InternalMed_Harrison

InternalMed_Harrison. Some risk factors increase vulnerability of the joint through local effects on the joint environment. With changes in joint anatomy, for example, load across the joint is no longer distributed evenly across the joint surface, but rather shows an increase in focal stress. In the hip, three uncommon developmental abnormalities occurring in utero or in childhood, congenital dysplasia, Legg-Perthes disease, and slipped capital femoral epiphysis, leave a child with distortions of hip joint anatomy that often lead to OA later in life. Girls are predominantly affected by acetabular dysplasia, a mild form of congenital dislocation, whereas the other abnormalities more often affect boys. Depending on the severity of the anatomic abnormalities, hip OA occurs either in young adulthood (severe abnormalities) or middle age (mild abnormalities).


InternalMed_Harrison

InternalMed_Harrison. Major injuries to a joint also can produce anatomic abnormalities that leave the joint susceptible to OA. For example, a fracture through the joint surface often causes OA in joints in which the disease is otherwise rare such as the ankle and the wrist. Avascular necrosis can lead to collapse of dead bone at the articular surface, producing anatomic irregularities and subsequent OA. Tears of ligamentous and fibrocartilaginous structures that protect the joints, such as the anterior cruciate ligament and the meniscus in the knee and the labrum in the hip, can lead to premature OA. Meniscal tears increase with age and when chronic are often asymptomatic but lead to adjacent cartilage damage and accelerated OA. Even injuries in which the affected person never received a diagnosis may increase risk of OA. For example, in the Framingham Study subjects, men with a history of major knee injury, but no surgery, had a 3.5-fold increased risk for subsequent knee OA.


InternalMed_Harrison

InternalMed_Harrison. Another source of anatomic abnormality is malalignment across the joint (Fig. 394-5). This factor has been best studied in the knee, which is the fulcrum of the longest lever arm in the body. Varus (bowlegged) knees with OA are at exceedingly high risk of cartilage loss in the medial or inner compartment of the knee, whereas valgus (knockkneed) malalignment predisposes to rapid cartilage loss in the lateral compartment. Malalignment causes this effect by increasing stress on a focal area of cartilage, which then breaks down. There is evidence that malalignment in the knee not only causes cartilage loss but leads FIGUrE 394-5 The two types of limb malalignment in the frontal plane: varus, in which the stress is placed across the medial compartment of the knee joint, and valgus, which places excess stress across the lateral compartment of the knee.


InternalMed_Harrison

InternalMed_Harrison. to underlying bone damage, producing bone marrow lesions seen on magnetic resonance imaging (MRI). Malalignment in the knee often produces such a substantial increase in focal stress within the knee (as evidenced by its destructive effects on subchondral bone) that severely malaligned knees may be destined to progress regardless of the status of other risk factors. Weaknessin the quadriceps muscles bridging theknee increasesthe risk of the development of painful OA in the knee. Patients with knee OA have impaired proprioception across their knees, and this may predispose them to further disease progression. The role of bone in serving as a shock absorber for impact load is not well understood, but persons with increased bone density are at high risk of OA, suggesting that the resistance of bone to impact during joint use may play a role in disease development.


InternalMed_Harrison

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


InternalMed_Harrison

InternalMed_Harrison. Obesity’s effect on the development and progression of disease is mediated mostly through the increased loading in weight-bearing joints that occurs in overweight persons. However, a modest association of obesity with an increased risk of hand OA suggests that there may be a systemic metabolic factor circulating in obese persons that affects disease risk also.


InternalMed_Harrison

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


InternalMed_Harrison

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


InternalMed_Harrison

InternalMed_Harrison. The pathology of OA provides evidence of the involvement of many joint structures in disease. Cartilage initially shows surface fibrillation and irregularity. As disease progresses, focal erosions develop there, and these eventually extend down to the subjacent bone. With further progression,cartilageerosiondowntoboneexpandstoinvolvealarger proportion of the joint surface, even though OA remains a focal disease with nonuniform loss of cartilage (Fig. 394-6). After an injury to cartilage, chondrocytes undergo mitosis and clustering. Although the metabolic activity of these chondrocyte clusters is FIGUrE 394-6 Pathologic changes of osteoarthritis in a toe joint.


InternalMed_Harrison

InternalMed_Harrison. FIGUrE 394-6 Pathologic changes of osteoarthritis in a toe joint. Notethenonuniformlossofcartilage(arrowhead vssolid arrow),theincreasedthicknessofthesubchondralboneenvelope(solid arrow),andtheosteophyte(open arrow).(From the American College of Rheumatology slide collection.) high, theneteffect of this activityisto promoteproteoglycandepletion in the matrix surrounding the chondrocytes. This is because the cata bolicisgreaterthanthesyntheticactivity.Asdiseasedevelops,collagen matrix becomes damaged, the negative charges of proteoglycans get exposed, and cartilage swells from ionic attraction to water molecules. Because in damaged cartilage proteoglycans are no longer forced into close proximity, cartilage does not bounce back after loading as it did when healthy, and cartilage becomes vulnerable to further injury. Chondrocytes at the basal level of cartilage undergo apoptosis.


InternalMed_Harrison

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


InternalMed_Harrison

InternalMed_Harrison. At the margin of the joint, near areas of cartilage loss, osteophytes form. These start as outgrowths of new cartilage, and with neurovascular invasion from the bone, this cartilage ossifies. Osteophytes are an important radiographic hallmark of OA. In malaligned joints, osteophytes grow larger on the side of the joint subject to most loading stress(e.g.,in varusknees,osteophytesgrowlargeron themedialside). The synovium produces lubricating fluids that minimize shear stress during motion. In healthy joints, the synovium consists of a single discontinuous layer filled with fat and containing two types of cells, macrophages and fibroblasts, but in OA, it can sometimes become edematousand inflamed.Thereisamigrationofmacrophages from the periphery into the tissue, and cells lining the synovium proliferate. Enzymes secreted by the synovium digest cartilage matrix that has been released from the surface of the cartilage.


InternalMed_Harrison

InternalMed_Harrison. Additionalpathologicchangesoccurinthecapsule,whichstretches, becomes edematous, and can become fibrotic. The pathology of OA is not identical across joints. In hand joints with severe OA, for example, there are often cartilage erosions in the center ofthejointprobablyproduced by bony pressure from the opposite side of the joint. Basic calcium phosphate and calcium pyrophosphate dihydrate crystals are present microscopically in most joints with end-stage OA. Their role in osteoarthritic cartilage is unclear, but their release from cartilage into the joint space and joint fluid likely triggers synovial 2230 inflammation, which can, in turn, produce release of enzymes and trigger nociceptive stimulation.


InternalMed_Harrison

InternalMed_Harrison. Because cartilage is aneural, cartilage loss in a joint is not accompanied by pain. Thus, pain in OA likely arises from structures outside the cartilage. Innervated structures in the joint include the synovium, ligaments, joint capsule, muscles, and subchondralbone.Mostof these are not visualized by the x-ray, and the severity of x-ray changes in OA correlates poorly with pain severity.


InternalMed_Harrison

InternalMed_Harrison. Based on MRI studies in osteoarthritic knees comparing those with and without pain and on studies mapping tenderness in unanesthetized joints, likely sources of pain include synovial inflammation, joint effusions, and bone marrow edema. Modest synovitis develops in many but not all osteoarthritic joints. Some diseased joints have no synovitis, whereas others have synovial inflammation that approaches the severity of joints with rheumatoid arthritis (Chap. 380). The presence of synovitis on MRI is correlated with the presence and severity of knee pain. Capsular stretching from fluid in the joint stimulates nociceptive fibers there, inducing pain. Increased focal loading as part of the disease not only damages cartilage but probably also injures the underlying bone. As a consequence, bone marrow edema appears on the MRI; histologically, this edema signals the presence of microcracks and scar, which are the consequences of trauma. These lesions may stimulate bone nociceptive fibers.


InternalMed_Harrison

InternalMed_Harrison. marrow edema appears on the MRI; histologically, this edema signals the presence of microcracks and scar, which are the consequences of trauma. These lesions may stimulate bone nociceptive fibers. Also, hemostatic pressure within bone rises in OA, and the increased pressure itself may stimulate nociceptive fibers, causing pain.


InternalMed_Harrison

InternalMed_Harrison. Painmayarisefromoutside the joint also, including bursaenearthe joints.Commonsourcesofpainnearthekneeareanserinebursitisand iliotibial band syndrome. Persons with chronic OA pain may develop nervous system alterations as a consequence of disease, changes which decrease inhibitory controls on nociception and its distribution. This may produce allodynia and hyperalgesia in some patients with OA.


InternalMed_Harrison

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


InternalMed_Harrison

InternalMed_Harrison. In knees, buckling may occur, in part, due to weakness of muscles crossing the joint. Mechanical symptoms, such as buckling, catching, or locking, could also signify internal derangement, such as meniscal tears, and need to be evaluated. In the knee, pain with activities requiring knee flexion, such as stair climbing and arising from a chair, often emanates from the patellofemoral compartment of the knee, which does not actively articulate until the knee is bent ~35°.


