Musckuloskeletal

Gouty Arthritis

Gout is a metabolic disease of a heterogeneous nature, often familial, associated with abnormal amounts of urates in the body and characterized early by a recurring acute arthritis, usually monarticular, and later by chronic deform- ing arthritis. The associated hyperuricemia is due to over- production or underexcretion of uric acid—sometimes both. The disease is especially common in Pacific islanders, eg, Filipinos and Samoans. Primary gout has a heritable component, and genome-wide surveys have linked risk of gout to several genes whose products regulate urate han- dling by the kidney. Secondary gout, which may have a heritable component, is related to acquired causes of hype- ruricemia, eg, medication use (especially diuretics, low- dose aspirin, cyclosporine, and niacin), myeloproliferative disorders, multiple myeloma, hemoglobinopathies, chronic kidney disease, hypothyroidism, psoriasis, sarcoidosis, and lead poisoning (Table 20-4). Alcohol ingestion promotes hyperuricemia by increasing urate production and decreas- ing the renal excretion of uric acid. Finally, hospitalized patients frequently suffer attacks of gout because of changes in diet, fluid intake, or medications that lead either to rapid reductions or increases in the serum urate level. About 90% of patients with primary gout are men, usu- ally over 30 years of age. In women, the onset is typically postmenopausal. The characteristic lesion is the tophus, a nodular deposit of monosodium urate monohydrate crys- tals with an associated foreign body reaction. Tophi are found in cartilage, subcutaneous and periarticular tissues, tendon, bone, the kidneys, and elsewhere. Urates have been demonstrated in the synovial tissues (and fluid) during acute arthritis; indeed, the acute inflammation of gout is believed to be initiated by the ingestion of uncoated urate crystals by monocytes and synoviocytes. Once inside the cells, the gout crystals are processed through Toll-like receptors and activate NALP-3 inflammasomes which in turn release a variety of chemotactic agents and cytokines capable of mediating inflammation. The precise relation- ship of hyperuricemia to gouty arthritis is still obscure, since chronic hyperuricemia is found in people who never develop gout or uric acid stones. Rapid fluctuations in serum urate levels, either increasing or decreasing, are important factors in precipitating acute gout. The mecha- nism of the late, chronic stage of gouty arthritis is better understood. This is characterized pathologically by topha- ceous invasion of the articular and periarticular tissues, with structural derangement and secondary degeneration (osteoarthritis). Uric acid kidney stones are present in 5-10% of patients with gouty arthritis. Hyperuricemia correlates highly with the likelihood of developing stones, with the risk of stone formation reaching 50% in patients with a serum urate level > 13 mg/dL. Chronic urate nephropathy is caused by the deposition of monosodium urate crystals in the renal medulla and pyramids. Although progressive chronic kid- ney disease occurs in a substantial percentage of patients with chronic gout, the role of hyperuricemia in causing this outcome is controversial, because many patients with gout have numerous confounding risk factors for chronic kid- ney disease (eg, hypertension, alcohol use, lead exposure, and other risk factors for vascular disease). ``Clinical Findings A. Symptoms and Signs Acute gouty arthritis is sudden in onset and frequently noc- turnal. It may develop without apparent precipitating cause or may follow rapid increases or decreases in serum urate levels. Common precipitants are alcohol excess (particularly beer), changes in medications that affect urate metabolism, and, in the hospitalized patient, fasting before medical pro- cedures. The MTP joint of the great toe is the most susceptible joint ("podagra"), although others, especially those of the feet, ankles, and knees, are commonly affected. Gouty attacks may develop in periarticular soft tissues such as the arch of the foot. Hips and shoulders are rarely affected. More than one joint may occasionally be affected during the same attack; in such cases, the distribution of the arthritis is usu- ally asymmetric. As the attack progresses, the pain becomes intense. The involved joints are swollen and exquisitely ten- der and the overlying skin tense, warm, and dusky red. Fever is common and may reach 39°C. Local desquamation and pruritus during recovery from the acute arthritis are charac- teristic of gout but are not always present. Tophi may be found in the external ears, feet, olecranon and prepatellar bursae, and hands (Figure 20-2). They usually develop years after the initial attack of gout. Asymptomatic periods of months or years commonly follow the initial acute attack. After years of recurrent severe monarthritis attacks of the lower extremities and untreated hyperuricemia, gout can evolve into a chronic, deforming polyarthritis of upper and lower extremities that mimics rheumatoid arthritis. B. Laboratory Findings The serum uric acid is elevated (> 7.4 mg/dL) in 95% of patients who have serial measurements during the course of an attack. However, a single uric acid determination is normal in up to 25% of cases, so it does not exclude gout, especially in patients taking urate-lowering drugs. During an acute attack, the peripheral blood white cell count is frequently elevated. Identification of sodium urate crystals in joint fluid or material aspirated from a tophus estab- lishes the diagnosis. The crystals, which may be extracel- lular or found within neutrophils, are needle-like and negatively birefringent when examined by polarized light microscopy. C. Imaging Early in the disease, radiographs show no changes. Later, punched-out erosions with an overhanging rim of cortical bone ("rat bite") develop. When these are adjacent to a soft tissue tophus, they are diagnostic of gout. ``Differential Diagnosis Acute gout is often confused with cellulitis. Bacteriologic studies usually exclude acute pyogenic arthritis. Pseudogout is distinguished by the identification of calcium pyrophos- phate crystals (positive birefringence) in the joint fluid, usually normal serum uric acid, and the radiographic appearance of chondrocalcinosis. Chronic tophaceous arthritis may resemble chronic rheumatoid arthritis; gout is suggested by an earlier his- tory of monarthritis and is established by the demonstra- tion of urate crystals in a suspected tophus. Likewise, hips and shoulders are generally spared in tophaceous gout. Biopsy may be necessary to distinguish tophi from rheumatoid nodules. A radiographic appearance similar to that of gout may be found in rheumatoid arthritis, sarcoidosis, multiple myeloma, hyperparathyroidism, or Hand-Schüller-Christian disease. Chronic lead intoxication may result in attacks of gouty arthritis (saturnine gout). ``Treatment A. Asymptomatic Hyperuricemia Asymptomatic hyperuricemia should not be treated; uric acid-lowering drugs need not be instituted until arthritis, renal calculi, or tophi become apparent. B. Acute Attack Arthritis is treated first and hyperuricemia weeks or months later, if at all. Sudden reduction of serum uric acid often precipitates further episodes of gouty arthritis. 1. NSAIDs—These drugs (see Table 5-3) are the treatment of choice for acute gout. Traditionally, indomethacin has been the most frequently used agent, but all of the other newer NSAIDs are probably equally effective. Indomethacin is initiated at a dosage of 25-50 mg orally every 8 hours and continued until the symptoms have resolved (usually 5-10 days). Active peptic ulcer disease, impaired kidney function, and a history of allergic reaction to NSAIDs are contraindications. For patients at high risk for upper gas- trointestinal bleeding, celecoxib (200 mg twice a day on day 1 then 100 mg twice daily until resolution), a cyclooxyge- nase type 2 (COX-2) inhibitor, may be an appropriate first choice for management of an acute gout attack. Long-term use of COX-2 inhibitors is not advised because of the asso- ciation with increased risk of cardiovascular events, which has led to the removal of some drugs (eg, rofecoxib and valdecoxib) from the US market. 2. Colchicine—Neither oral nor intravenous colchicine should be used for the treatment of acute gout flares. A patient who is taking prophylactic doses of colchicine may continue it through the flare. The use of oral colchicine during the intercritical period to prevent gout attacks is discussed below. 3. Corticosteroids—Corticosteroids often give dramatic symptomatic relief in acute episodes of gout and will con- trol most attacks. They are most useful in patients with contraindications to the use of NSAIDs. Corticosteroids may be given intravenously (eg, methylprednisolone, 40 mg/d tapered over 7 days) or orally (eg, prednisone, 40-60 mg/d tapered over 7 days). If the patient's gout is monarticular, intra-articular administration (eg, triamcinolone, 10-40 mg depending on the size of the joint) is very effective. Because gouty and septic arthritis can coexist, albeit rarely, joint aspiration and Gram stain with culture of synovial fluid should be performed when intra-articular corticosteroids are given. 4. Anakinra—Uncontrolled studies suggest that this inter- leukin-1 receptor antagonist has efficacy for the manage- ment of acute gout. C. Management between Attacks Treatment during symptom-free periods is intended to minimize urate deposition in tissues, which causes chronic tophaceous arthritis, and to reduce the frequency and severity of recurrences. Patients with a single episode of gout who are willing to lose weight and stop drinking alco- hol are at low risk for another attack and unlikely to ben- efit from long-term medical therapy. In contrast, older individuals with mild chronic kidney disease who require diuretic use and have a history of multiple attacks of gout are more likely to benefit from pharmacologic treatment. In general, the higher the uric acid level and the more fre- quent the attacks, the more likely that long-term medical therapy will be beneficial. 1. Diet—Potentially reversible causes of hyperuricemia are a high-purine diet, obesity, alcohol consumption, and use of certain medications (see below). Beer consumption appears to confer a higher risk of gout than does whiskey or wine. Higher levels of meat and seafood consumption are associated with increased risks of gout, whereas a higher level of dairy products consumption is associated with a decreased risk. Although dietary purines usually contribute only 1 mg/dL to the serum uric acid level, mod- eration in eating foods with high purine content is advis- able (Table 20-5). A high liquid intake and, more importantly, a daily urinary output of 2 L or more will aid urate excretion and minimize urate precipitation in the urinary tract. 2. Avoidance of hyperuricemic medications—Thiazide and loop diuretics inhibit renal excretion of uric acid and should be avoided in patients with gout. Similarly, low doses of aspirin aggravate hyperuricemia, as does niacin. 3. Colchicine—There are two indications for daily colchi- cine administration. First, colchicine can be used to pre- vent future attacks. For the person who has mild hyperuricemia and occasional attacks of gouty arthritis, long-term colchicine prophylaxis may be all that is needed. Second, colchicine can also be used when uricosuric drugs or allopurinol (see below) are started, to suppress attacks precipitated by abrupt changes in the serum uric acid level. For either indication, the usual dose is 0.6 mg either once or twice a day. Colchicine is renally cleared. Patients who have coexisting moderate chronic kidney disease should take colchicine only once a day or once every other day in order to avoid the peripheral neuromyopathy and other complications of colchicine toxicity. 4. Reduction of serum uric acid—Indications for a urate lowering intervention include frequent acute arthritis not controlled by colchicine prophylaxis, tophaceous deposits, or kidney damage. Hyperuricemia with infrequent attacks of arthritis may not require treatment. If instituted, the goal of medical treatment is to maintain the serum uric acid at or below 6 mg/dL, which allows urate crystals to solubilize. Three classes of agents may be used to lower the serum uric acid—the uricosuric drugs, xanthine oxidase inhibi- tors (allopurinol or febuxostat), and uricase (pegloticase); none is of value in the treatment of acute gout. Choosing between uricosuric drugs and allopurinol depends on the result of a 24-hour urine uric acid determination. A value under 800 mg/d indicates undersecretion of uric acid, which is amenable to uricosuric agents if kidney function is preserved or to a xanthine oxidase inhibitor (allopurinol or febuxostat) if kidney function is limited. Patients with > 800 mg of uric acid in a 24-hour urine collection are overproducers and require a xanthine oxidase inhibitor. The uricase, pegloticase, requires intravenous administra- tion and is indicated only in patients with chronic gout refractory to other treatments. A. Uricosuric drugs—Uricosuric drugs, which block the tubular reabsorption of filtered urate thereby reducing the metabolic urate pool, prevent the formation of new tophi and reduce the size of those already present. When administered concomitantly with colchicine, they may lessen the frequency of recurrences of acute gout. The indi- cation for uricosuric treatment is the increasing frequency or severity of acute attacks. Uricosuric agents are ineffec- tive in patients with an estimated glomerular filtration rate of < 60 mL/min. The following uricosuric drugs may be used: (1) Probenecid, 0.5 g orally daily initially, with gradual increase to 1-2 g daily; or (2) sulfinpyrazone, 50-100 mg orally twice daily initially, with gradual increase to 200-400 mg twice daily. Hypersensitivity to either with fever and rash occurs in 5% of cases; gastrointestinal complaints are observed in 10%. Probenecid also inhibits the excretion of penicillin, indomethacin, dapsone, and acetazolamide. Precautions with uricosuric drugs include maintain- ing a daily urinary output of 2000 mL or more in order to minimize the precipitation of uric acid in the urinary tract. This can be further prevented by giving alkalinizing agents (eg, potassium citrate, 30-80 mEq/d orally) to maintain a urine pH of > 6.0. Uricosuric drugs should not be used in patients with a history of uric acid nephrolithiasis. Aspirin in moderate doses antagonizes the action of uricosuric agents, but low doses (325 mg or less per day) do not; doses of aspirin > 3 g daily are themselves uricosuric. B. Xanthine oxidase inhibitors—The xanthine oxi- dase inhibitors promptly lower plasma urate and urinary uric acid concentrations and facilitate tophus mobilization. Inhibitors of xanthine oxidase are of special value in uric acid overproducers; in tophaceous gout; in patients unre- sponsive to the uricosuric regimen; and in gouty patients with uric acid renal calculi. Asymptomatic hyperuricemia should not be treated. Two xanthine oxidase inhibitors are available for treating chronic gout: allopurinol and febuxo- stat. One or the other should be chosen; allopurinol and febuxostat are not to be used together. The most frequent adverse effect with either medication is the precipitation of an acute gouty attack; thus, patients generally should be receiving prophylactic doses of colchicine and should not be experiencing an acute flare when xanthine oxidase inhibitors are initiated. Hypersensitivity to allopurinol occurs in 2% of cases and can be life-threatening. The most common sign of hypersensitivity is a pruritic rash that may progress to toxic epidermal necrolysis, particularly if allopurinol is continued; vasculitis and hepatitis are other manifestations. Patients should be instructed to stop allopurinol immediately if a rash develops. Febuxostat apparently does not cause the hypersensitivity reactions seen with allopurinol and can be given without dose adjustment to patients with mild to moderate renal disease. However, 2-3% of patients taking febuxostat may develop abnormal liver function tests. In addition, one clinical study showed that febuxostat was associated with a slightly higher rate of fatal and non-fatal cardiovascular events than allopurinol (0.97 vs 0.58 per 100 patient-years). The initial daily dose of allopurinol is 300 mg/d orally for most patients who have normal kidney function; the dose of allopurinol should be increased in 100-mg incre- ments to achieve the desired serum uric acid level of ≤ 6.0 mg/dL. Successful treatment usually requires a dose of 300-400 mg of allopurinol daily. The maximum daily dose is 800 mg. Allopurinol can be used in chronic kidney dis- ease, but the dose must be reduced to decrease the chance of side effects. For patients with renal impairment, the initial dose should be 50-100 mg daily. Allopurinol interacts with other drugs. The combined use of allopurinol and ampicillin causes a drug rash in 20% of patients. Allopurinol can increase the half-life of probenecid, while probenecid increases the excretion of allopurinol. Thus, a patient taking both drugs may need to use slightly higher than usual doses of allopurinol and lower doses of probenecid. The initial dose of febuxostat is 40 mg/d orally. If the target serum uric acid is not reached within 2 weeks, then the dose of febuxostat can be increased to its maximum of 80 mg/d. C. Uricase—Nonprimate mammals do not develop gout because they have an enzyme—uricase—that ensures that purine metabolism does not end with urate but the much more soluble metabolite, allantoin. In humans, the gene for uricase has been inactivated by a missense mutation, so purine metabolism dead ends with the production of uric acid, which becomes insoluble above a level of 6.8 mg/dL. Pegloticase, a recombinant uricase that must be adminis- tered intravenously (8 mg every 2 weeks), is indicated for the rare patient with chronic tophaceous gout who is refractory to all other therapies. Pegloticase carries a "Black Box Warning," which advises administering the drug only in healthcare settings and by healthcare professionals pre- pared to manage anaphylactic and other serious infusion reactions. D. Chronic Tophaceous Arthritis With rigorous medical compliance, allopurinol or febuxo- stat or pegloticase shrinks tophi and in time can lead to their disappearance. Resorption of extensive tophi requires maintaining a serum uric acid below 6 mg/dL. Surgical excision of large tophi offers mechanical improvement in selected deformities. E. Gout in the Transplant Patient Hyperuricemia and gout commonly develop in many transplant patients because they have decreased kidney function and require drugs that inhibit uric acid excretion (especially cyclosporine and diuretics). Treating acute gout in these patients is challenging: NSAIDs are usually contraindicated because of underlying chronic kidney dis- ease; intravenous colchicine should not be used because of its narrow therapeutic index (particularly in kidney dys- function); and corticosteroids are already being used. Often the best approach for monarticular gout—after excluding infection—is injecting corticosteroids into the joint (see above). For polyarticular gout, increasing the dose of systemic corticosteroid may be the only alternative. Since transplant patients often have multiple attacks of gout, long-term relief requires lowering the serum uric acid with allopurinol or febuxostat. (Kidney dysfunction seen in many transplant patients makes uricosuric agents inef- fective.) Both allopurinol and febuxostat inhibit the metab- olism of azathioprine and should be avoided in patients who must take azathioprine. ``Prognosis Without treatment, the acute attack may last from a few days to several weeks. The intervals between acute attacks vary up to years, but the asymptomatic periods often become shorter if the disease progresses. Chronic gouty arthritis occurs after repeated attacks of acute gout, but only after inadequate treatment. The younger the patient at the onset of disease, the greater the tendency to a progres- sive course. Destructive arthropathy is rarely seen in patients whose first attack is after age 50. Patients with gout are anecdotally thought to have an increased incidence of hypertension, kidney disease (eg, nephrosclerosis, interstitial nephritis, pyelonephritis), dia- betes mellitus, hypertriglyceridemia, and atherosclerosis.

