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Crystal Arthropathies Chronic Aspects of Gout If gout is not treated relatively early in its course, gout flares tend to become increasingly frequent and severe and are often polyarticular. These flares may eventually evolve into persis tent inflammatory arthritis (chronic gouty arthritis), with intermittent flares superimposed on the baseline persistent disease. Some patients develop tophi. Tophi are solid chalky white masses of uric acid, surrounded by inflammatory cells and a rind of flbrous tissue. They are located around joints and in soft tissues, with a predilection for the extensor surfaces ofthe elbows, distal Achilles tendon, fingers (usually the proximal and distal interphalangeal joints) (Figure 45), and helices of the ears. Tophi are deforming, can interfere with function, and directly erode bone. Ulceration of overlying skin can occur, and accompanying infection can be difficult to treat because tophi are avascular.

Chronic Aspects of Gout If gout is not treated relatively early in its course, gout flares tend to become increasingly frequent and severe and are often polyarticular. These flares may eventually evolve into persis tent inflammatory arthritis (chronic gouty arthritis), with intermittent flares superimposed on the baseline persistent disease. Some patients develop tophi. Tophi are solid chalky white masses of uric acid, surrounded by inflammatory cells and a rind of flbrous tissue. They are located around joints and in soft tissues, with a predilection for the extensor surfaces ofthe elbows, distal Achilles tendon, fingers (usually the proximal and distal interphalangeal joints) (Figure 45), and helices of the ears. Tophi are deforming, can interfere with function, and directly erode bone. Ulceration of overlying skin can occur, and accompanying infection can be difficult to treat because tophi are avascular. Diagnosis A diagnosis ofgout (the chronic disease state) should be con sidered in any patient who has had or is experiencing one or more episodes of acute monoarticular or oligoarticular inflam matory arthritis that may represent a gout flare. Although designed primarily for research, gout classification criteria are available, including as an online calculator (hftp://goutclassifi- cationcalculator.auckland.ac.nz), and are 92'ln sensitive and 89'X, specific. tIGURE 44. Goutof theleftbigtoe. The differential diagnosis ofa gout flare is listed in Table 34. The gold standard for diagnosing a gout flare is identification (MTP) joint of the great toe (podagra) (Figure aa). Inflammatory of negatively birefringent, needle-like monosodium urate states, such as infection, surgery and myocardial infarction, crystals, along with neutrophils, in synovial fluid. Crystals can provoke gout flares. The hallmarks ofa flare are pain, ten- within neutrophils are usually also seen. "Negatively birefrin derness, swelling, redness, and warmth. Flares typically begin gent" means that under polarized light, the crystals appear at night and peak within 12 to 24 hours. Untreated, most gout yellow when parallel to and blue when perpendicular to the flares self resolve within days to a few weeks, although with polarizing axis of an optical filter. Arthrocentesis is not always long standing disease, flares can persist for months. In men performed when gout flare is suspected, but when infection is with established disease, flares eventually affect the proximal feet, ankles, and knees, and later almost any joint, including the spine. Postmenopausal women may present differently, with initial flares often involving the knees, or finger joints affected by osteoarthritis. For patients with more severe or long-standing disease, polyarticular flares may occur. Soft tis sues can also be involved, manifesting as acute bursitis (olecra non and prepatellar, most commonly), periarthritis, and gouty panniculitis and cellulitis, the last of which can be misdiag- nosed as a refractory bacterial soft-tissue infection.

Diagnosis A diagnosis ofgout (the chronic disease state) should be con sidered in any patient who has had or is experiencing one or more episodes of acute monoarticular or oligoarticular inflam matory arthritis that may represent a gout flare. Although designed primarily for research, gout classification criteria are available, including as an online calculator (hftp://goutclassifi- cationcalculator.auckland.ac.nz), and are 92'ln sensitive and 89'X, specific. tIGURE 44. Goutof theleftbigtoe. The differential diagnosis ofa gout flare is listed in Table 34. The gold standard for diagnosing a gout flare is identification (MTP) joint of the great toe (podagra) (Figure aa). Inflammatory of negatively birefringent, needle-like monosodium urate states, such as infection, surgery and myocardial infarction, crystals, along with neutrophils, in synovial fluid. Crystals can provoke gout flares. The hallmarks ofa flare are pain, ten- within neutrophils are usually also seen. "Negatively birefrin derness, swelling, redness, and warmth. Flares typically begin gent" means that under polarized light, the crystals appear at night and peak within 12 to 24 hours. Untreated, most gout yellow when parallel to and blue when perpendicular to the flares self resolve within days to a few weeks, although with polarizing axis of an optical filter. Arthrocentesis is not always long standing disease, flares can persist for months. In men performed when gout flare is suspected, but when infection is with established disease, flares eventually affect the proximal feet, ankles, and knees, and later almost any joint, including the spine. Postmenopausal women may present differently, with initial flares often involving the knees, or finger joints affected by osteoarthritis. For patients with more severe or long-standing disease, polyarticular flares may occur. Soft tis sues can also be involved, manifesting as acute bursitis (olecra non and prepatellar, most commonly), periarthritis, and gouty panniculitis and cellulitis, the last of which can be misdiag- nosed as a refractory bacterial soft-tissue infection. Intercritical Gout lntercritical gout is the period between gout flares. Early in the disease course, the intercritical period can be years. As the disease progresses, the intercritical period can progressively shorten. Even in the absence of symptoms, urate crystals still t I G U R E 4 5. Fingers of a patient with numerous bulky tophaceous deposits of reside within joints and soft tissues, and low-grade systemic monosodium uric acid crystals, a consequence of years of gout with uncontrolled inflammation persists. hyperu ricem ia.

Intercritical Gout lntercritical gout is the period between gout flares. Early in the disease course, the intercritical period can be years. As the disease progresses, the intercritical period can progressively shorten. Even in the absence of symptoms, urate crystals still t I G U R E 4 5. Fingers of a patient with numerous bulky tophaceous deposits of reside within joints and soft tissues, and low-grade systemic monosodium uric acid crystals, a consequence of years of gout with uncontrolled inflammation persists. hyperu ricem ia. 68

Crystal Arthropathies TABLE 34. Differential Diagnosis of Acute Gout Flare Condition Comments lnfeclious arthritis Presentation may be identicalto gout. lnfectious arthritis is usually monoarticular but can be polyarticular. Onset may be less acute than gout. Gout and infectious arthritis can coexist. Acute calcium pyrophosphate crystal Pseudogout is less likely to present in the great toe, but acute presentations may otherwise arthritis (pseudogout) be identicalto gout. Synovial fluid analysis can distinguish these entities. Gout and pseudogout can coexist. Basic calcium phosphate deposition Basic calcium phosphate deposition occurs in articular cartilage and periarticular tissues. Because of their small size, basic calcium phosphate crystals are unlikely to be seen in synovialfluid on light microscopy except as aggregates stained with alizarin red. Trauma Trauma can lead to local pain and swelling, with or without a fracture, and can also trigger a gout flare. Other forms o{ inflammatory arthritis (e.g., Clinical context, affeaed joints, and pattern of arthritis help distinguish these entities. reactive arthritis, rheumatoid arthritis, Synovial fluid analysis is particularly important when there is diagnostic uncertainty. psoriatic arthritis, acute rheumatic fever)