InternalMed_Harrison

InternalMed_Harrison. OA is the most common cause of chronic knee pain in persons over age 45, but the differential diagnosis is long. Inflammatory arthritis is likely if there is prolonged morning stiffness and many other joints are affected. Bursitis occurs commonly around knees and hips. A physical examination should focus on whether tenderness is over the joint line (at the junction of the two bones around which the joint is articulating) or is outside of it. Anserine bursitis, medial and distal to the knee, is an extremely common cause of chronic knee pain that may respond to a glucocorticoid injection. Prominent nocturnal pain in the absence of end-stage OA merits a distinct workup. For hip pain, OA can be detected by loss of internal rotation on passive movement, and pain isolated to an area lateral to the hip joint usually reflects the presence of trochanteric bursitis. No blood tests are routinely indicated for workup of patients with OA unless symptoms and signs suggest inflammatory arthritis.


InternalMed_Harrison

InternalMed_Harrison. No blood tests are routinely indicated for workup of patients with OA unless symptoms and signs suggest inflammatory arthritis. FIGUrE 394-7 X-ray of knee with medial osteoarthritis. Notethenarrowedjointspaceonmedialsideofthejointonly(white arrow),thesclerosisoftheboneinthemedialcompartmentprovidingevi-denceofcorticalthickening(black arrow),andtheosteophytesinthemedialfemur(white wedge). Examination of the synovial fluid is often more helpful diagnostically than an x-ray. If the synovial fluid white count is >1000/μL, inflammatory arthritis or gout or pseudogout is likely, the latter two being also identified by the presence of crystals.


InternalMed_Harrison

InternalMed_Harrison. X-rays are indicated to evaluate chronic hand pain and hip pain thought to be due to OA, as the diagnosis is often unclear without confirming radiographs. For knee pain, x-rays should be obtained if symptoms or signs are not typical of OA or if knee pain persists after inauguration of effective treatment. In OA, radiographic findings (Fig. 394-7) correlate poorly with the presence and severity of pain. Further, radiographs may be normal in early disease as they are insensitive to cartilage loss and other early findings. Although MRI may reveal the extent of pathology in an osteoarthritic joint, it is not indicated as part of the diagnostic workup. Findings such as meniscal tears andcartilage and bone lesions occurin most patients with OA in the knee, but almost never warrant a change in therapy.


InternalMed_Harrison

InternalMed_Harrison. The goals of the treatment of OA are to alleviate pain and minimize loss of physical function. To the extent that pain and loss of function are consequences of inflammation, of weakness across the joint, and of laxity and instability, the treatment of OA involves addressing each of these impairments. Comprehensive therapy consists of a multimodality approach including nonpharmacologic and pharmacologic elements. Patients with mild and intermittent symptoms may need only reassurance or nonpharmacologic treatments. Patients with on-going, disabling pain are likely to need both nonpharmacotherapy and pharmacotherapy. Treatments for knee OA have been more completely evaluated than those for hip and hand OA or for disease in other joints. Thus, although the principles of treatment are identical for OA in all joints, we shall focus below on the treatment of knee OA, noting specific recommendations for disease in other joints, especially when they differ from those for the knee.


InternalMed_Harrison

InternalMed_Harrison. Because OA is a mechanically driven disease, the mainstay of treatment involves altering loading across the painful joint and improving the function of joint protectors, so they can better distribute load across the joint. Ways of lessening focal load across the joint include: 1. avoiding activities that overload the joint, as evidenced by their causing pain; 2. improving the strength and conditioning of muscles that bridge the joint, so as to optimize their function; and 3. unloading the joint, either by redistributing load within the joint with a brace or a splint or by unloading the joint during weight bearing with a cane or a crutch.


InternalMed_Harrison

InternalMed_Harrison. unloading the joint, either by redistributing load within the joint with a brace or a splint or by unloading the joint during weight bearing with a cane or a crutch. The simplest effective treatment for many patients is to avoid activities that precipitate pain. For example, for the middle-aged patient whose long-distance running brings on symptoms of knee OA, a less demanding form of weight-bearing activity may alleviate all symptoms. For an older person whose daily constitutionals up and down hills bring on knee pain, routing the constitutional away from hills might eliminate symptoms. Each pound of weight increases the loading across the knee threeto sixfold. Weight loss may have a commensurate multiplier effect, unloading both knees and hips and probably relieving pain in those joints.


InternalMed_Harrison

InternalMed_Harrison. In hand joints affected by OA, splinting, by limiting motion, often minimizes pain for patients with involvement especially in the base of the thumb. Weight-bearing joints such as knees and hips can be unloaded by using a cane in the hand opposite to the affected joint for partial weight bearing. A physical therapist can help teach the patient how to use the cane optimally, including ensuring that its height is optimal for unloading. Crutches or walkers can serve a similar beneficial function. Exercise Osteoarthritic pain in knees or hips during weight bearing results in lack of activity and poor mobility, and because OA is so common, the inactivity that results represents a public health concern, increasing the risk of cardiovascular disease and obesity. Aerobic capacity is poor in most elders with symptomatic knee OA, worse than others of the same age.


InternalMed_Harrison

InternalMed_Harrison. Weakness in muscles that bridge osteoarthritic joints is multi-factorial in etiology. First, there is a decline in strength with age. Second, with limited mobility comes disuse muscle atrophy. Third, patients with painful knee or hip OA alter their gait so as to lessen loading across the affected joint, and this further diminishes muscle use. Fourth, “arthrogenous inhibition” may occur, whereby contraction of muscles bridging the joint is inhibited by a nerve afferent feedback loop emanating in a swollen and stretched joint capsule; this prevents maximal attainment of voluntary maximal strength. Because adequate muscle strength and conditioning are critical to joint protection, weakness in a muscle that bridges a diseased joint makes the joint more susceptible to further damage and pain. The degree of weakness correlates strongly with the severity of joint pain and the degree of physical limitation. One of the cardinal elements of the treatment of OA is to improve the functioning of


InternalMed_Harrison

InternalMed_Harrison. The degree of weakness correlates strongly with the severity of joint pain and the degree of physical limitation. One of the cardinal elements of the treatment of OA is to improve the functioning of muscles surrounding the joint.


InternalMed_Harrison

InternalMed_Harrison. For knee and hip OA, trials have shown that exercise lessens pain and improves physical function. Most effective exercise regimens consist of aerobic and/or resistance training, the latter of which focuses on strengthening muscles across the joint. Exercises are likely to be effective, especially if they train muscles for the activities a person performs daily. Activities that increase pain in the joint should be avoided, and the exercise regimen needs to be individualized to optimize effectiveness. Range-of-motion exercises, which do not strengthen muscles, and isometric exercises that strengthen muscles, but not through range of motion, are unlikely to be effective by themselves. Low-impact exercises, including water aerobics and water resistance training, are often better tolerated by patients than exercises involving impact loading, such as running or treadmill exercises. A patient should be referred to an exercise class or to a therapist who can create an individualized regimen,


InternalMed_Harrison

InternalMed_Harrison. patients than exercises involving impact loading, such as running or treadmill exercises. A patient should be referred to an exercise class or to a therapist who can create an individualized regimen, and then an individualized home-based regimen can be crafted. In addition to conventional exercise regimens, tai chi may be effective for knee OA. However, there is no strong evidence that patients with hand OA benefit from therapeutic exercise.


InternalMed_Harrison

InternalMed_Harrison. Adherence over the long term is the major challenge to an exer-2231 cise prescription. In trials involving patients with knee OA, who are engaged in exercise treatment, from a third to over half of patients stopped exercising by 6 months. Less than 50% continued regular exercise at 1 year. The strongest predictor of a patient’s continued exercise is a previous personal history of successful exercise. Physicians should reinforce the exercise prescription at each clinic visit, help the patient recognize barriers to ongoing exercise, and identify convenient times for exercise to be done routinely. The combination of exercise with calorie restriction and weight loss is especially effective in lessening pain.


InternalMed_Harrison

InternalMed_Harrison. Correction of Malalignment Malalignment in the frontal plane (varusvalgus) markedly increases the stress across the joint, which can lead to progression of disease and to pain and disability (Fig. 394-5). Correcting malalignment, either surgically or with bracing, may relieve pain in persons whose knees are malaligned. Malalignment develops over years as a consequence of gradual anatomic alterations of the joint and bone, and correcting it is often very challeng ing. One way is with a fitted brace, which takes an often varus osteoarthritic knee and straightens it by putting valgus stress across the knee. Unfortunately, many patients are unwilling to wear a realigning knee brace; in addition, in patients with obese legs, braces may slip with usage and lose their realigning effect. They are indicated for willing patients who can learn to put them on correctly and on whom they do not slip.


InternalMed_Harrison

InternalMed_Harrison. Other ways of correcting malalignment across the knee include the use of orthotics in footwear. Unfortunately, although they may have modest effects on knee alignment, trials have heretofore not demonstrated efficacy of a lateral wedge orthotic versus placebo wedges. Pain from the patellofemoral compartment of the knee can be caused by tilting of the patella or patellar malalignment with the patella riding laterally or medially in the femoral trochlear groove. Using a brace to realign the patella, or tape to pull the patella back into the trochlear sulcus or reduce its tilt, has been shown, when compared to placebo taping in clinical trials, to lessen patellofemoral pain. However, patients may find it difficult to apply tape, and skin irritation from the tape is common. Commercial patellar braces may be a solution, but there is insufficient evidence on their efficacy to recommend them.