Osteoarthritis

Osteoarthritis, the most common form of joint disease, is chiefly a disease of aging. Ninety percent of all people have radiographic features of osteoarthritis in weight- bearing joints by age 40. Symptomatic disease also increases with age. Gender is also a risk factor, because osteoarthri- tis develops in women more frequently than in men. This arthropathy is characterized by degeneration of cartilage and by hypertrophy of bone at the articular mar- gins. Inflammation is usually minimal. Hereditary and mechanical factors may be involved in the pathogenesis. Obesity is a risk factor for osteoarthritis of the knee, hand, and probably of the hip. Recreational running does not increase the incidence of osteoarthritis, but participa- tion in competitive contact sports does. Jobs requiring frequent bending and carrying increase the risk of knee osteoarthritis. Signs and Symptoms Degenerative joint disease is divided into two types: (1) primary, which most commonly affects some or all of the following: the DIP and the proximal interphalangeal (PIP) joints of the fingers, the carpometacarpal joint of the thumb, the hip, the knee, the metatarsophalangeal (MTP) joint of the big toe, and the cervical and lumbar spine; and (2) secondary, which may occur in any joint as a sequela to articular injury resulting from either intra-articular or extra-articular causes. The injury may be acute, as in a fracture; or chronic, as that due to occupational overuse of a joint, metabolic disease (eg, hyperparathyroidism, hemochromatosis, ochronosis), or neurologic disorders (syringomyelia; see below). The onset is insidious. Initially, there is articular stiff- ness, seldom lasting more than 15 minutes; this develops later into pain on motion of the affected joint and is made worse by activity or weight bearing and relieved by rest. Flexion contracture or varus deformity of the knee is not unusual, and bony enlargements of the DIP (Heberden nodes) and PIP (Bouchard nodes) are occasionally promi- nent (Figure 20-1). There is no ankylosis, but limitation of motion of the affected joint or joints is common. Crepitus may often be felt over the knee. Joint effusion and other articular signs of inflammation are mild. There are no sys- temic manifestations. Osteoarthritis does not cause elevation of the erythrocyte sedimentation rate (ESR) or other laboratory signs of inflammation. Synovial fluid is noninflammatory. C. Imaging Radiographs may reveal narrowing of the joint space; osteophyte formation and lipping of marginal bone; and thickened, dense subchondral bone. Bone cysts may also be present. ``Differential Diagnosis Because articular inflammation is minimal and systemic manifestations are absent, degenerative joint disease should seldom be confused with other arthritides. The distribution of joint involvement in the hands also helps distinguish osteoarthritis from rheumatoid arthritis. Osteoarthritis chiefly affects the DIP and PIP joints and spares the wrist and metacarpophalangeal (MCP) joints; rheumatoid arthri- tis involves the wrists and MCP joints and spares the DIP joints. Furthermore, the joint enlargement is bony-hard and cool in osteoarthritis but spongy and warm in rheumatoid arthritis. Skeletal symptoms due to degenerative changes in joints—especially in the spine—may cause coexistent met- astatic neoplasia, osteoporosis, multiple myeloma, or other bone disease to be overlooked. ``Prevention Weight reduction reduces the risk of developing symptom- atic knee osteoarthritis. Correcting leg length discrepancy of > 1 cm with shoe modification may prevent knee osteoar- thritis from developing in the shorter leg. Maintaining normal vitamin D levels may reduce the occurrence and progression of osteoarthritis, in addition to being impor- tant for bone health. ``Treatment A. General Measures For patients with mild to moderate osteoarthritis of weight-bearing joints, moderate physical activity (eg, a supervised walking program, hydrotherapy classes, or Tai Chi classes), and use of assistive devices (eg, a cane on the contralateral side) may result in clinical improvement of functional status without aggravating the joint pain. Weight loss can also improve the symptoms. B. Analgesic and Anti-inflammatory Drugs Nonsteroidal anti-inflammatory drugs (NSAIDs) (see Table 5-3) are more effective (and more toxic) than acet- aminophen for osteoarthritis of the knee or hip. Their superiority is most convincing in persons with severe dis- ease. Patients with mild disease should start with acet- aminophen (2.6-4 g/d). NSAIDs should be considered for patients who do not respond to acetaminophen. (See dis- cussion of NSAID toxicity in the section on treatment of rheumatoid arthritis.) High doses of NSAIDs, as used in the inflammatory arthritides, are unnecessary. A topical NSAID—diclofenac gel 1% is approved by the US Food and Drug Administration (FDA) for treatment of osteoar- thritis; the recommended dose is 4 g applied to the affected joint four times daily. Topical diclofenac appears more effective than placebo for knee and hand osteoarthritis. Rates of systemic side effects are lower with topical than with oral diclofenac. Few studies have compared the effi- cacy of oral and topical NSAIDs. Chondroitin sulfate and glucosamine, alone or in combination, are no better than placebo in reducing pain in patients with knee or hip osteoarthritis. For many patients, it is possible eventually to reduce the dosage or limit use of drugs to periods of exacerbation. For patients with knee osteoarthritis and effusion, intra-articular injection of triamcinolone (20-40 mg) may obviate the need for analgesics or NSAIDs. Corticosteroid injections up to four times a year appear to be safe. Intra-articular injections of sodium hyaluronate reduce symptoms mod- erately in some patients. Capsaicin cream 0.025-0.075% applied three or four times a day can also reduce knee pain without NSAIDs. C. Surgical Measures Total hip and knee replacements provide excellent symp- tomatic and functional improvement when involvement of that joint severely restricts walking or causes pain at rest, particularly at night. Arthroscopic surgery for knee osteoar- thritis is ineffective. ``Prognosis Marked disability is less common in patients with osteoar- thritis than in those with rheumatoid arthritis, but symptoms may be quite severe and limit activity considerably (especially with involvement of the hips, knees, and cervical spine).