TABLE 34. Differential Diagnosis of Acute Gout Flare Condition Comments lnfeclious arthritis Presentation may be identicalto gout. lnfectious arthritis is usually monoarticular but can be polyarticular. Onset may be less acute than gout. Gout and infectious arthritis can coexist. Acute calcium pyrophosphate crystal Pseudogout is less likely to present in the great toe, but acute presentations may otherwise arthritis (pseudogout) be identicalto gout. Synovial fluid analysis can distinguish these entities. Gout and pseudogout can coexist. Basic calcium phosphate deposition Basic calcium phosphate deposition occurs in articular cartilage and periarticular tissues. Because of their small size, basic calcium phosphate crystals are unlikely to be seen in synovialfluid on light microscopy except as aggregates stained with alizarin red. Trauma Trauma can lead to local pain and swelling, with or without a fracture, and can also trigger a gout flare. Other forms o{ inflammatory arthritis (e.g., Clinical context, affeaed joints, and pattern of arthritis help distinguish these entities. reactive arthritis, rheumatoid arthritis, Synovial fluid analysis is particularly important when there is diagnostic uncertainty. psoriatic arthritis, acute rheumatic fever) a concern, joint aspiration for Gram stain and culture is Management mandatory. See Principles of Therapeutics for details on the medications In any acute arthritis in an adult, gout flare should be described in this section. considered. Findings that support a gout flare diagnosis when arthrocentesis is not feasible include onset of severe pain and Treatment of Gout Flares swelling over several hours, involvement of the first MTP joint Treatment of acute gout flares focuses on anti-inflammatory or midfoot/ankle, presence of erythema, and previous similar therapy; colchicine, NSAIDs, and glucocorticoids are all rea- acute arthritis episodes. Male sex and associated cardiovascu- sonable options. Treatment choice should be determined by lar disease are also supportive. The involved joints are warm, potential drug interactions and patient comorbidities. The red, swollen, and very tender. Low grade fever may be pre- simplest is colchicine, 1.2 mg at the first symptoms of a gout sent, particularly during polyarticular flares. Serum urate flare, followed t hour later by a 0.6-mg dose. Colchicine is measured at time of flare may not be helpful because levels most effective when used less than 24 hours after symptom can drop during acute systemic inflammation. Therefore, although an elevated serum urate level supports the possibil- ity of gout, hyperuricemia alone does not establish the diag- nosis, and lack of hyperuricemia at time of an acute arthritis does not definitively rule out gout. A serum urate level 2 weeks after gout flare resolution more accurately measures baseline level. C reactive protein and erythrocyte sedimenta- tion rate are elevated during gout flare but are nonspecific. Joint fluid has an inflammatory leukoclte count (>2000ipl [2.0 x 10e/L] and occasionally >100,000/pL [100 x 10ei L], with neutrophil predominance). The presence of intracellular crys- tals and leukocytes in synovial fluid does not rule out a con- comitant infection. Imaging is recommended when arthrocentesis is not pos- sible and a clinical diagnosis of gout is uncertain. The charac- teristic radiographic changes of established disease may help confirm a history ofpreviously unrecognized gout and support a diagnosis ofcurrent gout flare (Figure 46). Musculoskeletal ultrasonography and dual energr CT can demonstrate mono- sodium urate deposition in joints and are being assessed for their role in diagnosis. Ultrasonography can show unsus- pected tophi or a "double-contour" sign at cartilage surfaces (Figure 47), which is highly specific for urate deposits in joints. The double contour sign, identification of monosodium urate F I G UR E 4 6, Periarticular bony erosions, appearing as punched'out bone crystal deposition on dual-energr CT, and gout-related joint lesions with disruption of bone cortex (overhanging edges), represent areas of damage on radiography are included in gout classification tophaceous monosodium uric acid deposition and accompanying inflammation in criteria. a patient with severe, long-standing, inadequately treated gout.

a concern, joint aspiration for Gram stain and culture is Management mandatory. See Principles of Therapeutics for details on the medications In any acute arthritis in an adult, gout flare should be described in this section. considered. Findings that support a gout flare diagnosis when arthrocentesis is not feasible include onset of severe pain and Treatment of Gout Flares swelling over several hours, involvement of the first MTP joint Treatment of acute gout flares focuses on anti-inflammatory or midfoot/ankle, presence of erythema, and previous similar therapy; colchicine, NSAIDs, and glucocorticoids are all rea- acute arthritis episodes. Male sex and associated cardiovascu- sonable options. Treatment choice should be determined by lar disease are also supportive. The involved joints are warm, potential drug interactions and patient comorbidities. The red, swollen, and very tender. Low grade fever may be pre- simplest is colchicine, 1.2 mg at the first symptoms of a gout sent, particularly during polyarticular flares. Serum urate flare, followed t hour later by a 0.6-mg dose. Colchicine is measured at time of flare may not be helpful because levels most effective when used less than 24 hours after symptom can drop during acute systemic inflammation. Therefore, although an elevated serum urate level supports the possibil- ity of gout, hyperuricemia alone does not establish the diag- nosis, and lack of hyperuricemia at time of an acute arthritis does not definitively rule out gout. A serum urate level 2 weeks after gout flare resolution more accurately measures baseline level. C reactive protein and erythrocyte sedimenta- tion rate are elevated during gout flare but are nonspecific. Joint fluid has an inflammatory leukoclte count (>2000ipl [2.0 x 10e/L] and occasionally >100,000/pL [100 x 10ei L], with neutrophil predominance). The presence of intracellular crys- tals and leukocytes in synovial fluid does not rule out a con- comitant infection. Imaging is recommended when arthrocentesis is not pos- sible and a clinical diagnosis of gout is uncertain. The charac- teristic radiographic changes of established disease may help confirm a history ofpreviously unrecognized gout and support a diagnosis ofcurrent gout flare (Figure 46). Musculoskeletal ultrasonography and dual energr CT can demonstrate mono- sodium urate deposition in joints and are being assessed for their role in diagnosis. Ultrasonography can show unsus- pected tophi or a "double-contour" sign at cartilage surfaces (Figure 47), which is highly specific for urate deposits in joints. The double contour sign, identification of monosodium urate F I G UR E 4 6, Periarticular bony erosions, appearing as punched'out bone crystal deposition on dual-energr CT, and gout-related joint lesions with disruption of bone cortex (overhanging edges), represent areas of damage on radiography are included in gout classification tophaceous monosodium uric acid deposition and accompanying inflammation in criteria. a patient with severe, long-standing, inadequately treated gout. 69

! I Crystal Arthropathies I : 't more subcutaneous tophi; evidence of radiographic damage I I Soft tissue (any modality) attributable to gout; or frequent gout flares, .\

Crystal Arthropathies I : 't more subcutaneous tophi; evidence of radiographic damage I I Soft tissue (any modality) attributable to gout; or frequent gout flares, .\ with "frequent" being defined as two or more annually. For patients who are experiencing their first flare and have CKD Cartilage Double-contour sign (urate on cartilage) stage 3 or greater, a serum urate level exceeding 9.0 mg/dl (0.53 mmol/L), or urolithiasis, the ACR conditionally recom- mends initiating urate-lowering therapy. These guidelines strongly recommend that patients taking urate-lowering ther- apy continue it to achieve and maintain a serum urate target less than 6.0 mg/dl (0.3s mmol/L). Current evidence supports initiating urate-lowering ther- Bone-cartilage apy during an acute flare, but only if adequate anti-inflamma- inter{ace tory therapy is concurrently started; doing so may improve Subchondral bone Iong-term adherence. Administering urate lowering therapy during an acute flare, in the absence of anti-inflammatory FIGU RE 4 7. Ultrasound of the tibial side of the knee showing monosodium therapy, may extend the duration ofthe attack. Ifthe patient is urate deposition on the cartilage surface of a patient with gout. Ihe light already receiving urate-lowering therapy, it should not be heterogeneous area at the top represents soft tissue; the dark area at the bottom is stopped during an acute flare. su bchond ral bone. The bottom brig ht wh it e line (green anow) represents the bone/ Three classes of urate-lowering therapy are available: cartilage interface, and the clear zone aboueit(yellow arrow) is the cartilage. Above the cartilage, and between the ca(ilage and the soft tissue, a second bright white xanthine oxidase inhibitors (which reduce urate production), line may be seen (red arrow\,creatinga double-contour sign, which indicates the uricosuric agents (which decrease renal urate resorption), and presence of urale and is found in many patients with gout. pegloticase (a uricase).