InternalMed_Harrison

InternalMed_Harrison. Although their effect on malalignment is questionable, neoprene sleeves pulled to cover the knee lessen pain and are easy to use and popular among patients. The explanation for their therapeutic effect on pain is unclear. In patients with knee OA, acupuncture produces modest pain relief compared to placebo needles and may be an adjunctive treatment. Although nonpharmacologic approaches to therapy constitute its mainstay, pharmacotherapy serves an important adjunctive role in OA treatment. Available drugs are administered using oral, topical, and intraarticular routes. acetaminophen, Nonsteroidal anti-Inflammatory Drugs (NSaIDs), and Cyclooxygenase-2 (COX-2) Inhibitors Acetaminophen (paracetamol) is the initial analgesic of choice for patients with OA in knees, hips, or hands. For some patients, it is adequate to control symptoms, in which case more toxic drugs such as NSAIDs can be avoided. Doses up to 1 g three times daily can be used (Table 394-1).


InternalMed_Harrison

InternalMed_Harrison. NSAIDs are the most popular drugs to treat osteoarthritic pain. They can be administered either topically or orally. In clinical trials, oral NSAIDs produce ~30% greater improvement in pain than high-dose acetaminophen. Occasional patients treated with NSAIDs experience dramatic pain relief, whereas others experience little improvement. Initially, NSAIDs should be administered topically or taken orally on an “as needed” basis because side effects are less frequent with low intermittent doses. If occasional medication use is insufficiently effective, then daily treatment may be indicated, with Acetaminophen Up to 1 g tid Prolongs half-life of warfarin. Make sure patient is not taking other treatments containing acetaminophen to avoid hepatic toxicity.


InternalMed_Harrison

InternalMed_Harrison. Acetaminophen Up to 1 g tid Prolongs half-life of warfarin. Make sure patient is not taking other treatments containing acetaminophen to avoid hepatic toxicity. aPatients at high risk include those with previous gastrointestinal events, persons ≥60 years, and persons taking glucocorticoids. Trials have shown the efficacy of proton pump inhibitors and misoprostol in the prevention of ulcers and bleeding. Misoprostol is associated with a high rate of diarrhea and cramping; therefore, proton pump inhibitors are more widely used to reduce NSAID-related gastrointestinal symptoms. Abbreviations: COX-2, cyclooxygenase-2; NSAIDs, nonsteroidal anti-inflammatory drugs. Source: Adapted from DT Felson: N Engl J Med 354:841, 2006. an anti-inflammatory dose selected (Table 394-1). Patients should be reminded to take low-dose aspirin and ibuprofen at different times to eliminate a drug interaction.


InternalMed_Harrison

InternalMed_Harrison. NSAIDs taken orally have substantial and frequent side effects, the most common of which is upper gastrointestinal toxicity, including dyspepsia, nausea, bloating, gastrointestinal bleeding, and ulcer disease. Some 30–40% of patients experience upper gastrointestinal (GI) side effects so severe as to require discontinuation of medication. To minimize the risk of nonsteroidal-related GI side effects, patients should not take two NSAIDs and should take medications after food; if risk is high, patients should take a gastroprotective agent, such as a proton pump inhibitor. Certain oral agents are safer to the stomach than others, including nonacetylated salicylates and nabumetone. Major NSAID-related GI side effects can occur in patients who do not complain of upper GI symptoms. In one study of patients hospitalized for GI bleeding, 81% had no premonitory symptoms.


InternalMed_Harrison

InternalMed_Harrison. Because of the increased rates of cardiovascular events associated with COX-2 inhibitors and with some conventional NSAIDs such as diclofenac, many of these drugs are not appropriate long-term treatment choices for older persons with OA, especially those at high risk of heart disease or stroke. The American Heart Association has identified rofecoxib and all other COX-2 inhibitors as putting patients at high risk, although low doses of celecoxib (≤200 mg/d) may not be associated with an elevation of risk. The only conventional NSAID that appears safe from a cardiovascular perspective is naproxen, but it does have GI toxicity.


InternalMed_Harrison

InternalMed_Harrison. There are other common side effects of NSAIDs, including the tendency to develop edema because of prostaglandin inhibition of afferent blood supply to glomeruli in the kidneys and, for similar reasons, a predilection toward reversible renal insufficiency. Blood pressure may increase modestly in some NSAID-treated patients. Oral NSAIDs should not be used in patients with stage IV or V renal disease and should be used with caution in those with stage III disease.


InternalMed_Harrison

InternalMed_Harrison. NSAIDs can be placed into a gel or topical solution with another chemical modality that enhances penetration of the skin barrier creating a topical NSAID. When absorbed through the skin, plasma concentrations are an order of magnitude lower than with the same amount of drug administered orally or parenterally. However, when these drugs are administered topically in proximity to a superficial joint (knees, hands, but not hips), the drug can be found in joint tissues such as the synovium and cartilage. Trial results have varied but generally have found that topical NSAIDs are slightly less efficacious than oral agents, but have far fewer GI and systemic side effects. Unfortunately, topical NSAIDs often cause local skin irritation where the medication is applied, inducing redness, burning, or itching in up to 40% of patients (see Table 394-1).


InternalMed_Harrison

InternalMed_Harrison. Intraarticular Injections: Glucocorticoids and Hyaluronic acid Because synovial inflammation is likely to be a major cause of pain in patients with OA, local anti-inflammatory treatments administered intraarticularly may be effective in ameliorating pain, at least temporarily. Glucocorticoid injections provide such efficacy, but response is variable, with some patients having little relief of pain whereas others experience pain relief lasting several months. Glucocorticoid injections are useful to get patients over acute flares of pain and may be especially indicated if the patient has coexistent OA and crystal deposition disease, especially from calcium pyrophosphate dihydrate crystals (Chap. 395). There is no evidence that repeated glucocorticoid injections into the joint are dangerous. Hyaluronic acid injections can be given for treatment of symptoms in knee and hip OA, but there is controversy as to whether they have efficacy versus placebo (Table 394-1).


InternalMed_Harrison

InternalMed_Harrison. Hyaluronic acid injections can be given for treatment of symptoms in knee and hip OA, but there is controversy as to whether they have efficacy versus placebo (Table 394-1). Other Classes of Drugs and Nutraceuticals For patients with symptomatic knee or hip OA who have not had an adequate response to the treatments above and are either unwilling to undergo or are not candidates for total joint arthroplasty, opioid analgesics have shown modest efficacy and can be tried. Opioid management plans and patient selection are critical. Another option is the use of duloxetine, which has demonstrated modest efficacy in OA. Recent guidelines recommend against the use of glucosamine or chondroitin for OA. Large publicly supported trials have failed to show that, compared with placebo, these compounds relieve pain in persons with disease.


InternalMed_Harrison

InternalMed_Harrison. Optimal nonsurgical therapy for OA is often achieved by trial and error, with each patient having idiosyncratic responses to specific treatments. When medical therapies have failed and the patient has an unacceptable reduction in their quality of life and ongoing pain gout and Other Crystal-associated arthropathies H. Ralph Schumacher, Lan X. Chen Theuseofpolarizinglightmicroscopyduringsynovialfluidanalysisin1961byMcCartyandHollanderandthesubsequentapplication395 and disability, then at least for knee and hip OA, total joint arthroplasty is indicated.


InternalMed_Harrison

InternalMed_Harrison. For knee OA, several operations are available. Arthroscopic debridement and lavage have diminished in popularity after randomized trials evaluating this operation have showed that its efficacy is no greater than that of sham surgery or no treatment for relief of pain or disability. Even mechanical symptoms such as buckling, which are extremely common in patients with knee OA, do not respond to arthroscopic debridement. Although arthroscopic meniscectomy is indicated for acute meniscal tears in which symptoms such as locking and acute pain are clearly related temporally to a knee injury that produced the tear, recent trials show that doing a partial meniscectomy in persons with OA and a symptomatic meniscal tear does not relieve knee pain or improve function.


InternalMed_Harrison

InternalMed_Harrison. For patients with knee OA isolated to the medial compartment, operations to realign the knee to lessen medial loading can relieve pain. These include a high tibial osteotomy, in which the tibia is broken just below the tibial plateau and realigned so as to load the lateral, nondiseased compartment, or a unicompartmental replacement with realignment. Each surgery may provide the patient with years of pain relief before a total knee replacement is required.


InternalMed_Harrison

InternalMed_Harrison. Ultimately, when the patient with knee or hip OA has failed medical treatment modalities and remains in pain, with limitations of physical function that compromise the quality of life, the patient should be referred for total knee or hip arthroplasty. These are highly efficacious operations that relieve pain and improve function in the vast majority of patients, although rates of success are higher for hip than knee replacement. Currently failure rates for both are ~1% per year, although these rates are higher in obese patients. The chance of surgical success is greater in centers where at least 25 such operations are performed yearly or with surgeons who perform multiple operations annually. The timing of knee or hip replacement is critical. If the patient suffers for many years until their functional status has declined substantially, with considerable muscle weakness, postoperative functional status may not improve to a level achieved by others who underwent operation earlier in


InternalMed_Harrison

InternalMed_Harrison. their functional status has declined substantially, with considerable muscle weakness, postoperative functional status may not improve to a level achieved by others who underwent operation earlier in their disease course.