Osteoporosis

Osteoporosis is a skeletal disorder characterized by a loss of bone osteoid that reduces bone integrity, resulting in an increased risk of fractures. In the United States, osteoporo- sis causes about 2 million fractures annually, including 547,000 vertebral fractures, 300,000 hip fractures, and 135,000 pelvic fractures. White women have a 40% lifetime risk of sustaining one or more osteoporotic fractures. The morbidity and indirect mortality rates are very high. The rate of bone formation is often normal, whereas the rate of bone resorption is increased. Osteoporosis can be caused by a variety of factors, which are listed in Table 26-10. The most common causes are aging; high-dose corticosteroid administration; alco- holism; and sex hormone deficiency, particularly meno- pause in women. Osteogenesis imperfecta is caused by a major muta- tion in the gene encoding for type I collagen, the major collagen constituent of bone. This causes severe osteopo- rosis; spontaneous fractures occur in utero or during childhood. Blue sclerae may be present. Certain polymor- phisms in the genes encoding type I collagen are common, particularly in whites, resulting in collagen disarray and predisposing to hypogonadal (eg, menopausal) or idiopathic osteoporosis. `cClinical Findings A. Symptoms and Signs Osteoporosis is usually asymptomatic until fractures occur. It may present as backache of varying degrees of severity or as a spontaneous fracture or collapse of a vertebra. Loss of height is common. Once osteoporosis is identified, a carefully directed history and physical must be performed to determine its cause. B. Laboratory Findings Serum calcium, phosphate, and PTH are normal. The alka- line phosphatase is usually normal but may be slightly elevated, especially following a fracture. Vitamin D defi- ciency is very common and serum determination of 25-hydroxyvitamin D should be obtained for every indi- vidual with low bone density. Serum 25-hydroxyvitamin D levels below 20 ng/mL are considered frank vitamin D deficiency. Lesser degrees of vitamin D deficiency (serum 25-hydroxyvitamin D levels between 20 ng/mL and 30 ng/mL) may also increase the risk for hip fracture. (See Osteomalacia, below.) Testing for thyrotoxicosis and hypogonadism may be required. Celiac disease may be screened for with serum immunoglobulin A (IgA) endomysial antibody and tissue transglutaminase antibody determinations. C. Bone Densitometry DXA is used to determine the bone density of the lumbar spine and hip. Bone densitometry should be performed on all patients who are at risk for osteoporosis or osteomalacia or have pathologic fractures or radiographic evidence of diminished bone density. This test delivers negligible radia- tion, and the measurements are quite accurate. However, bone densitometry cannot distinguish osteoporosis from osteomalacia; in fact, both are often present. Also, the bone mineral density does not directly measure bone quality and is only fairly successful at predicting fractures. Vertebral bone mineral density may be misleadingly high in com- pressed vertebrae and in patients with extensive arthritis. DXA also overestimates the bone mineral density of taller persons and underestimates the bone mineral density of smaller persons. Quantitative CT delivers more radiation but is more accurate in the latter situations. Bone mineral density in typically expressed in g/cm2, for which there are different normal ranges for each bone and for each type of DXA-measuring machine. The "T score" is a simplified way of reporting bone density in which the patient's bone mineral density is compared to the young normal mean and expressed as a standard devia- tion score. The World Health Organization has established criteria for defining osteoporosis in postmenopausal white women, based on T score: T score ≥ -1.0: Normal. T score -1.0 to -2.5: Osteopenia ("low bone density"). T score < -2.5: Osteoporosis. T score < -2.5 with a fracture: Severe osteoporosis. This classification is somewhat arbitrary and there really is no bone mineral density fracture threshold; instead, the fracture risk increases about twofold for each standard deviation drop in bone mineral density. In fact, most women with fragility fractures have bone densities above -2.5. Surveillance DXA bone densitometry is recom- mended for postmenopausal women with a frequency according to their T scores: obtain DXA every 5 years for

Carpal Tunnel Syndrome

An entrapment neuropathy, carpal tunnel syndrome is a painful disorder caused by compression of the median nerve between the carpal ligament and other structures within the carpal tunnel. The contents of the tunnel can be compressed by synovitis of the tendon sheaths or carpal joints, recent or malhealed fractures, tumors, and occa- sionally congenital anomalies. Even though no anatomic lesion is apparent, flattening or even circumferential con- striction of the median nerve may be observed during operative section of the ligament. The disorder may occur in pregnancy, is seen in individuals with a history of repetitive use of the hands, and may follow injuries of the wrists. There is a familial type of carpal tunnel syndrome in which no etiologic factor can be identified. Carpal tunnel syndrome can also be a feature of many systemic diseases: rheumatoid arthritis and other rheu- matic disorders (inflammatory tenosynovitis); myxedema, localized amyloidosis in chronic kidney disease, sarcoido- sis, and leukemia (tissue infiltration); acromegaly; and hyperparathyroidism. ``Clinical Findings The initial symptoms are pain, burning, and tingling in the distribution of the median nerve (the palmar surfaces of the thumb, the index and long fingers, and the radial half of the ring finger). Aching pain may radiate proximally into the forearm and occasionally proximally to the shoulder and over the neck and chest. Pain is exacerbated by manual activity, particularly by extremes of volar flexion or dorsi- flexion of the wrist. It is most bothersome at night. Impairment of sensation in the median nerve distribution may or may not be demonstrable. Subtle disparity between the affected and opposite sides can be shown by testing for two-point discrimination or by requiring the patient to identify different textures of cloth by rubbing them between the tips of the thumb and the index finger. Tinel or Phalen sign may be positive. (Tinel sign is tingling or shock-like pain elicited by tapping the volar surface of the wrist; Phalen sign is pain or paresthesia in the distribution of the median nerve when the patient flexes both wrists to 90 degrees for 60 seconds.) The carpal compression test, in which numbness and tingling are induced by the direct application of pressure over the carpal tunnel, may be more sensitive and specific than the Tinel and Phalen tests. Muscle weakness or atrophy, especially of the thenar emi- nence, appears later than sensory disturbances. Specific examinations include electromyography and determina- tions of segmental sensory and motor conduction delay. Sensory conduction delay is evident before motor delay. ``Differential Diagnosis This syndrome should be differentiated from other cervi- cobrachial pain syndromes, from compression syndromes of the median nerve in the forearm or arm, and from mononeuritis multiplex. When left-sided, it may be con- fused with angina pectoris. ``Treatment Treatment is directed toward relief of pressure on the median nerve. When a causative lesion is discovered, it is treated appropriately. Otherwise, patients in whom carpal tunnel syndrome is suspected should modify their hand activities and have the affected wrist splinted for 2-6 weeks. NSAIDs can also be added. Patients should be referred to a specialist for injection of corticosteroid into the carpal tun- nel or for operation when they do not improve or when thenar muscle atrophy or weakness develops. Muscle strength returns gradually, but complete recovery cannot be expected when atrophy is pronounced.

Lumbar Spinal Stenosis

Lumbar spinal stenosis, defined as narrowing of the spinal canal with compression of the nerve roots, may be congenital or (more commonly) acquired. It most frequently results from enlarging osteophytes at the facet joints, hypertrophy of the ligamentum flavum, and protrusion or bulging of inter- vertebral disks. Lumbar spinal stenosis may produce symp- toms by directly compressing nerve roots or by compressing nutrient arterioles that supply the nerve roots. ``Clinical Findings A. Symptoms and Signs Most patients with lumbar spinal stenosis are over 60 years old and complain of either leg pain or trouble walking. The pain may originate in the low back but will extend below the buttock into the thigh in nearly 90% of patients. In approxi- mately 50% of patients, the pain will extend below the knee. The pain is often a combination of aching and numbness, which characteristically worsens with walking. The pain can also be brought on by prolonged standing. Not infrequently the symptoms are bilateral. Many patients are more troubled by poor balance, unsteadiness of gait, or leg weakness that develops as they walk. Some describe these neuroclaudica- tion symptoms as developing "spaghetti legs" or "walking like a drunk sailor." Because the lumbar spinal canal volume increases with back flexion and decreases with extension, some patients observe that they have fewer symptoms walk- ing uphill than down. The back and lower extremity exami- nation in patients with lumbar spinal stenosis is often unimpressive. Less than 10% have a positive straight leg raise sign, 25% have diminished deep tendon reflexes, and 60% have slight proximal weakness. Walking with the patient may reveal unsteadiness, although usually the patient's percep- tion of gait disturbance is greater than that of an observer. B. Imaging The diagnosis of spinal stenosis in a patient with symp- toms is best confirmed by MRI. ``Differential Diagnosis The onset of symptoms with standing, the location of the maximal discomfort to the thighs, and the preservation of pedal pulses help distinguish the "pseudoclaudication" of spinal stenosis from true claudication caused by vascular insufficiency. Distinguishing spinal stenosis from disk her- niation can be challenging since both conditions can pro- duce pain radiating down the back of the leg. Features that favor spinal stenosis are the gradual onset of symptoms, the marked exacerbation with walking, and the ameliora- tion of symptoms with sitting or lumbar flexion. Complaints of bilateral aching in the buttocks associated with stiffness may make some practitioners consider the diagnosis of polymyalgia rheumatica. However, patients with lumbar spinal stenosis do not have the shoulder or neck symptoms characteristic of polymyalgia rheumatica. ``Treatment Weight loss and exercises aimed at reducing lumbar lordo- sis, which aggravates symptoms of spinal stenosis, can help. Lumbar epidural corticosteroid injections provide some immediate relief for about 50% of patients and more sus- tained relief for approximately 25%. When disabling symp- toms persist, surgery will reduce pain and improve function substantially in approximately 75% of patients at 1 and 2 years; only about 25% of patients treated conservatively will experience a similar improvement.