with "frequent" being defined as two or more annually. For patients who are experiencing their first flare and have CKD Cartilage Double-contour sign (urate on cartilage) stage 3 or greater, a serum urate level exceeding 9.0 mg/dl (0.53 mmol/L), or urolithiasis, the ACR conditionally recom- mends initiating urate-lowering therapy. These guidelines strongly recommend that patients taking urate-lowering ther- apy continue it to achieve and maintain a serum urate target less than 6.0 mg/dl (0.3s mmol/L). Current evidence supports initiating urate-lowering ther- Bone-cartilage apy during an acute flare, but only if adequate anti-inflamma- inter{ace tory therapy is concurrently started; doing so may improve Subchondral bone Iong-term adherence. Administering urate lowering therapy during an acute flare, in the absence of anti-inflammatory FIGU RE 4 7. Ultrasound of the tibial side of the knee showing monosodium therapy, may extend the duration ofthe attack. Ifthe patient is urate deposition on the cartilage surface of a patient with gout. Ihe light already receiving urate-lowering therapy, it should not be heterogeneous area at the top represents soft tissue; the dark area at the bottom is stopped during an acute flare. su bchond ral bone. The bottom brig ht wh it e line (green anow) represents the bone/ Three classes of urate-lowering therapy are available: cartilage interface, and the clear zone aboueit(yellow arrow) is the cartilage. Above the cartilage, and between the ca(ilage and the soft tissue, a second bright white xanthine oxidase inhibitors (which reduce urate production), line may be seen (red arrow\,creatinga double-contour sign, which indicates the uricosuric agents (which decrease renal urate resorption), and presence of urale and is found in many patients with gout. pegloticase (a uricase). onset. High-dose NSAIDs for 5 to 7 days are effective, as are Xanthine Oxidose I nhibitors glucocorticoids in any form: intra articular injection, intra Allopurinol is the recommended flrst-line therapy for most muscular injection (e.g., depo-methylprednisolone, 40 80 mg), patients and is FDA approved for dosages up to 800 mg/d. or an oral "burst" of prednisone (e.g., 0.5 mg/kg/d for According to the ACR, allopurinol should be initiated at 100 mg/d 5 days). Topical ice helps reduce duration of the flare and may and the dosage titrated in 100-mg increments every several weeks be considered as adjunctive therapy. until a serum urate level less than 6.0 mg/dl (0.35 mmol/L) is Most gout flares respond to therapy lasting a week or less, achieved (or lower as needed to control flares or resolve tophi). although more severe flares may require longer treatment. For For patients with stage 4 or 5 CKD, allopurinol should be initiated patients with severe and refractory flares, or with contraindi- at 50 mg/d and the dosage titrated in 50 to 100 mg increments cations to other treatments, off label use of IL-lp inhibitors until serum urate target or dosage of 800 mg/d is achieved. (anakinra or canakinumab) can be considered. Gouty cellulitis An uncommon but serious complication of allopurinol is should be treated as any other acute gout flare. a hypersensitivity reaction heralded by a rash that may pro gress to DRESS (drug reaction with eosinophilia and systemic Urate-Lowering Therapy symptoms) syndrome (DRESS is also increasingly being Guidelines conflict as to whether patients with gout should referred to as drug inducedhypersensitiuiru sundrome [DIHS] receive dietary counseling to reduce serum urate levels. Ifrec- to emphasize the fact that eosinophilia is not always present). ommended, patients may limit intake of shellfish, oily fish, red The drug should therelore be discontinued in patients who meat, high-fructose foods, and alcohol. However, overly strict develop a rash. Patients with the HLA-B.58:01 allele have a diets that are unlikely to be adhered to are not helpful. Weight much higher incidence of this syndrome. The 2020 ACR gout loss (when appropriate) and increasing dairy intake may also guidelines therefore conditionally recommend genetic testing lower serum urate levels. In patients with hypertension, agents for HLA-B.58:01 before initiation of allopurinol therapy in all other than diuretics (which block renal urate excretion) should patients of southeast Asian (Han Chinese, Thai, and Korean) be considered; losartan may be a good alternative because it and African descent, given the high prevalence (+% to'2,) of has uricosuric effects. the allele in those populations. Patients who are HLA-B'58:01 The 2020 American College of Rheumatolory (ACR) and positive should usually receive alternative treatment. 2016 European League Against Rheumatism (EULAR) recom Febuxostat is as efficacious as or more efficacious than mendations support a "treat-to-target" approach, reducing the allopurinol. It is less likely to cause hypersensitivity reactions serum urate level to less than 6.0 mg/dl (0.35 mmol/L) and, in than allopurinol and does not require dose adjustment in mild the EULAR guidelines, to less than 5.0 mg/dl (0.30 mmol/L) to moderate CKD. In February 2019, the FDA mandated a in patients with tophi. boxed warning regarding cardiovascular risk with febuxostat The ACR strongly recommends initiating urate-lowering compared with allopurinol and has limited the approved use therapy for patients with gout and any of the following: one or offebuxostat for patients who are unresponsive to or cannot

onset. High-dose NSAIDs for 5 to 7 days are effective, as are Xanthine Oxidose I nhibitors glucocorticoids in any form: intra articular injection, intra Allopurinol is the recommended flrst-line therapy for most muscular injection (e.g., depo-methylprednisolone, 40 80 mg), patients and is FDA approved for dosages up to 800 mg/d. or an oral "burst" of prednisone (e.g., 0.5 mg/kg/d for According to the ACR, allopurinol should be initiated at 100 mg/d 5 days). Topical ice helps reduce duration of the flare and may and the dosage titrated in 100-mg increments every several weeks be considered as adjunctive therapy. until a serum urate level less than 6.0 mg/dl (0.35 mmol/L) is Most gout flares respond to therapy lasting a week or less, achieved (or lower as needed to control flares or resolve tophi). although more severe flares may require longer treatment. For For patients with stage 4 or 5 CKD, allopurinol should be initiated patients with severe and refractory flares, or with contraindi- at 50 mg/d and the dosage titrated in 50 to 100 mg increments cations to other treatments, off label use of IL-lp inhibitors until serum urate target or dosage of 800 mg/d is achieved. (anakinra or canakinumab) can be considered. Gouty cellulitis An uncommon but serious complication of allopurinol is should be treated as any other acute gout flare. a hypersensitivity reaction heralded by a rash that may pro gress to DRESS (drug reaction with eosinophilia and systemic Urate-Lowering Therapy symptoms) syndrome (DRESS is also increasingly being Guidelines conflict as to whether patients with gout should referred to as drug inducedhypersensitiuiru sundrome [DIHS] receive dietary counseling to reduce serum urate levels. Ifrec- to emphasize the fact that eosinophilia is not always present). ommended, patients may limit intake of shellfish, oily fish, red The drug should therelore be discontinued in patients who meat, high-fructose foods, and alcohol. However, overly strict develop a rash. Patients with the HLA-B.58:01 allele have a diets that are unlikely to be adhered to are not helpful. Weight much higher incidence of this syndrome. The 2020 ACR gout loss (when appropriate) and increasing dairy intake may also guidelines therefore conditionally recommend genetic testing lower serum urate levels. In patients with hypertension, agents for HLA-B.58:01 before initiation of allopurinol therapy in all other than diuretics (which block renal urate excretion) should patients of southeast Asian (Han Chinese, Thai, and Korean) be considered; losartan may be a good alternative because it and African descent, given the high prevalence (+% to'2,) of has uricosuric effects. the allele in those populations. Patients who are HLA-B'58:01 The 2020 American College of Rheumatolory (ACR) and positive should usually receive alternative treatment. 2016 European League Against Rheumatism (EULAR) recom Febuxostat is as efficacious as or more efficacious than mendations support a "treat-to-target" approach, reducing the allopurinol. It is less likely to cause hypersensitivity reactions serum urate level to less than 6.0 mg/dl (0.35 mmol/L) and, in than allopurinol and does not require dose adjustment in mild the EULAR guidelines, to less than 5.0 mg/dl (0.30 mmol/L) to moderate CKD. In February 2019, the FDA mandated a in patients with tophi. boxed warning regarding cardiovascular risk with febuxostat The ACR strongly recommends initiating urate-lowering compared with allopurinol and has limited the approved use therapy for patients with gout and any of the following: one or offebuxostat for patients who are unresponsive to or cannot 70

