender to palpation. Pain may be elicited along the course of the tendon by resisting supination of the forearm with the elbow at 90° (Yergason’s supination sign). Acute rupture of the tendon may occur with vigorous exercise of the arm and is often painful. In a young patient, it should be repaired surgically. Rupture of the tendon in an older person may be associated with little or no pain and is recognized by the presence of persistent swelling of the biceps produced by the retraction of the long head of the biceps. Surgery is usually not necessary in this setting.

DE QUERVAIN’S TENOSYNOVITIS

In this condition, inflammation involves the abductor pollicis longus and the extensor pollicis brevis as these tendons pass through a fibrous sheath at the radial styloid process. The usual cause is repetitive twisting of the wrist. It may occur in pregnancy, and it also occurs in mothers who hold their babies with the thumb outstretched. Patients experience pain on grasping with their thumb, such as with pinching. Swelling and tenderness are often present over the radial styloid process. The Finkelstein sign is positive, which is elicited by having the patient place the thumb in the palm and close the fingers over it. The wrist is then ulnarly deviated, resulting in pain over the involved tendon sheath in the area of the radial styloid. Treatment consists initially of splinting the wrist and an NSAID. When severe or refractory to conservative treatment, glucocorticoid injections can be very effective.

PATELLAR TENDINITIS

Tendinitis involves the patellar tendon at its attachment to the lower pole of the patella. Patients may experience pain when jumping during sports, going up stairs, or doing deep knee squats. Tenderness is noted on examination over the lower pole of the patella. Treatment consists of rest, icing, and NSAIDs, followed by strengthening and increasing flexibility.

DRUG-INDUCED TENDINOPATHIES

With the broadening range of available pharmacologic agents, the potential for drug-induced tendinopathies has become increasingly recognized. The drug classes most associated with tendinopathies include quinolones, glucocorticoids, aromatase inhibitors, and statins. Although any tendon can be affected, the tendons of the lower extremities are most often impacted, particularly the Achilles tendon. The pathophysiological mechanisms responsible for drug-induced tendinopathies remain unknown. Presenting features include pain and potentially swelling over the tendon, although some patients may first present with tendon rupture. Ultrasound and MRI can provide information on tendon structure and integrity in support of the diagnosis. When suspected, the potential agent should be withdrawn and not reintroduced where possible in the overall medical management of the patient. Tendon ruptures may require surgery.

ILIOTIBIAL BAND SYNDROME

The iliotibial band is a thick connective tissue that runs from the ilium to the fibula. Patients with iliotibial band syndrome most commonly present with aching or burning pain at the site where the band courses over the lateral femoral condyle of the knee; pain may also radiate up the thigh, toward the hip. Predisposing factors for iliotibial band syndrome include a varus alignment of the knee, excessive running distance, poorly fitted shoes, or continuous running on uneven terrain. Treatment consists of rest, NSAIDs, physical therapy, and addressing risk factors such as shoes and running surface. Glucocorticoid injection into the area of tenderness can provide relief, but running must be avoided for at least 2 weeks after the injection. Surgical release of the iliotibial band has been helpful in rare patients for whom conservative treatment has failed.

ADHESIVE CAPSULITIS

Often referred to as “frozen shoulder,” adhesive capsulitis is characterized by pain and restricted movement of the shoulder, usually in the absence of intrinsic shoulder disease. Adhesive capsulitis may follow bursitis or tendinitis of the shoulder or be associated with systemic disorders such as chronic pulmonary disease, myocardial infarction, and diabetes mellitus. Prolonged immobility of the arm contributes to the development of adhesive capsulitis. Pathologically, the capsule of the shoulder is thickened, and a mild chronic inflammatory infiltrate and fibrosis may be present.

Adhesive capsulitis occurs more commonly in women aged >50 years. Pain and stiffness usually develop gradually but progress rapidly in some patients. Night pain is often present in the affected shoulder, and pain may interfere with sleep. The shoulder is tender to palpation, and both active and passive movements are restricted. Radiographs of the shoulder show osteopenia. The diagnosis is typically made by physical examination but can be confirmed if necessary by arthrography, in that only a limited amount of contrast material, usually <15 mL, can be injected under pressure into the shoulder joint.

In most patients, the condition improves spontaneously 1–3 years after onset. While pain usually improves, many patients are left with some limitation of shoulder motion. Early mobilization of the arm following an injury to the shoulder may prevent the development of this disease. Physical therapy provides the foundation of treatment for adhesive capsulitis. Local injections of glucocorticoids and NSAIDs may also provide relief of symptoms. Slow but forceful injection of contrast material into the joint may lyse adhesions and stretch the capsule, resulting in improvement of shoulder motion. Manipulation under anesthesia may be helpful in some patients.