Principles of Pain Managment

The experience of pain includes the patient's emotional reaction to it and is influenced by many factors, including the patient's prior experiences with pain, meaning given to the pain, emotional stresses, and family and cultural influ- ences. Pain is a subjective phenomenon, and clinicians cannot reliably detect its existence or quantify its severity without asking the patient directly. A useful means of assessing pain and evaluating the effectiveness of analgesia is to ask the patient to rate the degree of pain along a numeric or visual pain scale (Table 5-1). General guidelines for management of pain are rec- ommended for the treatment of all patients with pain (Table 5-2). Clinicians should ask about the nature, severity, timing, location, quality, and aggravating and relieving factors of the pain. Distinguishing between neu- ropathic and nociceptive (somatic or visceral) pain is essential to proper tailoring of pain treatments. The goal of pain management is properly decided by the patient. Some patients may wish to be completely free of pain even at the cost of significant sedation, while others will wish to control pain to a level that still allows maximal functioning. Chronic severe pain should be treated continuously. For ongoing pain, a long-acting analgesic can be given around the clock with a short-acting medication as needed for "breakthrough" pain. Whenever possible, the oral route of administration is preferred because it is easier to adminis- ter at home, is not painful, and imposes no risk from needle exposure. Near the end of life, rectal, transdermal, subcuta- neous, and intravenous administration are also frequently used; intrathecal administration is used when necessary (albeit rarely). Patient-controlled analgesia (PCA) of intra- venous medications can achieve better analgesia faster with less medication use and its principles have been adapted for use with oral administration. The underlying cause of pain should be diagnosed and treated, balancing the burden of diagnostic tests with the patient's suffering. For example, radiation therapy for painful bone metastases or mechanical stents for obstruct- ing lesions, may obviate the need for ongoing treatment with analgesics and their side effects. Regardless of deci- sions about seeking and treating the underlying cause of pain, every patient should be offered prompt relief. Table 5-2. Recommended clinical approach to pain management. Ask about pain regularly. Assess pain systematically (quality, description, location, intensity or severity, aggravating and ameliorating factors, cognitive responses). Ask about goals for pain control, management preferences. Believe the patient and family in their reports of pain and what relieves it. Choose pain control options appropriate for the patient, family, and setting. Consider drug type, dosage, route, contraindications, side effects. Consider nonpharmacologic adjunctive measures. Deliver interventions in a timely, logical, coordinated manner. Empower patients and their families. Enable patients to control their course to the greatest extent possible. Follow up to reassess persistence of pain, changes in pain pattern, development of new pain. In general, pain can be well controlled with analgesic medications—both opioid and nonopioid—at any stage of illness. Evidence-based summaries and guidelines are avail- able from the Agency for Healthcare Research and Quality (http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1. chapter. 86205) and other organizations (http://www.nccn. org/professionals/physician_gls/PDF/pain.pdf ). For mild to moderate pain, acetaminophen, aspirin, and nonsteroi- dal anti-inflammatory drugs (NSAIDs) may be sufficient. For moderate to severe pain, these agents combined with opioids may be helpful. acetaminophen & nsaiDs Appropriate doses of acetaminophen may be just as effective an analgesic and antipyretic as NSAIDs but without the risk of gastrointestinal bleeding or ulceration. Acetaminophen can be given at a dosage of 500-1000 mg orally every 6 hours, although it can be taken every 4 hours as long as the risk of hepatotoxicity is kept in mind. Hepatotoxicity is of particular concern because of how commonly acetaminophen is also an ingredient in various over-the-counter medications. Total acetaminophen doses should not exceed 3-4 g/d long-term or 2 g/d for older patients and for those with liver disease. Aspirin (325-650 mg orally every 4 hours) is an effective analgesic, antipyretic, and anti-inflammatory medication. Gastrointestinal irritation and bleeding are side effects that are lessened with enteric-coated formulations of aspirin and concomitant use of proton-pump inhibitor medica- tion. Bleeding, allergy, and an association with Reye syn- drome in children and teenagers further limit its use. NSAIDS Commonly used NSAIDs and their dosages are listed in Table 5-3. Like aspirin, the NSAIDs are antipyretic, analgesic, and anti-inflammatory. NSAIDs increase the risk of gastrointestinal bleeding by 1.5 times normal. The risks of bleeding and nephrotoxicity from NSAIDs are both increased in elders. Gastrointestinal bleeding and ulceration may be prevented with the concurrent use of proton pump inhibitors (eg, omeprazole, 20-40 mg orally daily) or with the class of NSAIDs that inhibit only cyclo- oxygenase (COX)-2. Celecoxib (100 mg/d to 200 mg orally twice daily) is the only COX-2 inhibitor available and should be used with caution in patients with cardiac dis- ease. The NSAIDs, including COX-2 inhibitors, can lead to fluid retention and exacerbations of congestive heart failure and should be used with caution in patients with that condition. Topical formulations of NSAIDs (such as diclofenac 1.3% patch or 1% gel), placed over the painful body part, result in lower systemic levels of the medication and may be associated with fewer side effects than oral administration. Opiods For many patients, opioids are the mainstay of pain man- agement. Opioids are appropriate for severe pain due to any cause, including neuropathic pain. Opioid medications are listed in Table 5-4. Full opioid agonists such as mor- phine, hydromorphone, oxycodone, methadone, fentanyl, hydrocodone, and codeine are used most commonly. Hydrocodone and codeine are typically combined with acetaminophen or an NSAID, although the US Food and Drug Administration will be restricting the amounts of acetaminophen in these combinations due to the risk for toxicity. Short-acting formulations of oral morphine sul- fate (starting dosage 4-8 mg orally every 3-4 hours), hydro- morphone (1-2 mg orally every 3-4 hours), or oxycodone (5 mg orally every 3-4 hours) are useful for acute pain not controlled with other analgesics. These same oral medica- tions, or oral transmucosal fentanyl (200 mcg oralet dis- solved in mouth) or buccal fentanyl (100 mcg dissolved in the mouth), can be used for "rescue" treatment for patients experiencing pain that breaks through long-acting medica- tions. For chronic stable pain, long-acting medications are preferred, such as oral sustained-release morphine (one to three times a day), oxycodone (two or three times a day), or methadone (three or four times a day). Methadone is inex- pensive, available in a liquid formulation, and may have added efficacy for neuropathic pain. However, equianalgesic dosing is complex because it varies with the patient's opioid dose and caution must be used at higher methadone doses (generally > 100-150 mg/d) because of the risk of QT pro- longation. Consultation with a palliative medicine or pain specialist may be appropriate. Transdermal fentanyl is appropriate for patients already tolerant to other opioids at a dose equivalent to at least 60 mg/d of oral morphine (equivalent to transdermal fen- tanyl 25 mcg/h every 72 hours) and therefore should not be used in the postoperative setting or be the first opioid used. Medications that inhibit cytochrome P450 3A4, such as ritonavir, ketoconazole, itraconazole, troleandomycin, clar- ithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosam- prenavir, and verapamil, and grapefruit juice can cause increased levels and duration of transdermal fentanyl. Since the fentanyl patch can require 24-48 hours to achieve pharmacologic "steady state," patients should be given short-acting opioids while awaiting the full analgesic effect of transdermal fentanyl, and changes in dose of the fen- tanyl patch should be made no more frequently than every 6 days. For complete information about prescribing guide- lines for the fentanyl patch see http://www.duragesic.com/ prescribing-information.html. A useful technique for opioid management of chronic pain is equianalgesic dosing (Table 5-4). The dosages of any full opioid agonists used to control pain can be con- verted into an equivalent dose of any other opioid. In this way, 24-hour opioid requirements and dosing regimens established using shorter-acting opioid medications can be converted into equivalent dosages of long-acting medica- tions or formulations. Cross-tolerance is often incomplete, however, so less than the full calculated equianalgesic dosage is generally administered initially when switching between opioid formulations. Equianalgesic dosing for metha- done is more complex and varies by dose and duration of use. While some clinicians and patients inexperienced with the management of severe chronic pain may feel more comfortable with combined nonopioid-opioid agents, full agonist opioids are typically a better choice in patients with severe pain because the dose of opioid is not limited by the toxicities of the acetaminophen, aspirin, or NSAID compo- nent of combination preparations. There is no maximal allowable or effective dose for full opioid agonists. The dose should be increased to whatever is necessary to relieve pain, remembering that certain types of pain, such as neu- ropathic pain, may respond better to agents other than opioids, or to combinations of opioids with co-analgesics (see below). While physiologic tolerance is possible with opioids, failure of a previously effective opioid dose to adequately relieve pain is usually due to worsening of the underlying condition causing pain, such as growth of a tumor or a new metastasis in a patient with cancer. In this case, for moderate unrelieved pain, the dose of opioid can be increased by 25-50%. For severe unrelieved pain, a dose increase of 50-100% may be appropriate. The frequency of dosing should be adjusted so that pain control is continuous. Long-term dosing may then be adjusted by adding the average daily amount of short-acting opioid necessary for breakthrough pain over the preceding 72-96 hours to the long-acting medication dose. In establishing or reestablish- ing adequate dosing, frequent reassessment of the patient's pain and medication side effects is necessary. As opioids are titrated upwards, increasing difficulty with the side effects can be expected. Constipation is common at any dose of opioid, and tolerance to this side effect does not develop over time. Opioid-induced consti- pation should be anticipated and prevented in all patients (see below). Sedation can be expected with opioids, although toler- ance to this effect typically develops within 24-72 hours at a stable dose. Sedation typically appears well before signifi- cant respiratory depression. If treatment for sedation is desired, dextroamphetamine (2.5-7.5 mg orally at 8 am and noon) or methylphenidate (2.5-10 mg orally at 8 am and noon) may be helpful. Caffeinated beverages can also ame- liorate minor opioid sedation. Although sedation is more common, patients may experience euphoria when first taking opioids or when the dose is increased. However, tolerance to sedation or eupho- ria typically develops after a few days at a stable dose. Opioid-induced neurotoxicity—characterized by myoclo- nus, followed by hyperalgesia, delirium with hallucinosis, and seizures—may develop in patients who take high doses of opioids for a prolonged period. These symptoms may resolve after lowering the dose or switching opioids, espe- cially to ones like fentanyl or methadone that do not have active metabolites. While waiting for the level of the offending opioid to fall, low doses of lorazepam, baclofen, or gabapentin may be helpful for treating myoclonus; halo- peridol may be useful for treating delirium. Avoiding or correcting dehydration may be helpful for prevention and treatment of opioid-induced neurotoxicity. Nausea due to opioids may occur with initiation of therapy and resolve after a few days. Severe or persistent nausea can be treated by switching opioids or by giving halo- peridol, 0.5-4 mg orally, subcutaneously, or intravenously every 6 hours; prochlorperazine, 10 mg orally or intra- venously or 25 mg rectally every 6 hours; or metoclopramide, 5-20 mg orally, subcutaneously, or intravenously before meals and bed; or ondansetron, 4-8 mg orally or intravenously every 6 hours. Notably, unrelieved constipation may be a more common cause of nausea in the setting of opioid use than opioid-induced nausea. Although clinicians may worry about respiratory depression with opioids, this side effect is uncommon when a low dose is given initially and titrated upward slowly. Patients at particular risk for respiratory depres- sion include those with chronic obstructive pulmonary disease, obstructive sleep apnea, and baseline CO2 reten- tion, those with liver or kidney or combined liver-kidney failure, and those with adrenal insufficiency or frank myx- edema. Yet, even patients with severe pulmonary disease can tolerate low-dose opioids, but they should be moni- tored carefully. Clinicians should not allow concerns about respiratory depression to prevent them from treat- ing pain adequately. True allergy (with urticaria) to opioids is rare. More commonly, patients will describe intolerance due to side effects such as nausea, pruritus, or urinary retention in response to a particular opioid. If such symptoms develop, they can usually be relieved by lowering the dose or switch- ing to another opioid. Medications for neuropathic Pain It is essential when taking a patient's history to listen for descriptions such as burning, shooting, pins and needles, or electricity, and for pain associated with numbness. Such a history suggests neuropathic pain, which is treated with some medications not typically used for other types of pain. While opioids are effective for neuropathic pain, a number of nonopioid medications have been found to be effective in randomized trials (Table 5-5). Successful man- agement of neuropathic pain often requires the use of more than one effective medication. The tricyclic antidepressants (TCAs) are good first-line therapy. Desipramine, 10-200 mg/d orally, and nortripty- line, 10-150 mg/d orally, are good first choices because they cause less orthostatic hypotension and have fewer anticho- linergic effects than amitriptyline. Start with a low dosage (10-25 mg orally daily) and titrate upward every 4 or 5 days. The calcium channel a2-d ligands gabapentin and pre- gabalin are also considered first-line therapy for neuro- pathic pain. Both medications can cause sedation, dizziness, ataxia, and gastrointestinal side effects but have no signifi- cant drug interactions. Both drugs require dose adjust- ments in patients with kidney dysfunction. Gabapentin should be started at low dosages of 100-300 mg orally three times a day and titrated upward by 300 mg/d every 4 or 5 days with a typical effective dose of 1800-3600 mg/d. Pregabalin should be started at 150 mg/d in two or three divided doses. If necessary, the dose of pregabalin can be titrated upward to 300-600 mg/d in two or three divided doses. Both drugs are relatively safe in accidental overdose and may be preferred over TCAs for a patient with a history of congestive heart failure or arrhythmia or if there is a risk of suicide. Prescribing gabapentin and morphine for neu- ropathic pain may provide better analgesia at lower doses than if each is used as a single agent. The selective serotonin norepinephrine reuptake inhib- itors (SSNRIs), duloxetine (60 mg/d or 20 mg twice daily in elders), and venlafaxine (150-225 mg/d) are also consid- ered first-line treatments for neuropathic pain. Patients should be advised to take duloxetine on a full stomach because nausea is a common side effect. Duloxetine should not be combined with other serotonin or norepinephrine uptake inhibitors, but it can be combined with gabapentin or pregabalin. Because venlafaxine can cause hyperten- sion and induce ECG changes, patients with cardiovascular risk factors should be carefully monitored when starting this drug. Other medications effective for neuropathic pain include tramadol and the 5% lidocaine patch. Tramadol should be started at 50 mg orally daily and can be titrated up to 100 mg orally four times daily. The 5% lidocaine patch (1-4 patches at a time) is effective in postherpetic neuralgia and may be effective in other types of localized neuropathic pain. A new patch is applied to the painful region daily for up to 12 hours daily. Adjuvant Pain Medications & Treatments If pain cannot be controlled without uncomfortable medi- cation side effects, clinicians should consider using lower doses of multiple medications, as is done commonly for neuropathic pain, rather than larger doses of one or two medications. For metastatic bone pain, the anti-inflamma- tory effect of NSAIDs can be particularly helpful. Radiation therapy and bisphosphonates may also relieve bone pain. For some patients, a nerve block can provide substantial relief, such as a celiac plexus block for pain from pancreatic cancer. Intrathecal pumps may be useful for patients with severe pain responsive to opioids but who require such large doses that systemic side effects (eg, sedation and con- stipation) become limiting. There is some evidence for the use of cannabinoids as analgesics. Corticosteroids such as dexamethasone or prednisone can be helpful for patients with headache due to increased intracranial pressure, pain from spinal cord compression, metastatic bone pain, and neuropathic pain due to invasion or infiltration of nerves by tumor. Because of the side effects of long-term corticosteroid administration, they are most appropriate in patients with end-stage disease. Low-dose intravenous or oral ketamine has been used successfully for neuropathic and other pain syndromes refractory to opioids. Haloperidol and benzodiazepines may be used prophylacti- cally to minimize ketamine's psychotomimetic side effects. nonPharMaCologiC TreaTMenTs Nonpharmacologic therapies are valuable in treating pain. Hot or cold packs, massage, and physical therapy can be helpful for musculoskeletal pain. Similarly, biofeedback, acu- puncture, chiropractic, meditation, music therapy, cognitive behavioral therapy, guided imagery, cognitive distraction, and framing may be of help in treating pain. Because mood and psychological issues play an important role in the patient's perception of and response to pain, psychotherapy, support groups, prayer, and pastoral counseling can also help in the management of pain. Major depression, which may be insti- gated by chronic pain or may alter the response to pain, should be treated aggressively. When to refer • Pain not responding to opioids at typical doses. • Neuropathic pain not responding to first-line treatments. • Complex methadone management issues. • Intolerable side effects from oral opioids. • Severe pain from bone metastases. • For a surgical or anesthesia-based procedure, intrathecal pump, or nerve block. When to admit • Patients should be hospitalized for severe exacerbation of pain that is not responsive to previous stable oral opioid around-the-clock plus breakthrough doses. • Patients whose pain is so severe that they cannot be cared for at home should be hospitalized. • Uncontrollable side effects from opioids, including nausea, vomiting, and altered mental status, should prompt hospitalization.