InternalMed_Harrison

InternalMed_Harrison. Cartilage regeneration Chondrocyte transplantation has not been found to be efficacious in OA, perhaps because OA includes pathology of joint mechanics, which is not corrected by chondrocyte transplants. Similarly, abrasion arthroplasty (chondroplasty) has not been well studied for efficacy in OA, but it produces fibrocartilage in place of damaged hyaline cartilage. Both of these surgical attempts to regenerate and reconstitute articular cartilage may be more likely to be efficacious early in disease when joint malalignment and many of the other noncartilage abnormalities that characterize OA have not yet developed. of other crystallographic techniques, such as electron microscopy, energy-dispersive elemental analysis, and x-ray diffraction, have allowed investigators to identify the roles of different microcrystals, including monosodium urate (MSU), calcium pyrophosphate (CPP), calcium apatite (apatite), and calcium oxalate (CaOx), in inducing


InternalMed_Harrison

InternalMed_Harrison. Enthesitis Peculiar type of osteoarthritis acute or chronic arthritis or periarthritis. Theclinical events that result from deposition of MSU, CPP, apatite, and CaOx have many similarities but also have important differences. Because of often similar clinical presentations, the need to perform synovial fluid analysis to distinguish the type of crystal involved must be emphasized. Polarized light microscopy alone can identify most typical crystals; apatite, however, is an exception. Aspiration and analysis of effusions are also important to assess the possibility of infection. Apart from the identification of specific microcrystalline materials or organisms, synovial fluid characteristics in crystal-associated diseases are nonspecific, and synovial fluid can be inflammatory or noninflammatory. Without crystal identification, these diseases can be confused with rheumatoid or other types of arthritis. A list of possible musculoskeletal manifestations of crystal-associated arthritis is


InternalMed_Harrison

InternalMed_Harrison. Without crystal identification, these diseases can be confused with rheumatoid or other types of arthritis. A list of possible musculoskeletal manifestations of crystal-associated arthritis is shown in Table 395-1.


InternalMed_Harrison

InternalMed_Harrison. Goutisametabolicdiseasethatmostoftenaffectsmiddle-agedtoelderly men and postmenopausal women. It results from an increased body poolofuratewithhyperuricemia.Ittypicallyischaracterizedbyepisodic acute arthritis or chronic arthritis caused by deposition of MSU crystals in joints and connective tissue tophi and the risk for deposition in kidney interstitium or uric acid nephrolithiasis (Chap. 431e).


InternalMed_Harrison

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


InternalMed_Harrison

InternalMed_Harrison. length with no residual symptoms until the next episode. Several events may precipitate acute gouty arthritis: dietary excess, trauma, surgery, excessive ethanol ingestion, hypouricemic therapy, and serious medical illnesses such as myocardial infarction and stroke.


InternalMed_Harrison

InternalMed_Harrison. After many acute mono-or oligoarticular attacks, a proportion of gouty patients may present with a chronic nonsymmetric synovitis, causing potential confusion with rheumatoid arthritis (Chap. 380). Less commonly, chronic gouty arthritis will be the only manifestation, and, more rarely, the disease will manifest only as periarticular tophaceous deposits in the absence of synovitis. Women represent only 5–20% of all patients with gout. Most women with gouty arthritis are postmenopausalandelderly,haveosteoarthritis and arterial hypertension that causes mild renal insufficiency, and usually are receiving diuretics. Premenopausal gout is rare. Kindreds of precocious gout in young females caused by decreased renal urate clearance and renal insufficiency have been described.


InternalMed_Harrison

InternalMed_Harrison. Laboratory Diagnosis Even if the clinical appearance strongly suggests gout, the presumptive diagnosis ideally should be confirmed by needle aspiration of acutely or chronically involved joints or tophaceous deposits. Acute septic arthritis, several of the other crystalline-associated arthropathies, palindromic rheumatism, and psoriatic arthritis may present with similar clinical features. During acute gouty FIGUrE 395-1 Extracellular and intracellular monosodium urate crystals, as seen in a fresh preparation of synovial fluid, illustrate needle-and rod-shaped crystals. These crystals are strongly negative birefringent crystals under compensated polarized light microscopy; 400×.


InternalMed_Harrison

InternalMed_Harrison. attacks, needle-shaped MSU crystals typically are seen both intracellularly and extracellularly (Fig. 395-1). With compensated polarized light, thesecrystalsarebrightlybirefringentwithnegativeelongation.Synovial fluid leukocyte counts are elevated from 2000 to 60,000/μL. Effusions appear cloudy due to the increased numbers of leukocytes. Large amounts of crystals occasionally produce a thick pasty or chalky joint fluid. Bacterial infection can coexist with urate crystals in synovial fluid; if there is any suspicion of septic arthritis, joint fluid must be cultured. MSU crystals also can often be demonstrated in the first metatarsophalangeal joint and in knees not acutely involved with gout. Arthrocentesis of these joints is a useful technique to establish the diagnosis of gout between attacks.


InternalMed_Harrison

InternalMed_Harrison. Serum uric acid levels can be normal or low at the time of an acute attack, as inflammatory cytokines can be uricosuric and effective initiation of hypouricemic therapy can precipitate attacks. This limits the value of serum uric acid determinations for the diagnosis of gout. Nevertheless, serum urate levels are almost always elevated at some time and are important to use to follow the course of hypouricemic therapy. A 24-h urine collection for uric acid can, in some cases, be useful in assessing the risk of stones, elucidating overproduction or underexcretion of uric acid, and deciding whether it may be appropriate to use a uricosuric therapy (Chap. 431e). Excretion of >800 mg of uric acid per 24 h on a regular diet suggests that causes of overproduction of purine should be considered. Urinalysis, serum creatinine, hemoglobin, white blood cell (WBC) count, liver function tests, and serum lipids should be obtained because of possible pathologic sequelae of gout and other associated


InternalMed_Harrison

InternalMed_Harrison. Urinalysis, serum creatinine, hemoglobin, white blood cell (WBC) count, liver function tests, and serum lipids should be obtained because of possible pathologic sequelae of gout and other associated diseases requiring treatment and as baselines because of possible adverse effects of gout treatment.


InternalMed_Harrison

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


InternalMed_Harrison

InternalMed_Harrison. The mainstay of treatment during an acute attack is the administration of anti-inflammatory drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, or glucocorticoids. NSAIDs are used most often in individuals without complicating comorbid conditions. Both colchicine and NSAIDs may be poorly tolerated and dangerous in the elderly and in the presence of renal insufficiency and gastrointestinal disorders. Ice pack applications and rest of the involved joints can be helpful. Colchicine given orally is a traditional and effective treatment if used early in an attack. Useful regimens are one 0.6-mg tablet given every 8 h with subsequent tapering or 1.2 mg followed by 0.6 mg in 1 h with subsequent day dosing depending on response. This is generally better tolerated than the formerly advised higher dose regimens. The drug must be at least temporarily discontinued promptly at the first sign of loose stools, and symptomatic treatment must be given for the diarrhea. Intravenous


InternalMed_Harrison

InternalMed_Harrison. advised higher dose regimens. The drug must be at least temporarily discontinued promptly at the first sign of loose stools, and symptomatic treatment must be given for the diarrhea. Intravenous colchicine has been taken off the market. NSAIDs given in full anti-inflammatory doses are effective in ∼90% of patients, and the resolution of signs and symptoms usually occurs in 5–8 days. The most effective drugs are any of those with a short half-life and include indomethacin, 25–50 mg tid; naproxen, 500 mg bid; ibuprofen, 800 mg tid; diclofenac, 50 mg tid; and celecoxib 800 mg followed by 400 mg 12 h later, then 400 mg bid.


InternalMed_Harrison

InternalMed_Harrison. Glucocorticoids given IM or orally, for example, prednisone, 30–50 mg/d as the initial dose and gradually tapered with the resolution of the attack, can be effective in polyarticular gout. For a single joint or a few involved joints, intraarticular triamcinolone acetonide, 20–40 mg, or methylprednisolone, 25–50 mg, have been effective and well tolerated. Based on recent evidence on the essential role of the inflammasome and interleukin 1β (IL-1β) in acute gout, anakinra has been used, and other inhibitors of IL-1β, including canakinumab and rilonacept, are under investigation.