Crystal Arthropathies tolerate allopurinol. For patients taking febuxostat who have a l(tY P0 I tlTS (contlnucd) history of cardiovascular disease or a new cardiovascular o Colchicine, NSAIDs, and glucocorticoids are options for event, ACR guidelines conditionally recommend switching to treatment of acute gout. alternative urate lowering therapy if available. o The American College of Rheumatolory strongly recom mends that patients taking urate lowering therapy con Uricosuric Agents tinue doing so to achieve and maintain a serum urate The uricosuric agent probenecid is infrequently used as a sin target less than 6.0 mg/dl (0.35 mmol/L). gle agent because it is less effective than xanthine oxidase inhibitors; it should be avoided in patients with CKD (esti o Patients starting urate-lowering therapy should receive mated glomerular filtration rate <50 mLlmirrl7.73 m2) or anti inflammatory prophylaxis to prevent flares. nephrolithiasis. Combination therapy with a xanthine oxidase inhibitor and probenecid (or the incidentally uricosuric agent losartan) may be more effective than a xanthine oxidase inhib- Calcium Pyrophosphate itor alone. A more effective uricosuric agent, lesinurad, is available in Europe. Reversible kidney insufficiency may Deposition develop in some palienls. Deposition of calcium pyrophosphate (CPP) crystals in cafti lage can provoke an acute inflammatory arlhritis that clini cally resembles a gout flare. CPP deposition (CPPD) disease is Pegloticase less well characterized than gout, but four subgroups are Pegloticase is an option for patients with severe recurrent and/ described: (1) asymptomatic CPPD, (2) acute CPP crystal or tophaceous gout who are intolerant ofor resistant to stand- arthritis, (3) chronic CPP crystal inflammatory arthritis, and ard therapies. Infused every 2 weeks, pegloticase lowers semm (4) osteoarthritis with CPPD. urate to nearly zero. However, 30% to 50% ofpatients develop antibodies to the drug within weeks, rendering it ineffective and increasing the likelihood of infusion reactions, including Epidemiology and Pathophysiology anaphylaxis. Pegloticase should be discontinued in any patient CPPD primarily affects older patients, and prior joint trauma for whom it ceases to work because this suggests drug anti is a significant risk factor. The risk for cartilage calcification body formation. Serum urate should be checked before each (chondrocalcinosis) doubles for every decade past 60 years, infusion, and pegloticase should be discontinued if the serum and nearly halfofpatients in their late BOs have CPP visible on urate level exceeds 6.0 mg/dl (0.35 mmol/L) on two consecu plain radiographs. For younger patients with CPPD, laboratory tive assessments. evaluation for contributory metabolic disease (hyperparathy roidism, hemochromatosis, hypophosphatasia, hypomagne Prophylaxis semia) is warranted. Whenever urate lowering therapy is initiated for gout, mobili- The pathophysiologz of CPPD is incompletely under zation of monosodium urate crystals from joints and soft stood. Pyrophosphate produced by chondrocytes likely pre tissues can provoke flares. Accordingly, patients starting urate cipitates with calcium to form CPP crystals, which then lowering therapy during intercritical periods should be pre- deposit and can activate inflammatory pathways, resulting scribed anti inflammatory prophyl&xis to prevent flares. The in an acute arthritic flare. CPPD may also drive osteoarthritis ACR strongly recommends continuing prophylaxis for 3 to by causing mechanical damage and inducing proinflamma 6 months, with ongoing evaluation and continued prophylaxis tory activity in chondrocytes and synovial fibroblasts. as needed ifflares continue. I\4ost patients tolerate colchicine, Epidemiologic evidence suggests that cartilage calcification 0.6 mg once or twice daily; for those who do not, low-dose might play a role in osteoarthritis of the knees and wrists, but NSAIDs or glucocorticoids are appropriate substitutes. Most not at the hip. patients can use the same drug used for the acute flare, at a lower dose lor prophylaxis. Clinical Manifestations and Diagnosis KEY POIilTS Asymptomatic Calcium Pyrophosphate Deposition . The gold standard for diagnosis of gout flare is identifi- Asymptomatic CPPD occurs with radiographic changes in cation of negatively birefringent, needle-like intracellular the absence of clinical symptoms. Cartilage calcification and extracellular monosodium urate crystals within appears as a Iinear opacity below the surface of articular synovial fluid. cartilage (Figure 48). It most commonly occurs in the knees, . The diagnosis ofgout flare, even when confirmed by wrists (triangular fibrocartilage), pelvis (symphysis pubis), and metacarpophalangeal (MCP) joints, in descending order. intracellular crystals in synovial fluid, does not defini- Asymptomatic CPPD is common in older patients and in tively rule out concomitant infection. osteoarthritic joints, and it may be a precursor of sympto (Continued) matic osteoarthritis with CPPD.

tolerate allopurinol. For patients taking febuxostat who have a l(tY P0 I tlTS (contlnucd) history of cardiovascular disease or a new cardiovascular o Colchicine, NSAIDs, and glucocorticoids are options for event, ACR guidelines conditionally recommend switching to treatment of acute gout. alternative urate lowering therapy if available. o The American College of Rheumatolory strongly recom mends that patients taking urate lowering therapy con Uricosuric Agents tinue doing so to achieve and maintain a serum urate The uricosuric agent probenecid is infrequently used as a sin target less than 6.0 mg/dl (0.35 mmol/L). gle agent because it is less effective than xanthine oxidase inhibitors; it should be avoided in patients with CKD (esti o Patients starting urate-lowering therapy should receive mated glomerular filtration rate <50 mLlmirrl7.73 m2) or anti inflammatory prophylaxis to prevent flares. nephrolithiasis. Combination therapy with a xanthine oxidase inhibitor and probenecid (or the incidentally uricosuric agent losartan) may be more effective than a xanthine oxidase inhib- Calcium Pyrophosphate itor alone. A more effective uricosuric agent, lesinurad, is available in Europe. Reversible kidney insufficiency may Deposition develop in some palienls. Deposition of calcium pyrophosphate (CPP) crystals in cafti lage can provoke an acute inflammatory arlhritis that clini cally resembles a gout flare. CPP deposition (CPPD) disease is Pegloticase less well characterized than gout, but four subgroups are Pegloticase is an option for patients with severe recurrent and/ described: (1) asymptomatic CPPD, (2) acute CPP crystal or tophaceous gout who are intolerant ofor resistant to stand- arthritis, (3) chronic CPP crystal inflammatory arthritis, and ard therapies. Infused every 2 weeks, pegloticase lowers semm (4) osteoarthritis with CPPD. urate to nearly zero. However, 30% to 50% ofpatients develop antibodies to the drug within weeks, rendering it ineffective and increasing the likelihood of infusion reactions, including Epidemiology and Pathophysiology anaphylaxis. Pegloticase should be discontinued in any patient CPPD primarily affects older patients, and prior joint trauma for whom it ceases to work because this suggests drug anti is a significant risk factor. The risk for cartilage calcification body formation. Serum urate should be checked before each (chondrocalcinosis) doubles for every decade past 60 years, infusion, and pegloticase should be discontinued if the serum and nearly halfofpatients in their late BOs have CPP visible on urate level exceeds 6.0 mg/dl (0.35 mmol/L) on two consecu plain radiographs. For younger patients with CPPD, laboratory tive assessments. evaluation for contributory metabolic disease (hyperparathy roidism, hemochromatosis, hypophosphatasia, hypomagne Prophylaxis semia) is warranted. Whenever urate lowering therapy is initiated for gout, mobili- The pathophysiologz of CPPD is incompletely under zation of monosodium urate crystals from joints and soft stood. Pyrophosphate produced by chondrocytes likely pre tissues can provoke flares. Accordingly, patients starting urate cipitates with calcium to form CPP crystals, which then lowering therapy during intercritical periods should be pre- deposit and can activate inflammatory pathways, resulting scribed anti inflammatory prophyl&xis to prevent flares. The in an acute arthritic flare. CPPD may also drive osteoarthritis ACR strongly recommends continuing prophylaxis for 3 to by causing mechanical damage and inducing proinflamma 6 months, with ongoing evaluation and continued prophylaxis tory activity in chondrocytes and synovial fibroblasts. as needed ifflares continue. I\4ost patients tolerate colchicine, Epidemiologic evidence suggests that cartilage calcification 0.6 mg once or twice daily; for those who do not, low-dose might play a role in osteoarthritis of the knees and wrists, but NSAIDs or glucocorticoids are appropriate substitutes. Most not at the hip. patients can use the same drug used for the acute flare, at a lower dose lor prophylaxis. Clinical Manifestations and Diagnosis KEY POIilTS Asymptomatic Calcium Pyrophosphate Deposition . The gold standard for diagnosis of gout flare is identifi- Asymptomatic CPPD occurs with radiographic changes in cation of negatively birefringent, needle-like intracellular the absence of clinical symptoms. Cartilage calcification and extracellular monosodium urate crystals within appears as a Iinear opacity below the surface of articular synovial fluid. cartilage (Figure 48). It most commonly occurs in the knees, . The diagnosis ofgout flare, even when confirmed by wrists (triangular fibrocartilage), pelvis (symphysis pubis), and metacarpophalangeal (MCP) joints, in descending order. intracellular crystals in synovial fluid, does not defini- Asymptomatic CPPD is common in older patients and in tively rule out concomitant infection. osteoarthritic joints, and it may be a precursor of sympto (Continued) matic osteoarthritis with CPPD. 71