Low Back Pain

Up to 80% of the population experience low back pain at some time. The differential diagnosis is broad and includes muscular strain, primary spine disease (eg, disk herniation, degenerative arthritis), systemic diseases (eg, metastatic cancer), and regional diseases (eg, aortic aneurysm). A precise diagnosis cannot be made in the majority of cases. Even when anatomic defects—such as vertebral osteo- phytes or a narrowed disk space—are present, causality cannot be assumed since such defects are common in asymptomatic patients. Most patients with acute onset of low back pain will improve in 1-4 weeks and need no evaluation beyond the initial history and physical examina- tion. The diagnostic challenge is to identify those patients who require more extensive or urgent evaluation. In prac- tice, this means identifying those patients with pain caused by (1) infection, (2) cancer, (3) inflammatory back disease such as ankylosing spondylitis, or (4) pain referred from abdominal or pelvic processes, such as an expanding aortic aneurysm. Significant or progressive neurologic deficits also require identification. If there is no evidence of these problems, conservative therapy is called for. 1. Clinical Approach to Diagnosis ``General History & Physical Examination Low back pain is a final common pathway of many pro- cesses; the pain of vertebral osteomyelitis, for example, is not very different in quality and intensity from that due to back strain of the weekend gardener. Historical factors of importance include smoking, weight loss, age over 50, and cancer, all of which are risk factors for vertebral body metastasis. Osteomyelitis most frequently occurs in adults with a history of recurrent urinary tract infections and is especially common in diabetics and injection drug users. A history of a cardiac murmur should raise concern about endocarditis, since back pain is not an uncommon mani- festation. A background of renal calculi might indicate another cause of referred back pain. ``History of Back Pain Certain qualities of a patient's pain can indicate a specific diagnosis. Low back pain radiating down the buttock and below the knee suggests a herniated disk causing nerve root irritation. Other conditions—including sacroiliitis, facet joint degenerative arthritis, spinal stenosis, or irritation of the sciatic nerve from a wallet—also cause this pattern. The diagnosis of disk herniation is further suggested by physical examination (see below) and confirmed by imag- ing techniques. Disk herniation can be asymptomatic, so its presence does not invariably link it to the symptom. Low back pain at night, unrelieved by rest or the supine position, suggests the possibility of malignancy, either ver- tebral body metastasis (chiefly from prostate, breast, lung, multiple myeloma, or lymphoma) or a cauda equina tumor. Similar pain can also be caused by compression fractures (from osteoporosis or myeloma). Symptoms of large or rapidly evolving neurologic defi- cits identify patients who need urgent evaluation for pos- sible cauda equina tumor, epidural abscess or, rarely, massive disk herniation. When a herniated disk impinges a nerve root, pain is the most prominent symptom; numb- ness and weakness are less common and, when present, are of the magnitude consistent with compression of a single nerve root. Symptoms of bilateral leg weakness (from mul- tiple lumbar nerve root compressions) or of saddle area anesthesia, bowel or bladder incontinence, or impotence (indicating multiple sacral nerve root compressions) indi- cate a cauda equina process. Low back pain that worsens with rest and improves with activity is characteristic of ankylosing spondylitis or other seronegative spondyloarthropathies, especially when the onset is insidious and begins before age 40. Most degenerative back diseases produce precisely the opposite pattern, with rest alleviating and activity aggravating the pain. Low back pain causing the patient to writhe occurs in renal colic but can also indicate a leaking aneurysm. The pain associated with pseudoclaudication from lumbar spinal stenosis is discussed below. ``Physical Examination of the Back Several physical findings should be sought because they help identify those few patients who need more than con- servative management. Neurologic examination of the lower extremities will detect the small deficits produced by disk disease and the large deficits complicating such problems as cauda equina tumors. A positive straight leg raising test indicates nerve root irritation. The examiner performs the test on the supine patient by passively raising the patient's ipsilateral leg. The test is positive if radicular pain is produced with the leg raised 60 degrees or less. It has a specificity of 40% but is 95% sensitive in patients with herniation at the L4-5 or L5-S1 level (the sites of 95% of disk herniations). It can be falsely negative, especially in patients with herniation above the L4-5 level. The crossed straight leg sign is posi- tive when raising the contralateral leg reproduces the sci- atica. It has a sensitivity of 25% but is 90% specific for disk herniation. Detailed examination of the sacral and lumbar nerve roots, especially L5 and S1, is essential for detecting neuro- logic deficits associated with back pain. Disk herniation pro- duces deficits predictable for the site involved (Table 20-6). Deficits of multiple nerve roots suggest a cauda equina tumor or an epidural abscess, both requiring urgent evalu- ation and treatment. Measurement of spinal motion in the patient with acute pain is rarely of diagnostic utility and usually simply con- firms that pain limits motion. An exception is the decreased range of motion in multiple regions of the spine (cervical, thoracic, and lumbar) in a diffuse spinal disease such as ankylosing spondylitis. By the time the patient has such limits, however, the diagnosis is usually straightforward. If back pain is not severe and does not itself limit motion, the modified Schober test of lumbar motion is helpful in early diagnosis of ankylosing spondylitis. To perform this test, two marks are made with the patient upright: one 10 cm above the sacral dimples and another 5 cm below. The patient then bends forward as far as possible, and the dis- tance between the points is measured. Normally, the distance increases from 15 cm to at least 20 cm. Anything less indi- cates reduced lumbar motion. Palpation of the spine usually does not yield diagnostic information. Point tenderness over a vertebral body is reported to suggest osteomyelitis, but this association is uncommon. A step-off noted between the spinous process of adjacent vertebral bodies may indicate spondylolisthesis, but the sensitivity of this finding is extremely low. Tenderness of the soft tissues overlying the greater trochanter of the hip is a manifestation of trochanteric bursitis. Inspection of the spine is not often of value in identify- ing serious causes of low back pain. The classic posture of ankylosing spondylitis is a late finding. Scoliosis of mild degree is not associated with an increased risk of clinical back disease. Cutaneous neurofibromas can identify the rare patient with nerve root encasement. Examination of the hips should be part of the complete examination. While hip arthritis usually produces pain chiefly in the groin area, some patients have buttock or low back symptoms. ``Further Examination If the history and physical examination do not suggest the presence of infection, cancer, inflammatory back disease, major neurologic deficits, or pain referred from abdominal or pelvic disease, further evaluation can be deferred while conservative therapy is tried. The great majority of patients will improve with conservative care over 1-4 weeks. Regular radiographs of the lumbosacral spine give 20 times the radiation dose of a chest radiograph and pro- vide limited, albeit important, information. Oblique films double the radiation dose and are not routinely needed. Radiographs can provide evidence of vertebral body osteo- myelitis, cancer, fractures, or ankylosing spondylitis. Degenerative changes in the lumbar spine are ubiquitous in patients over 40 and do not prove clinical disease. Plain radiographs have very low sensitivity or specificity for disk disease. Thus, plain radiographs are warranted promptly for patients suspected of having infection, cancer, or fractures; selected other patients who do not improve after 2-4 weeks of conservative therapy are also candidates. The Agency for Healthcare Research and Quality guidelines for obtaining lumbar radiographs are summarized in Table 20-7. MRI provides exquisite anatomic detail but is reserved for patients who are considering surgery or have evidence of a systemic disease. For example, MRI is needed urgently for any patient in whom an epidural mass or cauda equina tumor is suspected but not for a patient believed to have a routine disk herniation, since most will improve over 4-6 weeks of conservative therapy. Noncontrast CT does not image cauda equina tumors or other intradural lesions, and if used instead of MRI it must include intrathecal contrast. Radionuclide bone scanning has limited usefulness. It is most useful for early detection of vertebral body osteomy- elitis or osteoblastic metastases. The bone scan is normal in multiple myeloma because lytic lesions do not take up isotope. 2. Management While any management plan must be individualized, key elements of most conservative treatments for back pain include analgesia and education. Analgesia can usually be provided with NSAIDs (see Table 5-3), but severe pain may require opioids (see Table 5-4). Rarely does the need for opioids extend beyond 1-2 weeks. Diazepam, cyclobenzaprine, carisoprodol, and meth- ocarbamol have been prescribed as muscle relaxants, though their sedative effects may limit their use. They should be reserved for patients who do not respond to NSAIDs and usually are needed only for 1-2 weeks, which reduces the chance of dependence. Their use should be avoided in older patients, who are at risk for falling. All patients should be taught how to protect the back in daily activities—ie, not to lift heavy objects, to use the legs rather than the back when lifting, to use a chair with arm rests, and to rise from bed by first rolling to one side and then using the arms to push to an upright position. Back manip- ulation for benign, mechanical low back pain appears safe and as effective as therapies provided by clinicians. Rest and back exercises, once thought to be corner- stones of conservative therapy, are now known to be inef- fective for acute back pain. Advice to rest in bed is less effective than advice to remain active. No bed rest with continuation of ordinary activities as tolerated is superior to 2 days of bed rest, 7 days of bed rest, and back mobilizing exercises. Similarly, for acute back pain, exercise therapy is not effective. The value of corsets or traction is dubious. Epidural corticosteroid injections can provide short-term relief of sciatica but do not improve functional status or reduce the need for surgery. In double-blind studies, repeated injections have been no more effective than a single injection. For chronic low back pain, yoga is as effec- tive as a back exercise program and more effective than a self-care book. Corticosteroid injections into facet joints are ineffective for chronic low back pain. Massage therapy is effective for treatment of chronic back pain, with benefits lasting at least 6 months. Surgical consultation is needed urgently for any patient with a major or evolving neurologic deficit. Randomized controlled trials have shown that for sciatica caused by disk herniation, conservative treatment and surgery achieve similar 1-year outcomes; however, pain relief and perceived recovery were obtained more quickly with surgery. Surgery tends to ameliorate leg pain more quickly and fully than back pain. Complaints without objective findings suggest a psy- chological role in symptom formation. Treatment includes reassurance and nonopioid analgesics. ``When to Refer • Suspected malignancy. • Inflammatory low back pain. ``When to Admit • Neurologic signs indicative of cauda equina syndrome. • Vertebral osteomyelitis.