InternalMed_Harrison

InternalMed_Harrison. Ultimate control of gout requires correction of the basic underlying defect: the hyperuricemia. Attempts to normalize serum uric acid to <300–360 μmol/L (5.0–6.0 mg/dL) to prevent recurrent gouty attacks and eliminate tophaceous deposits are critical and entail a commitment to hypouricemic regimens and medications that generally are required for life. Hypouricemic drug therapy should be considered when, as in most patients, the hyperuricemia cannot be corrected by simple means (control of body weight, low-purine diet, increase in liquid intake, limitation of ethanol use, decreased use of fructose-containing foods and beverages, and avoidance of diuretics). The decision to initiate hypouricemic therapy usually is made taking into consideration the number of acute attacks (urate lowering may be cost-effective after two attacks), serum uric acid levels (progression is more rapid in patients with serum uric acid >535 μmol/L [>9.0 mg/dL]), the patient’s willingness to commit to lifelong


InternalMed_Harrison

InternalMed_Harrison. may be cost-effective after two attacks), serum uric acid levels (progression is more rapid in patients with serum uric acid >535 μmol/L [>9.0 mg/dL]), the patient’s willingness to commit to lifelong therapy, or the presence of uric acid stones. Urate-lowering therapy should be initiated in any patient who already has tophi or chronic gouty arthritis. Uricosuric agents such as probenecid can be used in patients with good renal function who underexcrete uric acid, with <600 mg in a 24-h urine sample. Urine volume should be maintained by ingestion of 1500 mL of water every day. Probenecid can be started at a dose of 250 mg twice daily and increased gradually as needed up to 3 g per day to achieve and maintain a serum uric acid level of less than 6 mg/dL. Probenecid is generally not effective in patients with serum creatinine levels >177 μmol/L (2 mg/dL). These patients may require allopurinol or benzbromarone (not available in the United States). Benzbromarone is another uricosuric drug


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InternalMed_Harrison. in patients with serum creatinine levels >177 μmol/L (2 mg/dL). These patients may require allopurinol or benzbromarone (not available in the United States). Benzbromarone is another uricosuric drug that is more effective in patients with chronic kidney disease. Some agents used to treat common comorbidities, including losartan, fenofibrate, and amlodipine, have some mild uricosuric effects.


InternalMed_Harrison

InternalMed_Harrison. The xanthine oxidase inhibitor allopurinol is by far the most commonly used hypouricemic agent and is the best drug to lower serum urate in overproducers, urate stone formers, and patients with renal disease. It can be given in a single morning dose, usually 100 mg initially and increasing up to 800 mg if needed. In patients with chronic renal disease, the initial allopurinol dose should be lower and adjusted depending on the serum creatinine concentration; for example, with a creatinine clearance of 10 mL/min, one generally would use 100 mg every other day. Doses can be increased gradually to reach the target urate level of less than 6 mg/dL. Toxicity of allopurinol has been recognized increasingly in patients who use thiazide diuretics, in patients allergic to penicillin and ampicillin, and in Asians expressing HLA-B*5801. The most serious side effects include life-threatening toxic epidermal necrolysis, systemic vasculitis, bone marrow suppression, granulomatous hepatitis, and


InternalMed_Harrison

InternalMed_Harrison. and in Asians expressing HLA-B*5801. The most serious side effects include life-threatening toxic epidermal necrolysis, systemic vasculitis, bone marrow suppression, granulomatous hepatitis, and renal failure. Patients with mild cutaneous reactions to allopurinol can reconsider the use of a uricosuric agent, undergo an attempt at desensitization to allopurinol, or take febuxostat, a new, chemically unrelated specific xanthine oxidase inhibitor. Febuxostat is approved in the United States at 40 or 80 mg once a day and does not require dose adjustment in mild to moderate renal disease. Pegloticase is a pegylated uricase, now available for patients who do not tolerate or fail full doses of other treatments. It is given intravenously usually at 8 mg every 2 weeks and can dramatically lower serum uric acid in up to 50% of such patients. New uricosurics are also undergoing investigation.


InternalMed_Harrison

InternalMed_Harrison. Urate-lowering drugs are generally not initiated during acute attacks but after the patient is stable and low-dose colchicine has been initiated to decrease the risk of the flares that often occur with urate lowering. Colchicine anti-inflammatory prophylaxis in doses of 0.6 mg one to two times daily should be given along with the hypouricemic therapy until the patient is normouricemic and without gouty attacks for 6 months or as long as tophi are present. Colchicine should not be used in dialysis patients and is given in lower doses in patients with renal disease or with P glycoprotein or CYP3A4 inhibitors such as clarithromycin that can increase toxicity of colchicine.


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


InternalMed_Harrison

InternalMed_Harrison. to enhanced activity of ATP pyrophosphohydrolase and 5′-nucleotidase, which catalyze the reaction of ATP to adenosine and pyrophosphate. This pyrophosphate could combine with calcium to form CPP crystals in matrix vesicles or on collagen fibers. There are decreased levels of cartilage glycosaminoglycans that normally inhibit and regulate crystal nucleation. Highactivities of transglutaminaseenzymes also may contribute to the deposition of CPP crystals.


InternalMed_Harrison

InternalMed_Harrison. ReleaseofCPPcrystalsintothejointspaceisfollowedbythephagocytosis of those crystals by monocyte-macrophages and neutrophils, which respond by releasing chemotactic and inflammatory substances and, as with MSU crystals, activating the inflammasome.


InternalMed_Harrison

InternalMed_Harrison. A minority of patients with CPPD arthropathy have metabolic abnormalities or hereditary CPP disease (Table 395-2). These associations suggest that a variety of different metabolic products may enhance CPP crystal deposition either by directly altering cartilage or by inhibiting inorganic pyrophosphatases. Included among these conditions are hyperparathyroidism, hemochromatosis, hypophosphatasia, hypomagnesemia, and possibly myxedema. The presence of CPPD arthritis in individuals <50 years old should lead to consideration of these metabolic disorders (Table 395-2) and inherited forms of disease, including those identified in a variety of ethnic groups. Genomic DNA studies performed on different kindreds have shown a possible location of genetic defects on chromosome 8q or on chromosome 5p in a region that expresses the gene of the membrane pyrophosphate channel (ANKH gene). As noted above, mutations described in the ANKH gene in kindreds with CPPD arthritis can increase extracellular


InternalMed_Harrison

InternalMed_Harrison. in a region that expresses the gene of the membrane pyrophosphate channel (ANKH gene). As noted above, mutations described in the ANKH gene in kindreds with CPPD arthritis can increase extracellular pyrophosphate and induce CPP crystal formation. Investigation of younger patients with CPPD should include inquiry for evidence of familial aggregation and evaluation of serum calcium, phosphorus, alkaline phosphatase, magnesium, iron, and transferrin.


InternalMed_Harrison

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


InternalMed_Harrison

InternalMed_Harrison. The knee is the joint most frequently affected in CPPD arthropathy. Other sites include the wrist, shoulder, ankle, elbow, and hands. The temporomandibular joint may be involved. Clinical and radiographic evidenceindicates that CPPDdeposition is polyarticularinat least two-thirds of patients. When the clinical picture resembles that of slowly progressive osteoarthritis, diagnosis may be difficult. Joint distribution may provide important clues suggesting CPPD disease. For example, primary osteoarthritis less often involves metacarpophalangeal, wrist, elbow, shoulder, or ankle joints. If radiographs or ultrasound reveal punctate and/or linear radiodense deposits within fibrocartilaginous joint menisci or articular hyaline cartilage (chondrocalcinosis), the diagnostic likelihood of CPPD disease is further increased. Definitive diagnosis requires demonstration of typical rhomboid or rodlike crystals (generally weakly positively birefringent or nonbirefringent with polarized light) in


InternalMed_Harrison

InternalMed_Harrison. disease is further increased. Definitive diagnosis requires demonstration of typical rhomboid or rodlike crystals (generally weakly positively birefringent or nonbirefringent with polarized light) in synovial fluid or articular tissue (Fig. 395-2). In the absence of joint effusion or indications to obtain a synovial biopsy, chondrocalcinosis is presumptive of CPPD. One exception is chondrocalcinosis due to CaOx in some patients with chronic renal failure.


InternalMed_Harrison

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


InternalMed_Harrison

InternalMed_Harrison. Inasmanyas50%ofcases,episodesofCPPD-inducedinflammation are associated with low-grade fever and, on occasion, temperatures as high as 40°C (104°F). In such cases, synovial fluid analysis with microbial cultures is essential to rule out the possibility of infection. In fact, infection in a joint with any microcrystalline deposition process can lead to crystal shedding and subsequent synovitis from both crystals and microorganisms. The leukocyte count in synovial fluid in acute CPPD can range from several thousand cells to 100,000 cells/μL, with the mean being about 24,000 cells/μL and the predominant cell being the neutrophil. CPP crystals may be seen inside tissue fragments and fibrin clots and in neutrophils (Fig. 395-2). CPP crystals may coexist with MSU and apatite in some cases.


InternalMed_Harrison

InternalMed_Harrison. FIGUrE 395-2 Intracellular and extracellular calcium pyrophos-phate (CPP) crystals, asseeninafreshpreparationofsynovialfluid,illustraterectangular,rod-shaped,andrhomboidcrystalsthatareweaklypositivelyornonbirefringentcrystals(compensatedpolarizedlightmicroscopy;400×).


InternalMed_Harrison

InternalMed_Harrison. Untreated acute attacks may last a few days to as long as a month. Treatment by rest, joint aspiration, and NSAIDs or by intraarticular glucocorticoid injection may result in more rapid return to prior status. For patients with frequent recurrent attacks, daily prophylactic treatment with low doses of colchicine may be helpful in decreasing the frequency of the attacks. Severe polyarticular attacks usually require short courses of glucocorticoids or, as recently reported, an IL-1β antagonist, anakinra. Unfortunately, there is no effective way to remove CPP deposits from cartilage and synovium. Uncontrolled studies suggest that the administration of NSAIDS (with a gastric protective agent if required), hydroxychloroquine, or even methotrexate may be helpful in controlling persistent synovitis. Patients with progressive destructive large-joint arthropathy may require joint replacement.