Crystal Arthropathies Patients present with acute neck pain, fever, and headache mimicking meningitis. Chronic Calcium Pyrophosphate Arthropathy Chronic calcium pyrophosphate arthropathy may be present in one of two patterns: (t) chronic CPP crystal inflammatory arthritis and (2) osteoarthritis with CPPD. Chronic CPP crystal inflammatory arthritis is a polyarthritis involving the wrists and MCP joints ("pseudo rheumatoid arthritis"); it is rare and difficult to treat. Osteoarthritis with CPPD manifests as typical osteoarthritic findings involving joints not commonly associ ated with osteoarthritis (such as shoulders or MCP joints); radiographic CPPD often precedes osteoarthritis onset, sug- gesting a causal role for CPP FIGU RE 4 8. Cartilage calcification (chondrocalcinosis) of the knee. This radiograph shows linearly arranged calcific deposits in the articular cartilage (arow). Management In contrast to gout, there is no known mechanism for dissolv Acute Calcium Pyrophosphate Crystal Arthritis ing articular CPP crystals or preventing their formation. Acute CPP crystal arthritis (pseudogout) typically presents as a lnstead, treatment aims at abrogating the inflammatory mani monoarticular or oligoarticular inflammatory arthritis, char- festations of the disease (Table 35). Associated metabolic con- acterized by sudden onset of swelling, pain, loss of function, ditions should be treated, but this treatment rarely results in tenderness, and warmth of the alfected joint (usually a knee or remission of the CPPD disease. wrist). Like acute gout, CPP flares may be provoked by sys XEY POIIITS temic insults, such as major surgery or acute illness. Flares are usually milder than those of gout and less commonly affect the . Asymptomatic calcium pyrophosphate deposition is MTP joint, but if untreated they can persist for weeks or characterized by radiographic changes, including carti- months. Definitive diagnosis requires identification of CPP lage calcification (chondrocalcinosis).

Chronic Calcium Pyrophosphate Arthropathy Chronic calcium pyrophosphate arthropathy may be present in one of two patterns: (t) chronic CPP crystal inflammatory arthritis and (2) osteoarthritis with CPPD. Chronic CPP crystal inflammatory arthritis is a polyarthritis involving the wrists and MCP joints ("pseudo rheumatoid arthritis"); it is rare and difficult to treat. Osteoarthritis with CPPD manifests as typical osteoarthritic findings involving joints not commonly associ ated with osteoarthritis (such as shoulders or MCP joints); radiographic CPPD often precedes osteoarthritis onset, sug- gesting a causal role for CPP FIGU RE 4 8. Cartilage calcification (chondrocalcinosis) of the knee. This radiograph shows linearly arranged calcific deposits in the articular cartilage (arow). Management In contrast to gout, there is no known mechanism for dissolv Acute Calcium Pyrophosphate Crystal Arthritis ing articular CPP crystals or preventing their formation. Acute CPP crystal arthritis (pseudogout) typically presents as a lnstead, treatment aims at abrogating the inflammatory mani monoarticular or oligoarticular inflammatory arthritis, char- festations of the disease (Table 35). Associated metabolic con- acterized by sudden onset of swelling, pain, loss of function, ditions should be treated, but this treatment rarely results in tenderness, and warmth of the alfected joint (usually a knee or remission of the CPPD disease. wrist). Like acute gout, CPP flares may be provoked by sys XEY POIIITS temic insults, such as major surgery or acute illness. Flares are usually milder than those of gout and less commonly affect the . Asymptomatic calcium pyrophosphate deposition is MTP joint, but if untreated they can persist for weeks or characterized by radiographic changes, including carti- months. Definitive diagnosis requires identification of CPP lage calcification (chondrocalcinosis). crystals (along with leukocyes) in synovial fluid; in contrast to . The presentation of acute calcium pyrophosphate crys- urate crystals, CPP crystals are rhomboid-shaped and posi- tal arthritis (pseudogout) resembles gout; however, tively birefringent (blue when parallel to and yellow when crystals are rhomboid shaped and positively birefrin- perpendicular to the polarizing axis ofan optical filter). As in gent under polarized light. gout flares, joint infection may coexist with CPP arthritis, and o Chronic calcium pyrophosphate crystal inflammatory synovial fluid Gram stain and culture are usually warranted. arthritis often involves the wrists and metacar- Radiographic evidence of cartilage calcification in older pophalangeal joints ("pseudo-rheumatoid arthritis"). patients with acute monoarticular arthritis suggests, but is not o Osteoarthritis with calcium pyrophosphate deposition diagnostic of, acute CPP crystal arthritis. causes typical osteoarthritic findings involving joints The crowned dens syndrome is a rare presentation of CPP not commonly associated with osteoarthritis (shoulders, crystal arthritis involving the C2 vertebra. Radiographically it wrists, metacarpophalangeal joints). may present as calcification of the cartilage over the dens.

crystals (along with leukocyes) in synovial fluid; in contrast to . The presentation of acute calcium pyrophosphate crys- urate crystals, CPP crystals are rhomboid-shaped and posi- tal arthritis (pseudogout) resembles gout; however, tively birefringent (blue when parallel to and yellow when crystals are rhomboid shaped and positively birefrin- perpendicular to the polarizing axis ofan optical filter). As in gent under polarized light. gout flares, joint infection may coexist with CPP arthritis, and o Chronic calcium pyrophosphate crystal inflammatory synovial fluid Gram stain and culture are usually warranted. arthritis often involves the wrists and metacar- Radiographic evidence of cartilage calcification in older pophalangeal joints ("pseudo-rheumatoid arthritis"). patients with acute monoarticular arthritis suggests, but is not o Osteoarthritis with calcium pyrophosphate deposition diagnostic of, acute CPP crystal arthritis. causes typical osteoarthritic findings involving joints The crowned dens syndrome is a rare presentation of CPP not commonly associated with osteoarthritis (shoulders, crystal arthritis involving the C2 vertebra. Radiographically it wrists, metacarpophalangeal joints). may present as calcification of the cartilage over the dens. TABLE 35. Management of Calcium Pyrophosphate Deposition Clinical Presentation TreatmenVComments Cartilage calcification (chondrocalcinosis) No specific treatment Acute calcium pyrophosphate crystal Local treatment: joint aspiration, followed by intra-articular glucocorticoid injection, joint arthritis ( pseudogout) immobilization; ice packs Systemic treatment: anti-inflammatory doses of NSAIDs; colchicine; glucocorticoids (oral, intramuscular, or parenteral); if there are contraindications to the preceding drugs, anakinra may be considered off-label Prophylaxis if recurrent attacks (three or more annual attacks): low-dose colchicine or daily NSAI Ds (with gastrointestina I protection)