LATERAL EPICONDYLITIS

Lateral epicondylitis, also known as tennis elbow, is a painful condition involving the soft tissue over the lateral aspect of the elbow. The pain originates at or near the site of attachment of the common extensors to the lateral epicondyle and may radiate into the forearm and dorsum of the wrist. The pain usually appears after work or recreational activities involving repeated motions of wrist extension and supination against resistance. Most patients with this disorder injure themselves in activities other than tennis, such as pulling weeds, carrying suitcases or briefcases, or using a screwdriver. The injury in tennis usually occurs when hitting a backhand with the elbow flexed. Shaking hands and opening doors can reproduce the pain. Striking the lateral elbow against a solid object may also induce pain.

The treatment is usually rest along with administration of an NSAID. Ultrasound, icing, and friction massage may also help relieve pain. When pain is severe, the elbow is placed in a sling or splinted at 90° of flexion. When the pain is acute and well localized, injection of a glucocorticoid using a small-gauge needle may be effective. Following injection, the patient should be advised to rest the arm for at least 1 month and avoid activities that would aggravate the elbow. Once symptoms have subsided, the patient should begin rehabilitation to strengthen and increase flexibility of the extensor muscles before resuming physical activity involving the arm. A forearm band placed 2.5–5.0 cm (1–2 in.) below the elbow may help to reduce tension on the extensor muscles at their attachment to the lateral epicondyle. The patient should be advised to restrict activities requiring forcible extension and supination of the wrist. Improvement may take several months. The patient may continue to experience mild pain but, with care, can usually avoid the return of debilitating pain. Occasionally, surgical release of the extensor aponeurosis may be necessary.

MEDIAL EPICONDYLITIS

Medial epicondylitis is an overuse syndrome resulting in pain over the medial side of the elbow with radiation into the forearm. The cause of this syndrome is considered to be repetitive resisted motions of wrist flexion and pronation, which lead to microtears and granulation tissue at the origin of the pronator teres and forearm flexors, particularly the flexor carpi radialis. This overuse syndrome is usually seen in patients aged >35 years and is much less common than lateral epicondylitis. It occurs most often in work-related repetitive activities and also occurs with recreational activities such as swinging a golf club or throwing a baseball. On physical examination, there is tenderness just distal to the medial epicondyle over the origin of the forearm flexors. Pain can be reproduced by resisting wrist flexion and pronation with the elbow extended. Radiographs are usually normal. The differential diagnosis of patients with medial elbow symptoms includes tears of the pronator teres, acute medial collateral ligament tear, and medial collateral ligament instability. Ulnar neuritis has been found in 25–50% of patients with medial epicondylitis and is associated with tenderness over the ulnar nerve at the elbow as well as hypesthesia and paresthesia on the ulnar side of the hand.

The initial treatment of medial epicondylitis is conservative, involving rest, NSAIDs, friction massage, ultrasound, and icing. Some patients may require splinting. Injections of glucocorticoids at the painful site may also be effective. Patients should be instructed to rest for at least 1 month. Also, patients should start physical therapy once the pain has subsided. In patients with chronic debilitating medial epicondylitis that remains unresponsive after at least a year of treatment, surgical release of the flexor muscle at its origin may be necessary and is often successful.

PLANTAR FASCIITIS

Plantar fasciitis is a common cause of foot pain in adults, with the peak incidence occurring in people between the ages of 40 and 60 years. The pain originates at or near the site of the plantar fascia attachment to the medial tuberosity of the calcaneus. Several factors that increase the risk of developing plantar fasciitis include obesity, pes planus (flat foot or absence of the foot arch when standing), pes cavus (high-arched foot), limited dorsiflexion of the ankle, prolonged standing, walking on hard surfaces, and faulty shoes. In runners, excessive running and a change to a harder running surface may precipitate plantar fasciitis.

The diagnosis of plantar fasciitis can usually be made on the basis of history and physical examination alone. Patients experience severe pain with the first steps on arising in the morning or following inactivity during the day. The pain usually lessens with weight-bearing activity during the day, only to worsen with continued activity. Pain is made worse on walking barefoot or up stairs. On examination, maximal tenderness is elicited on palpation over the inferior heel corresponding to the site of attachment of the plantar fascia.

Imaging studies may be indicated when the diagnosis is not clear. Plain radiographs may show heel spurs, which are of little diagnostic significance. Ultrasonography in plantar fasciitis can demonstrate thickening of the fascia and diffuse hypoechogenicity, indicating edema at the attachment of the plantar fascia to the calcaneus. MRI is a sensitive method for detecting plantar fasciitis, but it is usually not required for establishing the diagnosis.

Resolution of symptoms occurs within 12 months in >80% of patients with plantar fasciitis. Initial treatment consists of ice, heat, massage, stretching, and eliminating activities that can exacerbate plantar fasciitis. Orthotics provide medial arch support and can be effective. Some patients may benefit from foot strapping or taping or by wearing a night splint designed to keep the ankle in a neutral position. A short course of NSAIDs can be given to patients when the benefits outweigh the risks. Local glucocorticoid injections have also been shown to be efficacious but may carry an increased risk for plantar fascia rupture. Plantar fasciotomy is reserved for those patients who have failed to improve after at least 6–12 months of conservative treatment.

FURTHER READING