InternalMed_Harrison

InternalMed_Harrison. Apatite is the primary mineral of normal bone and teeth. Abnormal accumulationofbasiccalciumphosphates,largelycarbonatesubstituted apatite, can occur in areas of tissue damage (dystrophic calcification), hypercalcemicorhyperparathyroidstates(metastaticcalcification),and certain conditions of unknown cause (Table 395-3). In chronic renal failure, hyperphosphatemia can contribute to extensive apatite deposition both in and around joints. Familial aggregation is rarely seen; no association with ANKH mutations has been described thus far. Apatite crystals are deposited primarily on matrix vessels. Incompletely understood alterations in matrix proteoglycans, phosphatases, hormones, and cytokines probably can influence crystal formation.


InternalMed_Harrison

InternalMed_Harrison. Apatite aggregates are commonly present in synovial fluid in an extremely destructive chronic arthropathy of the elderly that occurs mostoftenintheshoulders(Milwaukeeshoulder)andinasimilarprocess in hips, knees, and erosive osteoarthritis of fingers. Joint destruction is associated with damage to cartilage and supporting structures, leading to instability and deformity. Progression tends to be indolent. Symptoms range from minimal to severe pain and disability that may lead to joint replacement surgery. Whether severely affected patients represent an extreme synovial tissue response to the apatite crystals that are so common in osteoarthritis is uncertain. Synovial lining cell or fibroblast cultures exposed to apatite (or CPP) crystals can undergo Hemorrhagic shoulder effusions in the elderly (Milwaukee shoulder) Tendinitis, bursitis Connective tissue diseases (e.g., systemic sclerosis, dermatomyositis, SLE)


InternalMed_Harrison

InternalMed_Harrison. Hemorrhagic shoulder effusions in the elderly (Milwaukee shoulder) Tendinitis, bursitis Connective tissue diseases (e.g., systemic sclerosis, dermatomyositis, SLE) Heterotopic calcification after neurologic catastrophes (e.g., stroke, spinal Bursitis, arthritis Abbreviation: SLE, systemic lupus erythematosus. mitosis and markedly increase the release of prostaglandin E2, various cytokines, and also collagenases and neutral proteases, underscoring the destructivepotential of abnormallystimulated synovial lining cells.


InternalMed_Harrison

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


InternalMed_Harrison

InternalMed_Harrison. Intra-and/or periarticular calcifications with or without erosive, destructive, or hypertrophic changes may be seen on radiographs (Fig. 395-3). They should be distinguished from the linear calcifications typical of CPPD.


InternalMed_Harrison

InternalMed_Harrison. Definitive diagnosis of apatite arthropathy, also called basic calcium phosphate disease, depends on identification of crystals from synovial fluid or tissue (Fig. 395-3). Individual crystals are very small and can be seen only by electron microscopy. Clumps of crystals may appear as 1-to 20-μm shiny intra-or extracellular nonbirefringent globules or aggregates that stain purplish with Wright’s stain and bright red with alizarin red S. Tetracycline binding and other investigative techniques are under consideration as labeling alternatives. Absolute identification depends on electron microscopy with energy-dispersive elemental analysis, x-ray diffraction, infrared spectroscopy, or Raman microspectroscopy, but these techniques usually are not required in clinical diagnosis.


InternalMed_Harrison

InternalMed_Harrison. Treatment of apatite arthritis or periarthritis is nonspecific. Acute attacks of bursitis or synovitis may be self-limiting, resolving in days to several weeks. Aspiration of effusions and the use of either NSAIDs or oral colchicine for 2 weeks or intraor periarticular injection of a depot glucocorticoid appear to shorten the duration and intensity of symptoms. Local injection of disodium ethylenediaminetetraacetic acid (EDTA) and SC anakinra have been suggested as effective in single studies of acute calcific tendinitis at the shoulder. Other reports have described that IV gamma globulin, rituximab, calcium channel blockers, or bisphosphonates may help diffuse calcinosis. Periarticular apatite deposits may be resorbed with resolution of attacks. Agents to lower serum phosphate levels may lead to resorption of deposits in renal failure patients receiving hemodialysis. In patients with underlying severe destructive articular changes, response to medical therapy is usually less


InternalMed_Harrison

InternalMed_Harrison. may lead to resorption of deposits in renal failure patients receiving hemodialysis. In patients with underlying severe destructive articular changes, response to medical therapy is usually less rewarding.


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InternalMed_Harrison. FIGUrE 395-3 A. Radiographshowingcalcificationduetoapatitecrystalssurroundinganerodedjoint.B. Anelectronmicrographdem-onstratesdarkneedle-shapedapatitecrystalswithinavacuoleofasynovialfluidmononuclearcell(30,000×). FIGUrE 395-4 Bipyramidal and small polymorphic calcium oxa-late crystals fromsynovialfluidareaclassicfindingincalciumoxalatearthropathy(ordinarylightmicroscopy;400×). different enzyme defects, leading to hyperoxalemia and deposition of CaOx crystals in tissues. Nephrocalcinosis and renal failure are typical results. Acute and/or chronic CaOx arthritis, periarthritis, and bone disease may complicate primary oxalosis during later years of illness.


InternalMed_Harrison

InternalMed_Harrison. Secondary oxalosis is more common than the primary disorder. In chronic renal disease, calcium oxalate deposits have long been recognized in visceral organs, blood vessels, bones, and cartilage and arenow known to be one of the causes of arthritis in chronic renal failure. Thus far, reported patients have been dependent on long-term hemodialysis or peritonealdialysis (Chap. 336), and many had receivedascorbic acid supplements. Ascorbic acid is metabolized to oxalate, which is inadequately cleared in uremia and by dialysis. Such supplements and foods highinoxalatecontentusuallyareavoidedindialysisprogramsbecause of the risk of enhancing hyperoxalosis and its sequelae.


InternalMed_Harrison

InternalMed_Harrison. CaOx aggregates can be found in bone, articular cartilage, synovium, and periarticular tissues. From these sites, crystals may be shed, causing acute synovitis. Persistent aggregates of CaOx can, like apatite and CPP, stimulate synovial cell proliferation and enzyme release, resulting in progressive articular destruction. Deposits have been documented in fingers, wrists, elbows, knees, ankles, and feet. Clinical features of acute CaOx arthritis may not be distinguishable from those due to urate, CPP, or apatite. Radiographs may reveal chondrocalcinosis or soft tissue calcifications. CaOx-induced synovial effusions are usually noninflammatory, with <2000 leukocytes/μL, or mildly inflammatory. Neutrophils or mononuclear cells can predominate. CaOx crystals have a variable shape and variable birefringence to polarized light. The most easily recognized forms are bipyramidal, have strong birefringence (Fig. 395-4), and stain with alizarin red S.


InternalMed_Harrison

InternalMed_Harrison. Treatment of CaOx arthropathy with NSAIDs, colchicine, intra-articular glucocorticoids, and/or an increased frequency of dialysis has produced only slight improvement. In primary oxalosis, liver transplantation has induced a significant reduction in crystal deposits (Chap. 434e). AcknowledgmentPaTHOGENESIS This chapter has been revised for this and the previous two editions from Primary oxalosis is a rare hereditary metabolic disorder (Chap. 434e). an original version written by Antonio Reginato, MD, in earlier editions Enhanced production of oxalic acid may result from at least two of Harrison’s Principles of Internal Medicine.


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InternalMed_Harrison. 2238 fibromyalgia Leslie J. Crofford DEFINITION Fibromyalgia(FM)ischaracterizedbychronicwidespreadmuscu-loskeletalpainandtenderness.AlthoughFMisdefinedprimarilyasapainsyndrome,patientsalsocommonlyreportassociatedneuro-396 psychological symptoms of fatigue, unrefreshing sleep, cognitive dysfunction, anxiety, and depression. Patients with FM have an increased prevalence of other syndromes associated with pain and fatigue, including chronic fatigue syndrome (Chap. 464e), temporomandibular disorder, chronic headaches, irritable bowel syndrome, interstitial cystitis/painful bladder syndrome, and other pelvic pain syndromes. Available evidence implicates the central nervous system askeytomaintainingpainandothercoresymptomsofFMandrelated conditions. The presence of FM is associated with substantial negative consequences for physical and social functioning.


InternalMed_Harrison

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


InternalMed_Harrison

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


InternalMed_Harrison

InternalMed_Harrison. The clinical pain of FM is associated with increased evoked pain sensitivity. In clinical practice, this elevated sensitivity may be determined by a tender-point examination in which the examiner uses the thumbnail to exert pressure of ∼4 kg/m2 (or the amount of pressure leading to blanching of the tip of the thumbnail) on well-defined musculotendinous sites (Fig. 396-1). Previously, the classification criteria of the American College of Rheumatology required that 11 of 18 sites be perceived as painful for a diagnosis of FM. In practice, tenderness is a continuous variable, and strict application of a categorical threshold for diagnostic specifics is not necessary. Newer criteria eliminate the need for tender points and focus instead on clinical symptoms of widespread pain and neuropsychological symptoms. The newer criteria perform well in a clinical setting in comparison to the older, tender-point criteria. However, it appears that when the new criteria


InternalMed_Harrison

InternalMed_Harrison. pain and neuropsychological symptoms. The newer criteria perform well in a clinical setting in comparison to the older, tender-point criteria. However, it appears that when the new criteria areappliedtopopulations,theresultisanincreaseinprevalenceofFM and a change in the sex ratio (see “Epidemiology,” earlier).