TABLE 35. Management of Calcium Pyrophosphate Deposition Clinical Presentation TreatmenVComments Cartilage calcification (chondrocalcinosis) No specific treatment Acute calcium pyrophosphate crystal Local treatment: joint aspiration, followed by intra-articular glucocorticoid injection, joint arthritis ( pseudogout) immobilization; ice packs Systemic treatment: anti-inflammatory doses of NSAIDs; colchicine; glucocorticoids (oral, intramuscular, or parenteral); if there are contraindications to the preceding drugs, anakinra may be considered off-label Prophylaxis if recurrent attacks (three or more annual attacks): low-dose colchicine or daily NSAI Ds (with gastrointestina I protection) Chronic calcium pyrophosphate crystal Low-dose colchicine or daily low-dose NSAIDs (with gastrointestinal protection); inflammatory arthritis low-dose glucocorticoids Osteoarthritis with calcium pyrophosphate Same treatment as for osteoarthritis without calcium pyrophosphate deposition (e.9., deposition physical therapy, pain control, local glucocorticoids) 72

Infectious Arthritis Basic Calcium Phosphate fluid leukocyte counts are typically greater than 50,000/pL (50 x 10e/L) and often exceed 100,000/pL (100 x 10e/L), with Deposition a polymorphonuclear cell predominance. Such high leuko- Basic calcium phosphate (BCP) deposition occurs in older cyte counts may occur in other conditions (e.g., crystal persons and targets both articular cartilage and periarticu- arthropathies) but should be presumed infectious until lar tendons and ligaments. BCP deposition is rarely associ- proven otherwise. Notably, the presence of crystals does not ated with inflammatory arthritis and periarthritis, most exclude the possibility of concomitant infection. Synovial classically manifesting in older women as "Milwaukee fluid leukocyte counts may be lower in patients with gono shoulder," an inflammatory state that causes progressive coccal, mycobacterial, or fungal infections; patients who destruction of the rotator cuff and glenohumeral joint. inject drugs; or those who are immunocompromised. A Gram Diagnosis is usually clinical; radiographs show calcium stain positive for bacteria should be considered definitive, but deposition in the affected tissues. Visualization of BCP crys- the sensitivity of the test is inadequate for a negative result to tals requires special stains and/or electron microscopy and rule out infection when suspicion is high. Synovial fluid cul- is rarely performed. tures are usually positive in bacterial infections unless antibi- TEY ?OITT otics were administered before arthrocentesis. Peripheral . Basic calcium phosphate deposition can rarely cause blood leukocyte count, erythrocyte sedimentation rate, and C-reactive protein level are often elevated; however, normal "Milwaukee shoulder," a destructive inflammatory levels do not exclude the diagnosis, and elevated levels may arthritis and periarthritis ofthe shoulder; diagnosis is occur in noninfectious inflammatory arthritis and other usually clinical. conditions. Blood cultures should always be drawn before antibiotic administration. When gonococcal arthritis is suspected, uro-

Basic Calcium Phosphate fluid leukocyte counts are typically greater than 50,000/pL (50 x 10e/L) and often exceed 100,000/pL (100 x 10e/L), with Deposition a polymorphonuclear cell predominance. Such high leuko- Basic calcium phosphate (BCP) deposition occurs in older cyte counts may occur in other conditions (e.g., crystal persons and targets both articular cartilage and periarticu- arthropathies) but should be presumed infectious until lar tendons and ligaments. BCP deposition is rarely associ- proven otherwise. Notably, the presence of crystals does not ated with inflammatory arthritis and periarthritis, most exclude the possibility of concomitant infection. Synovial classically manifesting in older women as "Milwaukee fluid leukocyte counts may be lower in patients with gono shoulder," an inflammatory state that causes progressive coccal, mycobacterial, or fungal infections; patients who destruction of the rotator cuff and glenohumeral joint. inject drugs; or those who are immunocompromised. A Gram Diagnosis is usually clinical; radiographs show calcium stain positive for bacteria should be considered definitive, but deposition in the affected tissues. Visualization of BCP crys- the sensitivity of the test is inadequate for a negative result to tals requires special stains and/or electron microscopy and rule out infection when suspicion is high. Synovial fluid cul- is rarely performed. tures are usually positive in bacterial infections unless antibi- TEY ?OITT otics were administered before arthrocentesis. Peripheral . Basic calcium phosphate deposition can rarely cause blood leukocyte count, erythrocyte sedimentation rate, and C-reactive protein level are often elevated; however, normal "Milwaukee shoulder," a destructive inflammatory levels do not exclude the diagnosis, and elevated levels may arthritis and periarthritis ofthe shoulder; diagnosis is occur in noninfectious inflammatory arthritis and other usually clinical. conditions. Blood cultures should always be drawn before antibiotic administration. When gonococcal arthritis is suspected, uro- lnfestious Arthritis genital, rectal, and pharyngeal specimens should also be obtained for nucleic acid amplification testing. Diagnosis Plain radiographs are usually normal early in the course of the infection, but baseline fllms are helpful to identi$/ other Clinical Manifestations diseases or contiguous osteomyelitis. Radiographs obtained Infectious arthritis typically presents with pain, swelling, later (from weeks to months) often show nonspecific changes. warmth, and erythema of the affected joint, accompanied by In advanced or particularly virulent infection, periosteal reac- fever and constitutional symptoms. Knee joint infection is tion, marginal or central erosions, and subchondral bone common, but any joint may be affected. Previously damaged destruction may be seen (Figure 49). Bony ankylosis is a late joints are at increased risk for involvement; acute monoarthri- tis or new inflammation of a single joint in a patientwithwell- controlled inflammatory arthritis should prompt evaluation for infection. Physical examination commonly shows loss of both active and passive range of motion in addition to signs of inflamma- tion. Careful skin examination can reveal signs suggesting gonococcal infection (pustular skin lesions) or potential portals of entry for pathogens (scratches, bites, or foreign bodies).

lnfestious Arthritis genital, rectal, and pharyngeal specimens should also be obtained for nucleic acid amplification testing. Diagnosis Plain radiographs are usually normal early in the course of the infection, but baseline fllms are helpful to identi$/ other Clinical Manifestations diseases or contiguous osteomyelitis. Radiographs obtained Infectious arthritis typically presents with pain, swelling, later (from weeks to months) often show nonspecific changes. warmth, and erythema of the affected joint, accompanied by In advanced or particularly virulent infection, periosteal reac- fever and constitutional symptoms. Knee joint infection is tion, marginal or central erosions, and subchondral bone common, but any joint may be affected. Previously damaged destruction may be seen (Figure 49). Bony ankylosis is a late joints are at increased risk for involvement; acute monoarthri- tis or new inflammation of a single joint in a patientwithwell- controlled inflammatory arthritis should prompt evaluation for infection. Physical examination commonly shows loss of both active and passive range of motion in addition to signs of inflamma- tion. Careful skin examination can reveal signs suggesting gonococcal infection (pustular skin lesions) or potential portals of entry for pathogens (scratches, bites, or foreign bodies). Laboratory and lmaging Studies In patients suspected of having infectious arthritis, the most important diagnostic procedure is expeditious arthrocentesis. The slmovial fluid should be sent for Gram stain, culture (bac- terial and, when indicated, mycobacterial and/or fungal), leukocyte count, and crystal analysis. Synovial fluid levels of glucose, lactate dehydrogenase, and total protein do not aid in diagnosis and should not be ordered. Depending on the clinical picture, the fluid may be sent for polymerase chain reaction assay to detect mycobacteria or Borrelia burgdorferi DNA. Bacteria-infected synovial fluid is cloudy and less viscous FIGURE 49. Radiographshowing infectiousarthritis-related bonedestruction than that seen in noninflammatory arthritis. Elevated synovial of the hip.