Neck Pain

At any point in time, about 15% of adults are experiencing neck pain, which develops more commonly in women than in men. The prevalence of neck pain peaks at age 50. A large group of articular and extra-articular disorders are characterized by pain that may involve simultaneously the neck, shoulder girdle, and upper extremity. Diagnostic dif- ferentiation may be difficult. Some represent primary dis- orders of the cervicobrachial region; others are local manifestations of systemic disease. It is frequently not pos- sible to make a specific diagnosis. ``Clinical Findings A. Symptoms and Signs Neck pain may be limited to the posterior region or, depending on the level of the symptomatic joint, may radi- ate segmentally to the occiput, anterior chest, shoulder girdle, arm, forearm, and hand. It may be intensified by active or passive neck motions. The general distribution of pain and paresthesias corresponds roughly to the involved dermatome in the upper extremity. Radiating pain in the upper extremity is often intensified by hyperextension of the neck and deviation of the head to the involved side. Limitation of cervical movements is the most common objective finding. Neurologic signs depend on the extent of compression of nerve roots or the spinal cord. Compression of the spinal cord may cause paraparesis or paraplegia. B. Imaging The radiographic findings depend on the cause of the pain; many plain radiographs are completely normal in patients who have suffered an acute cervical strain. Loss of cervical lordosis is often seen but is nonspecific. In osteoarthritis, comparative reduction in height of the involved disk space is a frequent finding. The most common late radiographic finding is osteophyte formation anteriorly, adjacent to the disk; other chronic abnormalities occur around the apo- physial joint clefts, chiefly in the lower cervical spine. Use of advanced imaging techniques is indicated in the patient who has severe pain of unknown cause that fails to respond to conservative therapy or in the patient who has evidence of myelopathy. MRI is more sensitive than CT in detecting disk disease, extradural compression, and intra- medullary cord disease. CT is preferable for demonstration of fractures. ``Differential Diagnosis & Treatment The causes of neck pain include acute and chronic cervical strain or sprains, herniated nucleus pulposus, osteoarthri- tis, ankylosing spondylitis, rheumatoid arthritis, fibromy- algia, osteomyelitis, neoplasms, polymyalgia rheumatica, compression fractures, pain referred from visceral struc- tures (eg, angina), and functional disorders. A. Nonspecific Neck Pain In the absence of trauma or evidence of infection, malig- nancy, neurologic findings, or systemic inflammation, the patient can be treated conservatively. Conservative therapy can include rest, analgesics, or physical therapy. B. Acute Cervical Musculotendinous Strain Cervical strain is generally caused by mechanical postural disorders, overexertion, or injury (eg, whiplash). Acute episodes are associated with pain, decreased cervical spine motion, and paraspinal muscle spasm, resulting in stiffness of the neck and loss of motion. Muscle trigger points can often be localized. After whiplash injury, patients often experience not only neck pain but also shoulder girdle discomfort and headache. Management includes adminis- tration of analgesics. Soft cervical collars are commonly recommended, but evidence suggests they may delay recov- ery. Acupuncture, manipulation, or physical therapy can help some patients, but the precise role of these treatments is not well established. Corticosteroid injection into cervi- cal facet joints is ineffective. Gradual return to full activity is encouraged. C. Herniated Nucleus Pulposus Rupture or prolapse of the nucleus pulposus of the cervical disks into the spinal canal causes pain radiating at a C6-7 level. When intra-abdominal pressure is increased by coughing, sneezing, or other movements, symptoms are aggravated, and cervical muscle spasm may occur. Neurologic abnormalities include decreased reflexes of the deep tendons of the biceps and triceps and decreased sen- sation and muscle atrophy or weakness in the forearm or hand. Cervical traction, bed rest, and other conservative measures are usually successful. Radicular symptoms usu- ally respond to conservative therapy, including NSAIDs, activity modification, intermittent cervical traction, and neck immobilization. Cervical epidural corticosteroid injections may help those who fail conservative therapy. Surgery is indicated for unremitting pain and progressive weakness despite a full trial of conservative therapy and if a surgically correctable abnormality is identified by MRI or CT myelography. Surgical decompression achieves excel- lent results in 70-80% of such patients. D. Arthritic Disorders Cervical spondylosis (degenerative arthritis) is a collective term describing degenerative changes that occur in the apophysial joints and intervertebral disk joints, with or without neurologic signs. Osteoarthritis of the articular facets is characterized by progressive thinning of the carti- lage, subchondral osteoporosis, and osteophytic prolifera- tion around the joint margins. Degeneration of cervical disks and joints may occur in adolescents but is more com- mon after age 40. Degeneration is progressive and is marked by gradual narrowing of the disk space, as demon- strated by radiography. Osteocartilaginous proliferation occurs around the margin of the vertebral body and gives rise to osteophytic ridges that may encroach upon the intervertebral foramina and spinal canal, causing compres- sion of the neurovascular contents. Osteoarthritis of the cervical spine is often asymptom- atic but may cause diffuse neck pain. A minority of patients with neck pain also suffer from radicular pain or myelopa- thy. Myelopathy develops insidiously and is manifested by sensory dysfunction and clumsy hands. Some patients also complain of unsteady walking, urinary frequency and urgency, or electrical shock sensations with neck flexion or extension (Lhermitte sign). Weakness, sensory loss, and spasticity with exaggerated reflexes develop below the level of spinal cord compression. Amyotrophic lateral sclerosis, multiple sclerosis, syringomyelia, spinal cord tumors, and tropical spastic paresis from HTLV-1 infection can mimic myelopathy from cervical arthritis. The mainstay of con- servative therapy is immobilizing the cervical spine with a collar. With moderate to severe neurologic symptoms, sur- gical treatment is indicated. Atlantoaxial subluxation may occur in patients with either rheumatoid arthritis or ankylosing spondylitis. Inflammation of the synovial structures resulting from erosion and laxity of the transverse ligament can lead to neurologic signs of spinal cord compression. Treatment may vary from use of a cervical collar or more rigid bracing to operative treatment, depending on the degree of sublux- ation and neurologic progression. Surgical treatment for stabilization of the cervical spine is a last resort. E. Other Disorders Osteomyelitis and neoplasms are discussed below. Osteoporosis is discussed in Chapter 26.

Fibromyalgia

Fibromyalgia is one of the most common rheumatic syn- dromes in ambulatory general medicine affecting 3-10% of the general population. It shares many features with the chronic fatigue syndrome, namely, an increased frequency among women aged 20-50, absence of objective findings, and absence of diagnostic laboratory test results. While many of the clinical features of the two conditions overlap, musculoskeletal pain predominates in fibromyalgia whereas lassitude dominates the chronic fatigue syndrome. The cause is unknown, but aberrant perception of pain- ful stimuli, sleep disorders, depression, and viral infections have all been proposed. Fibromyalgia can be a rare compli- cation of hypothyroidism, rheumatoid arthritis or, in men, sleep apnea. ``Clinical Findings The patient complains of chronic aching pain and stiffness, frequently involving the entire body but with prominence of pain around the neck, shoulders, low back, and hips. Fatigue, sleep disorders, subjective numbness, chronic headaches, and irritable bowel symptoms are common. Even minor exertion aggravates pain and increases fatigue. Physical examination is normal except for "trigger points" of pain produced by palpation of various areas such as the trapezius, the medial fat pad of the knee, and the lateral epicondyle of the elbow. ``Differential Diagnosis Fibromyalgia is a diagnosis of exclusion. A detailed history and repeated physical examination can obviate the need for extensive laboratory testing. Rheumatoid arthritis and sys- temic lupus erythematosus (SLE) present with objective physical findings or abnormalities on routine testing. Thyroid function tests are useful, since hypothyroidism can produce a secondary fibromyalgia syndrome. Polymyositis produces weakness rather than pain. The diagnosis of fibro- myalgia probably should be made hesitantly in a patient over age 50 and should never be invoked to explain fever, weight loss, or any other objective signs. Polymyalgia rheumatica produces shoulder and pelvic girdle pain, is associated with anemia and an elevated ESR, and occurs after age 50. Hypophosphatemic states, such as oncogenic osteomalacia, should also be included in the differential diagnosis of mus- culoskeletal pain unassociated with physical findings. In contrast to fibromyalgia, oncogenic osteomalacia usually produces pain in only a few areas and is associated with a low serum phosphate level. ``Treatment A multidisciplinary approach is most effective. Patient edu- cation is essential. Patients can be comforted that they have a diagnosable syndrome treatable by specific though imper- fect therapies and that the course is not progressive. Cognitive behavioral therapy, including programs that emphasize mindfulness meditation is often helpful. There is modest efficacy of amitriptyline, fluoxetine, duloxetine, milnacipran, chlorpromazine, cyclobenzaprine, pregabalin, or gabapen- tin. Amitriptyline is initiated at a dosage of 10 mg orally at bedtime and gradually increased to 40-50 mg depending on efficacy and toxicity. Less than 50% of the patients experi- ence a sustained improvement. Exercise programs are also beneficial. NSAIDs are generally ineffective. Tramadol and acetaminophen combinations have ameliorated symptoms modestly in short-term trials. Opioids and corticosteroids are ineffective and should not be used to treat fibromyalgia. Acupuncture is also ineffective. ``Prognosis All patients have chronic symptoms. With treatment, however, many do eventually resume increased activities. Progressive or objective findings do not develop.

Bursitis

Inflammation of bursae—the synovium-like cellular mem- branes overlying bony prominences—may be secondary to trauma, infection, or arthritic conditions such as gout, rheumatoid arthritis, or osteoarthritis. The most common locations are the subdeltoid, olecranon (Figure 20-3), ischial, trochanteric, semimembranous-gastrocnemius (Baker cyst), and prepatellar bursae. There are several ways to distinguish bursitis from arthritis. Bursitis is more likely than arthritis to cause focal tenderness and swelling and less likely to affect range of motion of the adjacent joint. Olecranon bursitis, for example, causes an oval (or, if chronic, bulbous) swelling at the tip of the elbow and does not affect elbow motion, whereas an elbow joint inflammation produces more dif- fuse swelling and reduces range of motion. Similarly, a patient with prepatellar bursitis has a small focus of swell- ing over the kneecap but no distention of the knee joint itself and preserved knee motion. A patient with trochant- eric bursitis will have tenderness over the greater trochanter and normal internal rotation of the hip; a patient with hip arthritis usually will have reduced internal rotation. Bursitis caused by trauma responds to local heat, rest, NSAIDs, and local corticosteroid injections. Bursitis can result from infection. The two most com- mon sites are the olecranon and prepatellar bursae. Acute swelling and redness at either of these two sites calls for aspiration to rule out infection. The absence of fever does not exclude infection; one-third of those with septic ole- cranon bursitis are afebrile. A bursal fluid white blood cell count of >1000/mcL indicates inflammation from infec- tion, rheumatoid arthritis, or gout. In septic bursitis, the white cell count averages over 50,000/mcL. Most cases are caused by Staphylococcus aureus; the Gram stain is positive in two-thirds. Treatment involves antibiotics and aspira- tion for tense effusions. Chronic, stable olecranon bursa swelling usually does not require aspiration. Aspiration of the olecranon bursa runs the risk of creating a chronic drainage site, which can be reduced by using a "zig-zag" approach with a small needle (25-gauge if possible) and pulling the skin over the bursa before introducing it. Applying a pressure bandage may also help prevent chronic drainage. Surgical removal of the bursa is indicated only for cases in which repeated infections occur. Repetitive minor trauma to the olecranon bursa should be eliminated by avoiding resting the elbow on a hard surface or by wearing an elbow pad. A bursa can also become symptomatic when it ruptures. This is particularly true for Baker cyst, whose rupture can cause calf pain and swelling that mimic thrombophlebitis. Ruptured Baker cysts are imaged easily by sonography or MRI. In most cases, imaging is unnecessary because the cyst and an associated knee effusion are detectable on physical examination. It may be important to exclude a deep venous thrombosis, which can be mimicked by a ruptured Baker cyst. Treatment of a ruptured cyst includes rest, leg elevation, and injection of triamcinolone, 20-40 mg into the knee anteriorly (the knee compartment communicates with the cyst). Rarely, Baker cyst can compress vascular structures and cause leg edema and true thrombophlebitis.