InternalMed_Harrison

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


InternalMed_Harrison

InternalMed_Harrison. Neuropsychological Symptoms In addition to widespread pain, FM patients typically report fatigue, stiffness, sleep disturbance, cognitive dysfunction, anxiety, and depression. These symptoms are present to varyingdegreesinmostFMpatientsbutarenotpresentineverypatient or at all times in a given patient. Relative to pain, such symptoms may, however, have an equal or even greater impact on function and quality of life. Fatigue is highly prevalent in patients under primary care who ultimately are diagnosed with FM. Pain, stiffness, and fatigue often Occiput: Trapezius: midpoint of the upper border Supraspinatus: above the medial border of the scapular spine Gluteal: upper outer quadrants of buttocks Greater trochanter: posterior to the trochanteric prominence Low cervical: anterior aspects of the intertransverse spaces at C5-C7 Second rib: Lateral epicondyle: 2 cm distal to the epicondyles Knee: medial fat pad proximal to the joint line


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InternalMed_Harrison. FIGUrE 396-1 Tender-point assessment in patients with fibromyalgia. (Figure created using data from F Wolfe et al: Arthritis Care Res 62:600, 2010.) are worsened by exercise or unaccustomed activity (postexertional malaise). The sleep complaints include difficulty falling asleep, difficulty staying asleep, and early-morning awakening. Regardless of the specific complaint, patients awake feeling unrefreshed. Patients with FM may meet criteria for restless legs syndrome and sleep-disordered breathing; frank sleep apnea can also be documented. Cognitive issues are characterized as slowness in processing, difficulties with attention or concentration, problems with word retrieval, and short-term memory loss. Studies have demonstrated altered cognitive function in these domains in patients with FM, though speed of processing is age-appropriate. Symptoms of anxiety and depression are common, and the lifetime prevalence of mood disorders in patients with FM approaches 80%. Although depression


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InternalMed_Harrison. FM, though speed of processing is age-appropriate. Symptoms of anxiety and depression are common, and the lifetime prevalence of mood disorders in patients with FM approaches 80%. Although depression is neither necessary nor sufficient for the diagnosis of FM, it is important to screen for major depressive disorders by querying for depressed mood and anhedonia. Analysis of genetic factors that are likely to predispose to FM reveals shared neurobiologic pathways with mood disorders, providing the basis for comorbidity (see later in this chapter).


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InternalMed_Harrison. Overlapping Syndromes Because FM can overlap in presentation with other chronic pain conditions, review of systems often reveals headaches, facial/jaw pain, regional myofascial pain particularly involving the neck or back, and arthritis. Visceral pain involving the gastrointestinal tract, bladder, and pelvic or perineal region is often present as well. Patients may or may not meet defined criteria for specific syndromes.Itisimportantforpatients tounderstandthatsharedpathwaysmay mediate symptoms andthattreatmentstrategieseffectivefor one condition may help with global symptom management.


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


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InternalMed_Harrison. development of neuropsychological symptoms, or tenderness on physical examination—treatment of central pain processes will be undertaken as opposed to a continued focus on treatment of peripheral or inflammatory causes of pain.


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


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InternalMed_Harrison. Functional Impairment It is crucial to evaluate the impact of FM symptoms on functionand role fulfillment. Indefining the successof a management strategy, improved function is a key measure. Functional assessment should include physical, mental, and social domains. A recognition of the ways in which role functioning falls short will be helpful in the establishment of treatment goals. Because musculoskeletal pain is such a common complaint, the differential diagnosis of FM is broad. Table 396-1 lists some of the more common conditions that should be considered. Patients with inflammatory causes for widespread pain should be identifiable on the basis of specific history, physical findings, and laboratory or radiographic tests. Polymyalgia rheumatica Inflammatory arthritis: rheumatoid arthritis, spondyloarthritides Connective tissue diseases: systemic lupus erythematosus, Sjögren’s


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InternalMed_Harrison. Polymyalgia rheumatica Inflammatory arthritis: rheumatoid arthritis, spondyloarthritides Connective tissue diseases: systemic lupus erythematosus, Sjögren’s Degenerative joint/spine/disk disease Myofascial pain syndromes Bursitis, tendinitis, repetitive strain injuries Routine laboratory and radiographic tests yield normal results in FM. Thus diagnostic testing is focused on exclusion of other diagnoses and evaluation for pain generators or comorbid conditions (Table 396-2). Mostpatientswithnewchronicwidespreadpainshouldbeassessedfor the most common entities in the differential diagnosis. Radiographic testing should be used sparingly and only for diagnosis of inflammatory arthritis. After the patient has been evaluated thoroughly, repeat testing is discouraged unless the symptom complex changes. Particularly to be discouraged is advanced imaging (MRI) of the spine unless there are features suggesting inflammatory spine disease or neurologic symptoms.


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InternalMed_Harrison. As in most complex diseases, it is likely that a number of genes contribute to vulnerability to the development of FM. To date, these genes appear to be in pathways controlling pain and stress Source: LM Arnold et al: J Women’s Health 21:231, 2012; MA Fitzcharles et al: J Rheumatol 40:1388, 2013.


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InternalMed_Harrison. 2240 responses. Some of the genetic underpinnings of FM are shared across other chronic pain conditions. Genes associated with metabolism, transport, and receptors of serotonin and other monoamines have been implicated in FM and overlapping conditions. Genes associated with other pathways involved in pain transmission have also been describedasvulnerabilityfactorsforFM.Takentogether,thepathways in which polymorphisms have been identified in FM patients further implicate central factors in mediation of the physiology that leads to the clinical manifestations of FM. Psychophysical testing of patients with FM has demonstrated altered sensory afferent pain processing and impaired descending noxious inhibitory control leading to hyperalgesia and allodynia. Functional MRI and other research imaging procedures clearly demonstrate activation of the brain regions involved in the experience of pain in response to stimuli that are innocuous in study participants without FM. Pain perception in FM


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InternalMed_Harrison. procedures clearly demonstrate activation of the brain regions involved in the experience of pain in response to stimuli that are innocuous in study participants without FM. Pain perception in FM patients is influenced by the emotional and cognitive dimensions, such as catastrophizing and perceptions of control, providing a solid basis for recommendations for cognitive and behavioral treatment strategies.


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InternalMed_Harrison. APPROACH TO THE PATIENT: FM is common and has an extraordinary impact on the patient’s function and health-related quality of life. However, its symptoms and impact can be managed effectively by physicians and other health professionals. Developing a partnership with patients is essential for improving the outcome of FM, with a goal of understanding the factors involved, implementing a treatment strategy, and choosing appropriate nonpharmacologic and pharmacologic treatments.


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InternalMed_Harrison. Patients with chronic pain, fatigue, and other neuropsychological symptoms require a framework for understanding the symptoms that have such an important impact on their function and quality of life. Explaining the genetics, triggers, and physiology of FM can be an important adjunct in relieving associated anxiety and in reducing the overall cost of health care resources. In addition, patients must be educated regarding expectations for treatment. The physician should focus on improved function and quality of life rather than elimination of pain. Illness behaviors, such as frequent physician visits, should be discouraged and behaviors that focus on improved function strongly encouraged.


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InternalMed_Harrison. Treatment strategies should include physical conditioning, with encouragement to begin at low levels of aerobic exercise and to proceed with slow but consistent advancement. Patients who have been physically inactive or who report postexertional malaise may do best in supervised or water-based programs at the start. Activities that promote improved physical function with relaxation, such as yoga and Tai Chi, may also be helpful. Strength training may be recommended after patients reach their aerobic goals. Exercise programs are helpful in reducing tenderness and enhancing self-efficacy. Cognitive-behavioral strategies to improve sleep hygiene and reduce illness behaviors can also be helpful in management.


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InternalMed_Harrison. It is essential for the clinician to treat any comorbid triggering condition and to clearly delineate for the patient the treatment goals for each medication. For example, glucocorticoids or nonsteroidal anti-inflammatory drugs may be useful for management of inflammatory triggers but are not effective against FM-related symptoms. At present, the treatment approaches that have proved most successful in FM patients target afferent or descending pain pathways. Table 396-3 lists the drugs with demonstrated effectiveness. It should be emphasized Antidepressants: balanced serotonin–norepinephrine reuptake inhibitors Duloxetineb,c Milnacipranb,c Anticonvulsants: ligands of the alpha-2-delta subunit of voltage-gated calcium channels aRA Moore et al: Cochrane Database Syst Rev 12:CD008242, 2012. bApproved by the U.S. Food and Drug Administration. cW Hauser et al: Cochrane Database Syst Rev 1: CD010292, 2013. Source: LM Arnold: Arthritis Rheum 56:1336, 2007.