Laboratory and lmaging Studies In patients suspected of having infectious arthritis, the most important diagnostic procedure is expeditious arthrocentesis. The slmovial fluid should be sent for Gram stain, culture (bac- terial and, when indicated, mycobacterial and/or fungal), leukocyte count, and crystal analysis. Synovial fluid levels of glucose, lactate dehydrogenase, and total protein do not aid in diagnosis and should not be ordered. Depending on the clinical picture, the fluid may be sent for polymerase chain reaction assay to detect mycobacteria or Borrelia burgdorferi DNA. Bacteria-infected synovial fluid is cloudy and less viscous FIGURE 49. Radiographshowing infectiousarthritis-related bonedestruction than that seen in noninflammatory arthritis. Elevated synovial of the hip. 73

lnfectious Arthritis sequela. In joints that are difficult to evaluate clinically or have TABLE 36. Risk Factors for lnfectious Arthritis in Adults complex anatomic structures, ultrasonography, Cl and MRI General can delineate the extent of an effusion and identi$r early bony Age >80 years changes. Alcoholism TEY POIXIS Cutaneous ulcers or skin infections o Infectious arthritis typically presents with pain, swell Diabetes mellitus ing, warmth, and erythema of the affected joint, accom- End-stage kidney disease panied by fever and constitutional symptoms. lnjection drug use o Acute monoarthritis or new inllammation of a single joint in a patient with well-controlled inflammatory Malignancy arthritis should prompt evaluation for infection. Hereditary immunodeficiency states or therapy with immunosuppressive agents . Diagnosis of infectious arthritis is confirmed by arthro- Preexisting arthritis or joint damage (e.g., rheumatoid arthritis centesis and evaluation of the qmovial fluid for Gram or osteoarthritis) stain, culture, leukocyte count, and crystal analysis. Prosthetic joint or recent joint surgery Sickle cell disease

arthritis should prompt evaluation for infection. Hereditary immunodeficiency states or therapy with immunosuppressive agents . Diagnosis of infectious arthritis is confirmed by arthro- Preexisting arthritis or joint damage (e.g., rheumatoid arthritis centesis and evaluation of the qmovial fluid for Gram or osteoarthritis) stain, culture, leukocyte count, and crystal analysis. Prosthetic joint or recent joint surgery Sickle cell disease Gonococcal Arthritis Causes Sexually active patients See MKSAP 19 Infectious Disease for details on the specific Terminal complement deficiency infections and diseases discussed in this section. Lyme Arthritis lnfection With Gram-Positive Organisms Travel to or residence in an endemic area Bacterial arthritis is a medical emergency requiring immedi Documented tick bite or erythema ns ate diagnosis and treatment. Risk factors include an immuno Mycobacterial or Fungal Arthritis compromised state (including diabetes mellitus), injection HIV infection or other immunosuppression drug use, a history of joint surgery and having a prosthetic joint. A recent break in the skin may be a contributing factor. Therapy with tumor necrosis factor inhibitors

Gonococcal Arthritis Causes Sexually active patients See MKSAP 19 Infectious Disease for details on the specific Terminal complement deficiency infections and diseases discussed in this section. Lyme Arthritis lnfection With Gram-Positive Organisms Travel to or residence in an endemic area Bacterial arthritis is a medical emergency requiring immedi Documented tick bite or erythema ns ate diagnosis and treatment. Risk factors include an immuno Mycobacterial or Fungal Arthritis compromised state (including diabetes mellitus), injection HIV infection or other immunosuppression drug use, a history of joint surgery and having a prosthetic joint. A recent break in the skin may be a contributing factor. Therapy with tumor necrosis factor inhibitors lnfections occur rarely after invasive procedures, such as Travel to or residence in an endemic area arthrocentesis or joint injection (Table 36). Most joint infec- Viral Arthritis tions are monoarticular and derive from hematogenous seed- Chronic viral infection (HlV, hepatitis B virus, hepatitis C virus) ing to the synovium. Polyarticular infectious arthritis may Exposure to infectious agent or vaccine (e.g., rubella) occur in persons who use injection drugs, those with systemic Travel to or residence in an endemic area (e.9., chikungunya, inflammatory disorders (such as rheumatoid arthritis), dengue, Zika) immunosuppressed patients, and patients experiencing over- Exposure to affected children (parvovirus B19, rubella) whelming sepsis. Approximately 75"/,, of cases of nongonococcal infectious arthritis in adults are caused by gram-positive cocci. Staphylcxrtccus this syndrome from other forms of infectious arthritis. Risk oureus is the most frequent microorganism in both native and factors for dissemination include HIV infection, pregnancy, prosthetic joints. Stophylococcus epidermidis infections occur recent menstruation, and deficiencies in immunoglobulin more commonly in prosthetic than in native joints. and terminal complement. The second presentation is a purulent arthritis, usually without associated skin lesions or lnfection With Gram-Negative Organisms fever. Patients present with acute onset of mono or oligo- Disseminated Gonococcal Infection arthritis; the knees, wrists, and ankles are most commonly Neisserio gonorrhoeoe most typically occurs in younger, sexu- involved. ally active individuals. Disseminated infection occurs in 1% to Patients with the arthritis dermatitis syndrome are more 3'7, of patients infected with N. gonorrhoeae, with arthritis a likely to have positive blood cultures, whereas those with common feature. purulent arthritis are more likely to have positive synovial Disseminated gonococcal infection may present in one fluid cultures. Nucleic acid amplification testing should also of two ways, although there may be overlap. The first is be obtained on samples from genital, rectal. and pharyngeal the arthritis-dermatitis syndrome, a triad of tenosynovitis, sites. dermatitis (usually painless pustular or vesiculopustular lesions) (Figure 5O), and polyarthralgia without frank arthri Nongonococcal Gram-Negative Infections tis. Feveq chills, and malaise are common. Inf'lammation of Aerobic gram-negative bacilli are the predominant cause of tendons of the wrists, fingers, ankles, and toes distinguishes nongonococcal gram-negative joint infections. Predisposing