Rheumatoid Arthritis

Rheumatoid arthritis is a chronic systemic inflammatory disease whose major manifestation is synovitis of multiple joints. It has a prevalence of 1% and is more common in women than men (female:male ratio of 3:1). Rheumatoid arthritis can begin at any age, but the peak onset is in the fourth or fifth decade for women and the sixth to eighth decades for men. The cause is not known. Susceptibility to rheumatoid arthritis is genetically determined with multi- ple genes contributing. Inheritance of class II HLA mole- cules with a distinctive five-amino-acid sequence known as the "shared epitope" is the best characterized genetic risk factor. Untreated, rheumatoid arthritis causes joint destruc- tion with consequent disability and shortens life expec- tancy. Early, aggressive treatment is the standard of care. The pathologic findings in the joint include chronic synovitis with formation of a pannus, which erodes carti- lage, bone, ligaments, and tendons. In the acute phase, effusion and other manifestations of inflammation are common. In the late stage, organization may result in fibrous ankylosis; true bony ankylosis is rare. ``Clinical Findings A. Symptoms and Signs 1. Joint symptoms—The clinical manifestations of rheu- matoid disease are highly variable, but joint symptoms usu- ally predominate. Although acute presentations may occur, the onset of articular signs of inflammation is usually insidious, with prodromal symptoms of vague periarticular pain or stiffness. Symmetric swelling of multiple joints with tenderness and pain is characteristic. Monarticular disease is occasionally seen initially. Stiffness persisting for > 30 min- utes (and usually many hours) is prominent in the morning. Stiffness may recur after daytime inactivity and be much more severe after strenuous activity. Although any diarthro- dial joint may be affected, PIP joints of the fingers, MCP joints (Figure 20-4), wrists, knees, ankles, and MTP joints are most often involved. Synovial cysts and rupture of ten- dons may occur. Entrapment syndromes are not unusual— particularly of the median nerve at the carpal tunnel of the wrist. Rheumatoid arthritis can affect the neck but spares the other components of the spine and does not involve the sacroiliac joints. In advanced disease, atlantoaxial (C1-C2) subluxation can lead to myelopathy. 2. Rheumatoid nodules—Twenty percent of patients have subcutaneous rheumatoid nodules, most commonly situated over bony prominences but also observed in the bursae and tendon sheaths (Figure 20-5). Nodules are occasionally seen in the lungs, the sclerae, and other tissues. Nodules correlate with the presence of rheumatoid factor in serum ("seropositivity"), as do most other extra-articular manifestations. 3. Ocular symptoms—Dryness of the eyes, mouth, and other mucous membranes is found especially in advanced disease (see Sjögren syndrome). Other ocular manifesta- tions include episcleritis, scleritis, and scleromalacia due to scleral nodules. 4. Other symptoms—Interstitial lung disease is not uncommon (estimates of prevalence vary widely according to method of detection) and manifests clinically as cough and progressive dyspnea. Pericarditis and pleural disease, when present, are usually silent clinically. Patients with active joint disease often have palmar erythema. Occasionally, a small vessel vasculitis develops and mani- fests as tiny hemorrhagic infarcts in the nail folds or finger pulps. Although necrotizing arteritis is well reported, it is rare. A small subset of patients with rheumatoid arthritis have Felty syndrome, the occurrence of splenomegaly and neutropenia, usually in the setting of severe, destructive arthritis. Felty syndrome must be distinguished from the large granular lymphocyte syndrome, with which it shares many features. Aortitis is a rare late complication that can result in aortic regurgitation or rupture and is usually associated with evi- dence of rheumatoid vasculitis elsewhere in the body. B. Laboratory Findings Anti-CCP antibodies and rheumatoid factor, an IgM anti- body directed against the Fc fragment of IgG, are present in 70-80% of patients with established rheumatoid arthritis but have sensitivities of only 50% in early disease. Anti- CCP antibodies are the most specific blood test for rheu- matoid arthritis (specificity ~95%). Rheumatoid factor can occur in other autoimmune disease and in chronic infec- tions, including hepatitis C, syphilis, subacute bacterial endocarditis, and tuberculosis. The prevalence of rheuma- toid factor positivity also rises with age in healthy individu- als. Approximately 20% of rheumatoid patients have antinuclear antibodies. The ESR and levels of C-reactive protein are typically elevated in proportion to disease activity. A moderate hypo- chromic normocytic anemia is common. The white cell count is normal or slightly elevated, but leukopenia may occur, often in the presence of splenomegaly (eg, Felty syn- drome). The platelet count is often elevated, roughly in proportion to the severity of overall joint inflammation. Initial joint fluid examination confirms the inflammatory nature of the arthritis. (See Table 20-2.) Arthrocentesis is needed to diagnose superimposed septic arthritis, which is a common complication of rheumatoid arthritis and should be considered whenever a patient with rheumatoid arthritis has one joint inflamed out of proportion to the rest. C. Imaging Of all the laboratory tests, radiographic changes are the most specific for rheumatoid arthritis. Radiographs obtained during the first 6 months of symptoms, however, are usually normal. The earliest changes occur in the wrists or feet and consist of soft tissue swelling and juxta-articular demineralization. Later, diagnostic changes of uniform joint space narrowing and erosions develop. The erosions are often first evident at the ulnar styloid and at the juxta- articular margin, where the bony surface is not protected by cartilage. Diagnostic changes also occur in the cervical spine, with C1-2 subluxation, but these changes usually take many years to develop. Although both MRI and ultra- sonography are more sensitive than radiographs in detect- ing bony and soft tissue changes in rheumatoid arthritis, their value in early diagnosis relative to that of plain radio- graphs has not been established. ``Differential Diagnosis The differentiation of rheumatoid arthritis from other joint conditions and immune-mediated disorders can be difficult. In 2010, the American College of Rheumatology updated their classification criteria for rheumatoid arthritis. In con- trast to rheumatoid arthritis, osteoarthritis spares the wrist and the MCP joints. Osteoarthritis is not associated with constitutional manifestations, and the joint pain is charac- teristically relieved by rest, unlike the morning stiffness of rheumatoid arthritis. Signs of articular inflammation, prom- inent in rheumatoid arthritis, are usually minimal in degen- erative joint disease. CPPD deposition disease can cause a degenerative arthropathy of the MCPs and wrists; radio- graphs are usually diagnostic. Although gouty arthritis is almost always intermittent and monarticular in the early years, it may evolve with time into a chronic polyarticular process that mimics rheumatoid arthritis. Gouty tophi can resemble rheumatoid nodules both in typical location and appearance. The early history of intermittent monarthritis and the presence of synovial urate crystals are distinctive features of gout. Spondyloarthropathies, particularly earlier in their course, can be a source of diagnostic uncertainty; predilection for lower extremities and involvement of the spine and sacroiliac joints point to the correct diagnosis. Chronic Lyme arthritis typically involves only one joint, most commonly the knee, and is associated with positive serologic tests (see Chapter 34). Human parvovirus B19 infection in adults can mimic early rheumatoid arthritis. However, arthralgias are more prominent than arthritis, fever is common, IgM antibodies to parvovirus B19 are pres- ent, and the arthritis usually resolves within weeks. Infection with hepatitis C can cause a chronic nonerosive polyarthritis associated with rheumatoid factor; tests for anti-CCP anti- bodies are negative. Malar rash, photosensitivity, discoid skin lesions, alope- cia, high titer antibodies to double-stranded DNA, glomeru- lonephritis, and central nervous system abnormalities point to the diagnosis of SLE. Polymyalgia rheumatica occasion- ally causes polyarthralgias in patients over age 50, but these patients remain rheumatoid factor-negative and have chiefly proximal muscle pain and stiffness, centered on the shoulder and hip girdles. Rheumatic fever is characterized by the migratory nature of the arthritis, an elevated antistreptolysin titer, and a more dramatic and prompt response to aspirin; carditis and erythema marginatum may occur in adults, but chorea and subcutaneous nodules virtually never do. Finally, a variety of cancers produce paraneoplastic syndromes, including polyarthritis. One form is hypertrophic pulmo- nary osteoarthropathy most often produced by lung and gastrointestinal carcinomas, characterized by a rheumatoid- like arthritis associated with clubbing, periosteal new bone formation, and a negative rheumatoid factor. Diffuse swell- ing of the hands with palmar fasciitis occurs in a variety of cancers, especially ovarian carcinoma. ``Treatment The primary objectives in treating rheumatoid arthritis are reduction of inflammation and pain, preservation of func- tion, and prevention of deformity. Success requires early, effective pharmacologic intervention. Disease-modifying antirheumatic drugs (DMARDs) should be started as soon as the diagnosis of rheumatoid disease is certain and then adjusted with the aim of suppressing disease activity. The American College of Rheumatology recommends using standardized assessments, such as the Disease Activity Score 28 Joints (DAS28), to gauge therapeutic responses, with the target of mild disease activity or remission by these measures. In advanced disease, surgical intervention may help improve function of damaged joints and to relieve pain. A. Nonsteroidal Anti-inflammatory Drugs NSAIDs provide some symptomatic relief in rheumatoid arthritis but do not prevent erosions or alter disease pro- gression. They are not appropriate for monotherapy and should only be used in conjunction with DMARDs. A large number of NSAIDs are available; all appear equivalent in terms of efficacy (see Table 5-3). Celecoxib, a selective COX-2 inhibitor, is FDA-approved for the treatment of osteoarthritis and rheumatoid arthri- tis. Compared with traditional NSAIDs, COX-2 inhibitors are as effective for treating rheumatoid arthritis but less likely in some circumstances to cause upper gastrointesti- nal tract adverse events (eg, obstruction, perforation, hem- orrhage, or ulceration). Long-term use of COX-2 inhibitors, particularly in the absence of concomitant aspirin use, has been associated with an increased risk of cardiovascular events, leading to the removal of some COX-2 inhibitors from the US market and intense scrutiny of all drugs in that class. 1. Gastrointestinal side effects—For traditional NSAIDs that inhibit both COX-1 and COX-2, gastrointestinal side effects, such as gastric ulceration, perforation, and gastro- intestinal hemorrhage, are the most common serious side effects. The overall rate of bleeding with NSAID use in the general population is low (1:6000 users or less) but is increased by long-term use, higher NSAID dose, concomi- tant corticosteroids or anticoagulants, the presence of rheumatoid arthritis, history of peptic ulcer disease or alcoholism, and age over 70. Twenty-five percent of all hospitalizations and deaths from peptic ulcer disease result from traditional NSAID therapy. Each year, 1:1000 patients with rheumatoid arthritis will require hospitalization for NSAID-related gastrointestinal bleeding or perforation. Although all traditional NSAIDs can cause massive gastro- intestinal bleeding, the risk may be higher with indomethacin and piroxicam, probably because these drugs preferentially inhibit COX-1 in the stomach. One approach to reducing the gastrointestinal toxicity of traditional NSAIDs is to add a proton pump inhibitor (eg, omeprazole 20 mg orally daily). Sucralfate, antacids, and H2-blockers (such as ranitidine) either do not work or do not work as well as proton pump inhibitors. The expense of proton pump inhibitors and misoprostol dic- tates that their use should be reserved for patients with risk factors for NSAID-induced gastrointestinal toxicity (noted above). Patients who have recently recovered from an NSAID-induced bleeding gastric ulcer appear to be at high risk for rebleeding (about 5% in 6 months) when an NSAID is reintroduced, even if prophylactic measures such as proton pump inhibitors are used. NSAIDs can also affect the lower intestinal tract, causing perforation or aggravat- ing inflammatory bowel disease. Acute liver injury from NSAIDs is rare, occurring in about 1 of every 25,000 patients using these agents. Having rheuma- toid arthritis or taking sulindac may increase the risk. 2. Renal side effects—All of the NSAIDs, including aspi- rin and the COX-2 inhibitors, can produce renal toxicity, including interstitial nephritis, nephrotic syndrome, prerenal azotemia, and aggravation of hypertension. Hyperkalemia due to hyporeninemic hypoaldosteronism may also be seen rarely. The risk of renal toxicity is low but is increased by age over 60, a history of kidney disease, congestive heart failure, ascites, and diuretic use. COX-2 inhibitors appear to cause as much nephrotoxicity as tradi- tional NSAIDs. 