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InternalMed_Harrison. Source: LM Arnold: Arthritis Rheum 56:1336, 2007. strongly that opioid analgesics are to be avoided in patients with FM. These agents have no demonstrated efficacy in FM and are associated with opioid-induced hyperalgesia that can worsen both symptoms and function. Use of single agents to treat multiple symptom domains is strongly encouraged. For example, if a patient’s symptom complex is dominated by pain and sleep disturbance, use of an agent that exerts both analgesic and sleep-promoting effects is desirable. These agents include sedating antidepressants such as amitriptyline and alpha-2delta ligands such as gabapentin and pregabalin. For patients whose pain is associated with fatigue, anxiety, or depression, drugs that have both analgesic and antidepressant/anxiolytic effects, such as duloxetine or milnacipran, may be the best first choice. arthritis associated with Systemic Disease, and Other arthritides Carol A. Langford, Brian F. Mandell


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InternalMed_Harrison. arthritis associated with Systemic Disease, and Other arthritides Carol A. Langford, Brian F. Mandell Acromegaly is the result of excessive production of growth hormone by an adenoma in the anterior pituitary gland (Chap. 403). The excessive secretion of growth hormone along with insulin-like growth factor I stimulates proliferation of cartilage, periarticular connective tissue, and bone, resulting in several musculoskeletal problems, including osteoarthritis, back pain, muscle weakness, and carpal tunnel syndrome.


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InternalMed_Harrison. Osteoarthritis is a common feature, most often affecting the knees, shoulders, hips, and hands. Single or multiple joints may be affected. Hypertrophy of cartilage initially produces radiographic widening of the joint space. The newly synthesized cartilage is abnormally susceptible to fissuring, ulceration, and destruction. Ligamental laxity of joints further contributes to the development of osteoarthritis. Cartilage degrades, the joint space narrows, and subchondral sclerosis and osteophytes develop. Joint examination reveals crepitus and laxity. Joint fluid is noninflammatory. Calcium pyrophosphate dihydrate crystals are found in the cartilage in some cases of acromegaly arthropathy and, when shed into the joint, can elicit attacks of pseudogout. Chondrocalcinosis may be observed on radiographs. Back pain is extremely common, perhaps as a result of spine hyper-mobility. Spine radiographs show normal or widened intervertebral disk spaces, hypertrophic anterior osteophytes, and


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InternalMed_Harrison. on radiographs. Back pain is extremely common, perhaps as a result of spine hyper-mobility. Spine radiographs show normal or widened intervertebral disk spaces, hypertrophic anterior osteophytes, and ligamental calcification. The latter changes are similar to those observed in patients with diffuse idiopathic skeletal hyperostosis. Dorsal kyphosis in conjunction with elongation of the ribs contributes to the development of the barrel chest seen in acromegalic patients. The hands and feet become enlarged as a result of soft tissue proliferation. The fingers are thickened and have spadelike distal tufts. One-third of patients have a thickened heel pad. Approximately 25% of patients exhibit Raynaud’s phenomenon.Carpaltunnelsyndromeoccursinabouthalfofpatients. The median nerve is compressed by excess connective tissue in the carpal tunnel. Patients with acromegaly may develop proximal muscle weakness, which is thought to be caused by the effect of growth hormone on muscle. Serum muscle


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InternalMed_Harrison. by excess connective tissue in the carpal tunnel. Patients with acromegaly may develop proximal muscle weakness, which is thought to be caused by the effect of growth hormone on muscle. Serum muscle enzyme levels and electromyographic findings arenormal. Muscle biopsy specimens containmuscle fibers of varying size without inflammation.


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InternalMed_Harrison. Hemochromatosis is a disorder of iron storage. Absorption of excessive amounts of iron from the intestine leads to iron deposition in parenchymal cells, which results in impairment of organ function (Chap. 428). Symptoms of hemochromatosis usually begin between the ages of 40 and 60 but can appear earlier. Arthropathy, which occurs in 20–40% of patients, usually begins after the age of 50 and may be the first clinical feature of hemochromatosis. The arthropathy is an osteoarthritis-like disorder affecting the small joints of the hands and later the larger joints, such as knees, ankles, shoulders, and hips. The second and third metacarpophalangeal joints of both hands are often the first and most prominent joints affected; this clinical picture may provide an important clue to the possibility of hemochromatosis becausethese jointsarenotpredominantlyaffectedby “routine”osteoarthritis.Patients experience some morningstiffness andpainwith use of involved joints. The affected joints are


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InternalMed_Harrison. of hemochromatosis becausethese jointsarenotpredominantlyaffectedby “routine”osteoarthritis.Patients experience some morningstiffness andpainwith use of involved joints. The affected joints are enlarged and mildly tender. Radiographs show narrowing of the joint space, subchondral sclerosis, subchondral cysts, and juxtaarticular proliferation of bone. Hooklike osteophytes are seen in up to 20% of patients; although they are regarded as a characteristic feature of hemochromatosis, they can also occur in osteoarthritis and are not disease specific. The synovial fluid is noninflammatory. The synovium shows mild to moderate proliferation of iron-containing lining cells, fibrosis, and some mononuclear cell infiltration. In approximately half of patients, there is evidence of calcium pyrophosphate deposition disease, and some patients late in the course of disease experience episodes of acute pseudogout (Chap. 395). An early diagnosis is suggested by high serum transferrin saturation, which


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InternalMed_Harrison. deposition disease, and some patients late in the course of disease experience episodes of acute pseudogout (Chap. 395). An early diagnosis is suggested by high serum transferrin saturation, which is more sensitive than ferritin elevation.


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InternalMed_Harrison. Iron may damage the articular cartilage in several ways. Iron catalyzes superoxide-dependent lipid peroxidation, which may play a role in joint damage. In animal models, ferric iron has been shown to interfere with collagen formation and increase the release of lysosomal enzymes from cells in the synovial membrane. Iron inhibits synovial tissue pyrophosphatase in vitro and therefore may inhibit pyrophosphatase in vivo, resulting in chondrocalcinosis. The treatment of hemochromatosis is repeated phlebotomy. Unfortunately, this treatment has little effect on established arthritis, which, along with chondrocalcinosis, may progress. Symptom-based treatment of the arthritis consists of administration of acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), as tolerated. Acute pseudogout attacks are treated with high doses of an NSAID or a short course of glucocorticoids. Hip or knee total joint replacement has been successful in advanced disease.


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InternalMed_Harrison. Hemophilia is a sex-linked recessive genetic disorder characterized by the absence or deficiency of factor VIII (hemophilia A, orclassic hemophilia) or factor IX (hemophilia B, or Christmas disease) (Chap. 141). Hemophilia A constitutes 85% of cases. Spontaneous hemarthrosis is a common problem with both types of hemophilia and can lead to a deforming arthritis. The frequency and severity of hemarthrosis are related to the degree of clotting factor deficiency. Hemarthrosis is not common in other disorders of coagulation such as von Willebrand disease, factor V deficiency, warfarin therapy, or thrombocytopenia. Hemarthrosis occurs after 1 year of age, when a child begins to walk 2241 and run. In order of frequency, the joints most commonly affected are theknees,ankles,elbows,shoulders,andhips.Smalljointsofthehands and feet are occasionally involved.


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


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


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InternalMed_Harrison. treatment of hemophilia. Surgical removal is indicated if the pseudotumor continues to enlarge. In adults, pseudotumors develop in the femur and pelvis and are usually refractory to treatment. When bleeding occurs in muscle, cysts may develop within the muscle. Needle aspiration of a cyst is contraindicated because this procedure can induce further bleeding; however, if the cyst becomes secondarily infected, drainage may be necessary (after factor repletion).


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InternalMed_Harrison. Septic arthritis is rare in hemophilia and is difficult to distinguish from acute hemarthrosis on physical examination. If there is serious suspicion of an infected joint, the joint should be aspirated immediately, the fluid cultured, and treatment with broad-spectrum antibiotics administered, with coverage for microorganisms including Staphylococcus, until culture results become available. Clotting-factor deficiency should be corrected before arthrocentesis to minimize the risk of traumatic bleeding. Radiographs of joints reflect the stage of disease. In early stages, there is only capsule distention; later, juxtaarticular osteopenia, marginal erosions, and subchondral cysts develop. Late in the disease, the joint space is narrowed and there is bony overgrowth similar to that in osteoarthritis.


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InternalMed_Harrison. The treatment of musculoskeletal bleeding is initiated with the immediate infusion of factor VIII or IX at the first sign of joint or muscle hemorrhage. Patients who have developed factor inhibitors are at elevated risk for joint damage and may benefit from receiving recombinant activated factor VII or activated prothrombin complex concentrate. The joint should be rested in a position of forced extension, as tolerated, to avoid contracture. Analgesia should be provided; nonselective NSAIDs, which can diminish platelet function, should be avoided if possible. Selective cyclooxygenase-2 inhibitors do not interfere with platelet function, although cardiovascular and gastrointestinal risks must still be weighed. Synovectomy—open or arthroscopic—may be attempted in patients with chronic symptomatic synovial proliferation and recurrent hemarthrosis, although hypertrophied synovium is highly vascular and subject to bleeding. Both types of synovectomy reduce the number of hemarthroses. Open


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InternalMed_Harrison. synovial proliferation and recurrent hemarthrosis, although hypertrophied synovium is highly vascular and subject to bleeding. Both types of synovectomy reduce the number of hemarthroses. Open surgical synovectomy, however, is associated with some loss


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InternalMed_Harrison. Arthritis Associated with Systemic Disease, and Other Arthritides 2242 of range of motion. Both require aggressive prophylaxis against bleeding. Radiosynovectomy with either yttrium 90 silicate or phosphorus 31 colloid has been effective and may be attempted when surgical synovectomy is not practical. Total joint replacement is indicated for severe joint destruction and incapacitating pain.