3. Platelet effects—All NSAIDs except the nonacetylated salicylates and the COX-2 inhibitors interfere with platelet function and prolong bleeding time. For all older NSAIDs except aspirin, the effect on bleeding time resolves as the drug is cleared. Aspirin irreversibly inhibits platelet func- tion, so the bleeding time effect resolves only as new plate- lets are made. Concomitant administration of a traditional NSAID can interfere with the ability of aspirin to acetylate platelets and thus may interfere with the cardioprotective effects of low-dose aspirin. COX-2 inhibitors, which differ from other NSAIDs in not inhibiting platelet function, do not increase the risk of bleeding with surgical procedures as most NSAIDs do. Unfortunately, this failure to inhibit platelets is now known to lead to increased risks of myocar- dial infarction and stroke, particularly when the medica- tions are used in high doses for prolonged periods of time. Patients requiring low-dose aspirin who are not compliant have a greater risk of developing a thrombotic event while taking a COX-2 inhibitor than while taking a traditional NSAID. Whether combination therapy with low-dose aspi- rin and a COX-2 inhibitor maintains the gastrointestinal advantage of selective COX-2 inhibitors is not yet known. Although groups of patients with rheumatoid arthritis respond similarly to NSAIDs, individuals may respond differently—an NSAID that works for one patient may not work for another. Thus, if the first NSAID chosen is not effective after 2-3 weeks of use, another should be tried. B. Corticosteroids Low-dose corticosteroids (eg, oral prednisone 5-10 mg daily) produce a prompt anti-inflammatory effect in rheumatoid arthritis and slow the rate of articular ero- sion. However, their multiple side effects limit their long- term use. Low-dose corticosteroids often are used as a "bridge" to reduce disease activity until the slower acting DMARDs take effect or as adjunctive therapy for active disease that persists despite treatment with DMARDs. No more than 10 mg of prednisone or equivalent per day is appropriate for articular disease. Many patients do reasonably well on 5-7.5 mg daily. (The use of 1 mg tablets, to facilitate doses of < 5 mg/d, is encouraged.) Higher doses are used to man- age serious extra-articular manifestations (eg, pericarditis, necrotizing scleritis). When the corticosteroids are to be discontinued, they should be tapered gradually on a planned schedule appropriate to the duration of treatment. All patients receiving long-term corticosteroid therapy should take measures to prevent osteoporosis. Intra-articular corticosteroids may be helpful if one or two joints are the chief source of difficulty. Intra-articular triamcinolone, 10-40 mg depending on the size of the joint to be injected, may be given for symptomatic relief but not more than four times a year. C. Synthetic DMARDs 1. Methotrexate—Methotrexate is usually the initial syn- thetic DMARD of choice for patients with rheumatoid arthritis. It is generally well tolerated and often produces a beneficial effect in 2-6 weeks. The usual initial dose is 7.5 mg of methotrexate orally once weekly. If the patient has tolerated methotrexate but has not responded in 1 month, the dose can be increased to 15 mg orally once per week. The maximal dose is usually 20-25 mg/wk. The most fre- quent side effects are gastric irritation and stomatitis. Cytopenia, most commonly leukopenia or thrombocy- topenia but rarely pancytopenia, due to bone marrow sup- pression is another important potential problem. The risk of developing pancytopenia is much higher in patients with elevation of the serum creatinine (≥2 mg/dL). Hepatotoxicity with fibrosis and cirrhosis is an important toxic effect that correlates with cumulative dose and is uncommon with appropriate monitoring of liver function tests. Methotrexate is contraindicated in a patient with any form of chronic hepatitis. Heavy alcohol use increases the hepatotoxicity, so patients should be advised to drink alco- hol in extreme moderation, if at all. Diabetes, obesity, and kidney disease also increase the risk of hepatotoxicity. Liver function tests should be monitored at least every 12 weeks, along with a complete blood count. The dose of metho- trexate should be reduced if aminotransferase levels are elevated, and the drug should be discontinued if abnor- malities persist despite dosage reduction. Gastric irritation, stomatitis, cytopenias, and hepatotoxicity are reduced by prescribing either daily folate (1 mg orally) or weekly leu- covorin calcium (2.5-5 mg taken orally 24 hours after the dose of methotrexate). Hypersensitivity to methotrexate can cause an acute or subacute interstitial pneumonitis that can be life-threatening but which usually responds to ces- sation of the drug and institution of corticosteroids. Because methotrexate is teratogenic, women of child- bearing age as well as men must use effective contraception while taking the medication. Methotrexate is associated with an increased risk of B cell lymphomas, some of which resolve following the discontinuation of the medication. The combination of methotrexate and other folate antago- nists, such as trimethoprim-sulfamethoxazole, should be used cautiously, since pancytopenia can result. Probenecid should also be avoided since it increases methotrexate drug levels and toxicity. 2. Sulfasalazine—This drug is a second-line agent for rheumatoid arthritis. It is usually introduced at a dosage of 0.5 g orally twice daily and then increased each week by 0.5 g until the patient improves or the daily dose reaches 3 g. Side effects, particularly neutropenia and thrombocy- topenia, occur in 10-25% and are serious in 2-5%. Sulfasalazine also causes hemolysis in patients with glucose-6- phosphate dehydrogenase (G6PD) deficiency, so a G6PD level should be checked before initiating sulfasalazine. Patients with aspirin sensitivity should not be given sul- fasalazine. Patients taking sulfasalazine should have com- plete blood counts monitored every 2-4 weeks for the first 3 months, then every 3 months. 3. Leflunomide—Leflunomide, a pyrimidine synthesis inhibitor, is also FDA-approved for treatment of rheuma- toid arthritis and is administered as a single oral daily dose of 20 mg. The most frequent side effects are diarrhea, rash, reversible alopecia, and hepatotoxicity. Some patients experience dramatic unexplained weight loss. The drug is carcinogenic, teratogenic, and has a half-life of 2 weeks. Thus, it is contraindicated in premenopausal women or in men who wish to father children. 4. Antimalarials—Hydroxychloroquine sulfate is the anti- malarial agent most often used against rheumatoid arthri- tis. Monotherapy with hydroxychloroquine should be reserved for patients with mild disease because only a small percentage will respond and in some of those cases only after 3-6 months of therapy. Hydroxychloroquine is often used in combination with other conventional DMARDs, particularly methotrexate and sulfasalazine. The advantage of hydroxychloroquine is its comparatively low toxicity, especially at a dosage of 200-400 mg/d orally (not to exceed 6.5 mg/kg/d). The most important reaction, pig- mentary retinitis causing visual loss, is rare at this dose. Ophthalmologic examinations every 12 months are required when this drug is used for long-term therapy. Other reactions include neuropathies and myopathies of both skeletal and cardiac muscle, which usually improve when the drug is withdrawn. 5. Minocycline—Minocycline is more effective than pla- cebo for rheumatoid arthritis. It is reserved for early, mild cases, since its efficacy is modest, and it works better during the first year of rheumatoid arthritis. The mechanism of action is not clear, but tetracyclines do have anti-inflam- matory properties, including the ability to inhibit destruc- tive enzymes such as collagenase. The dosage of minocycline is 200 mg orally daily. Adverse effects are uncommon except for dizziness, which occurs in about 10%. D. Biologic DMARDs usually administered at a dosage of 50 mg subcutaneously once per week. Infliximab, a chimeric monoclonal anti- body, is administered at a dosage of 3-10 mg/kg intrave- nously; infusions are repeated after 2, 6, 10, and 14 weeks and then are administered every 8 weeks. Adalimumab, a human monoclonal antibody that binds to TNF, is given at a dosage of 40 mg subcutaneously every other week. The dose for golimumab, a human anti-TNF monoclonal anti- body, is 50 mg subcutaneously once monthly. Certolizumab pegol is a PEGylated monoclonal antibody TNF inhibitor; the dose is 200-400 mg subcutaneously every 2 to 4 weeks. Each drug produces substantial improvement in more than 60% of patients. Each is usually very well tolerated. Minor irritation at injection sites is the most common side effect of etanercept and adalimumab. Rarely, nonrecurrent leu- kopenia develops in patients. TNF plays a physiologic role in combating many types of infection; TNF inhibitors have been associated with a several-fold increased risk of serious bacterial infections and a striking increase in granuloma- tous infections, particularly reactivation of tuberculosis. Screening for latent tuberculosis (see Chapter 9) is manda- tory before the initiation of TNF blockers. It is prudent to suspend TNF blockers when a fever or other manifesta- tions of a clinically important infection develops in a patient. Demyelinating neurologic complications that resemble multiple sclerosis have been reported rarely in patients taking etanercept, but the true magnitude of this risk—likely quite small—has not been determined with precision. While there are conflicting data with respect to increased risk of malignancy, in 2009, the FDA issued a safety alert about case reports of malignancies, including leukemias, in patients treated with TNF inhibitors. Contrary to expectation, TNF inhibitors were not effective in the treatment of congestive heart failure. The use of infliximab, in fact, was associated with increased morbidity in a con- gestive heart failure trial. Consequently, TNF inhibitors should be used with extreme caution in patients with con- gestive heart failure. Infliximab can rarely cause anaphy- laxis and induce anti-DNA antibodies (but rarely clinically evident SLE). A final concern about TNF inhibitors is the expense, which is more than $10,000 per year. 2. Abatacept—Abatacept, a recombinant protein made by fusing a fragment of the Fc domain of human IgG with the extracellular domain of a T cell inhibitory receptor (CTLA4), blocks T-cell costimulation. It is approved by the FDA for use in rheumatoid arthritis and produces clinically meaningful responses in approximately 50% of individuals whose disease is active despite the combination of metho- trexate and a TNF inhibitor. 1. Tumor necrosis factor inhibitors—Inhibitors of tumor necrosis factor (TNF)—a pro-inflammatory 3. Rituximab—Rituximab is a humanized mouse mono- cytokine—are fulfilling the aim of targeted therapy for rheumatoid arthritis. These medications are frequently added to the treatment of patients who have not responded adequately to methotrexate and are increasingly used as initial therapy in combination with methotrexate for patients with poor prognostic factors. Five inhibitors are in use: etanercept, infliximab, adali- mumab, golimumab, and certolizumab pegol. Etanercept, a soluble recombinant TNF receptor:Fc fusion protein, is clonal antibody that depletes B cells. It is approved by the FDA to be used in combination with methotrexate for patients whose disease has been refractory to treatment with a TNF inhibitor. 4. Tocilizumab—Tocilizumab is a monoclonal antibody that blocks the receptor for IL-6, an inflammatory cytokine involved in the pathogenesis of rheumatoid arthritis. It also is approved by the FDA to be used in combination with methotrexate for patients whose disease has been refrac- tory to treatment with a TNF inhibitor. E. DMARD Combinations As a general rule, DMARDs have greater efficacy when administered in combination than when used individually. Currently, the most commonly used combination is that of methotrexate with one of the TNF inhibitors, which clearly is superior to methotrexate alone. The urge to use combi- nation therapies with TNF inhibitors as the initial treat- ment for rheumatoid arthritis, however, has been tempered by concerns about their safety and cost. The American College of Rheumatology has published detailed recom- mendations on the initiation of DMARD combinations. ``Course & Prognosis After months or years, deformities may occur; the most common are ulnar deviation of the fingers, boutonnière deformity (hyperextension of the DIP joint with flexion of the PIP joint), "swan-neck" deformity (flexion of the DIP joint with extension of the PIP joint), valgus deformity of the knee, and volar subluxation of the MTP joints. The excess mortality associated with rheumatoid arthritis is largely due to cardiovascular disease that is unexplained by traditional risk factors and that appears to be a result of deleterious effects of chronic systemic inflammation on the vascular system. ``When to Refer Early referral to a rheumatologist is essential for appropriate diagnosis and the timely introduction of effective pharma- cologic and nonpharmacologic (physical and occupational) therapy.