lnfections occur rarely after invasive procedures, such as Travel to or residence in an endemic area arthrocentesis or joint injection (Table 36). Most joint infec- Viral Arthritis tions are monoarticular and derive from hematogenous seed- Chronic viral infection (HlV, hepatitis B virus, hepatitis C virus) ing to the synovium. Polyarticular infectious arthritis may Exposure to infectious agent or vaccine (e.g., rubella) occur in persons who use injection drugs, those with systemic Travel to or residence in an endemic area (e.9., chikungunya, inflammatory disorders (such as rheumatoid arthritis), dengue, Zika) immunosuppressed patients, and patients experiencing over- Exposure to affected children (parvovirus B19, rubella) whelming sepsis. Approximately 75"/,, of cases of nongonococcal infectious arthritis in adults are caused by gram-positive cocci. Staphylcxrtccus this syndrome from other forms of infectious arthritis. Risk oureus is the most frequent microorganism in both native and factors for dissemination include HIV infection, pregnancy, prosthetic joints. Stophylococcus epidermidis infections occur recent menstruation, and deficiencies in immunoglobulin more commonly in prosthetic than in native joints. and terminal complement. The second presentation is a purulent arthritis, usually without associated skin lesions or lnfection With Gram-Negative Organisms fever. Patients present with acute onset of mono or oligo- Disseminated Gonococcal Infection arthritis; the knees, wrists, and ankles are most commonly Neisserio gonorrhoeoe most typically occurs in younger, sexu- involved. ally active individuals. Disseminated infection occurs in 1% to Patients with the arthritis dermatitis syndrome are more 3'7, of patients infected with N. gonorrhoeae, with arthritis a likely to have positive blood cultures, whereas those with common feature. purulent arthritis are more likely to have positive synovial Disseminated gonococcal infection may present in one fluid cultures. Nucleic acid amplification testing should also of two ways, although there may be overlap. The first is be obtained on samples from genital, rectal. and pharyngeal the arthritis-dermatitis syndrome, a triad of tenosynovitis, sites. dermatitis (usually painless pustular or vesiculopustular lesions) (Figure 5O), and polyarthralgia without frank arthri Nongonococcal Gram-Negative Infections tis. Feveq chills, and malaise are common. Inf'lammation of Aerobic gram-negative bacilli are the predominant cause of tendons of the wrists, fingers, ankles, and toes distinguishes nongonococcal gram-negative joint infections. Predisposing 74

lnfectious Arthritis positive results on enzyme-linked immunosorbent assay and Western biot confirmatory serologiesl this is the primary means of diagnosing Lyme arthritis and is preferred to poly merase chain testing for B. burgdorleri DNA or culture of blood or synovial fluid.

positive results on enzyme-linked immunosorbent assay and Western biot confirmatory serologiesl this is the primary means of diagnosing Lyme arthritis and is preferred to poly merase chain testing for B. burgdorleri DNA or culture of blood or synovial fluid. Mycobaaerium tuberculosis lnfection The most common musculoskeletal manifestation of tuber culosis is vertebral osteomyelitis (Pott disease), usually resulting from the hematogenous spread of Mycobacterium tuberculosis into the cancellous bone ofthe vertebral bodies. The onset of symptoms is commonly insidious and is not accompanied by systemic symptoms. Disease progression is slow sometimes resulting in delayed diagnosis. Predisposing F I G U R E 5 0. Disseminated gonococcal infertion can present as a febrile factors for skeletal tuberculosis include previous tuberculosis arthritis dermatitis syndrome with migratory polyarthralgia that may evolve to infectious arthritis, tenosynovitis, and painless skin rash that may involve the infection, malnutrition, alcoholism, diabetes mellitus, and palms and soles. Skin lesions can vary from maculopapular to pustular, often with a HIV infection. hemorrhagic component. Peripheral arthritis may also occur and typically presents with chronic pain in a single weight-bearing joint, such as the Iactors include injection drug use, advanced age, and an knee or hip. As in vertebral osteomyelitis, concurrent pulmo- immunocompromised state. Pseudomones oerugirloso can nary tuberculosis is present in only a minority of patients be seen in infection related to injection drug use. Patients with peripheral arthritis. Laboratory indicators of inflamma with sickle cell anemia may become infected with tion may be only slightly abnormal, synovial fluid findings Salmonella species. Gram negative anaerobes account fbr can be nonspecific, and radiographic abnormalities can be only 5'7, to 7'7, of bacterial arthritis cases, most commonly in delayed. Synovial biopsy is usually necessary for diagnosis prosthetic joint infections and/or immunocompromised because the yield of synovial fluid stain and culture is less hosts. than 50'1,. Atypical mycobacteria can occasionally infect joints. Lyme Arthritis Mycobacterium marinum is acquired through skin breaks Although arthralgia and myalgia often occur at the earlier exposed to fresh or salt water (seen in fishermen and stages of Lyme disease, Lyme afthritis is a late-stage manifesta aquarium hobbyists), and usually causes skin nodules and tion. It is typically monoarticular, most commonly in the knee arthritis. (Figure 5l). It should be suspected in patients who may have had untreated or incompletely treated Lyme disease, although Fungal tnfections not all patients will have a history compatible with prior Lyme Fungi are uncommon but important causes of bone and joint disease. All patients with Lyme arthritis, however, shriuld have infections. Risk factors include immunosuppression and

Mycobaaerium tuberculosis lnfection The most common musculoskeletal manifestation of tuber culosis is vertebral osteomyelitis (Pott disease), usually resulting from the hematogenous spread of Mycobacterium tuberculosis into the cancellous bone ofthe vertebral bodies. The onset of symptoms is commonly insidious and is not accompanied by systemic symptoms. Disease progression is slow sometimes resulting in delayed diagnosis. Predisposing F I G U R E 5 0. Disseminated gonococcal infertion can present as a febrile factors for skeletal tuberculosis include previous tuberculosis arthritis dermatitis syndrome with migratory polyarthralgia that may evolve to infectious arthritis, tenosynovitis, and painless skin rash that may involve the infection, malnutrition, alcoholism, diabetes mellitus, and palms and soles. Skin lesions can vary from maculopapular to pustular, often with a HIV infection. hemorrhagic component. Peripheral arthritis may also occur and typically presents with chronic pain in a single weight-bearing joint, such as the Iactors include injection drug use, advanced age, and an knee or hip. As in vertebral osteomyelitis, concurrent pulmo- immunocompromised state. Pseudomones oerugirloso can nary tuberculosis is present in only a minority of patients be seen in infection related to injection drug use. Patients with peripheral arthritis. Laboratory indicators of inflamma with sickle cell anemia may become infected with tion may be only slightly abnormal, synovial fluid findings Salmonella species. Gram negative anaerobes account fbr can be nonspecific, and radiographic abnormalities can be only 5'7, to 7'7, of bacterial arthritis cases, most commonly in delayed. Synovial biopsy is usually necessary for diagnosis prosthetic joint infections and/or immunocompromised because the yield of synovial fluid stain and culture is less hosts. than 50'1,. Atypical mycobacteria can occasionally infect joints. Lyme Arthritis Mycobacterium marinum is acquired through skin breaks Although arthralgia and myalgia often occur at the earlier exposed to fresh or salt water (seen in fishermen and stages of Lyme disease, Lyme afthritis is a late-stage manifesta aquarium hobbyists), and usually causes skin nodules and tion. It is typically monoarticular, most commonly in the knee arthritis. (Figure 5l). It should be suspected in patients who may have had untreated or incompletely treated Lyme disease, although Fungal tnfections not all patients will have a history compatible with prior Lyme Fungi are uncommon but important causes of bone and joint disease. All patients with Lyme arthritis, however, shriuld have infections. Risk factors include immunosuppression and FTGURE 51, Unilateral kneeeffusion in Lyme arthritis.

Mycobaaerium tuberculosis lnfection The most common musculoskeletal manifestation of tuber culosis is vertebral osteomyelitis (Pott disease), usually resulting from the hematogenous spread of Mycobacterium tuberculosis into the cancellous bone ofthe vertebral bodies. The onset of symptoms is commonly insidious and is not accompanied by systemic symptoms. Disease progression is slow sometimes resulting in delayed diagnosis. Predisposing F I G U R E 5 0. Disseminated gonococcal infertion can present as a febrile factors for skeletal tuberculosis include previous tuberculosis arthritis dermatitis syndrome with migratory polyarthralgia that may evolve to infectious arthritis, tenosynovitis, and painless skin rash that may involve the infection, malnutrition, alcoholism, diabetes mellitus, and palms and soles. Skin lesions can vary from maculopapular to pustular, often with a HIV infection. hemorrhagic component. Peripheral arthritis may also occur and typically presents with chronic pain in a single weight-bearing joint, such as the Iactors include injection drug use, advanced age, and an knee or hip. As in vertebral osteomyelitis, concurrent pulmo- immunocompromised state. Pseudomones oerugirloso can nary tuberculosis is present in only a minority of patients be seen in infection related to injection drug use. Patients with peripheral arthritis. Laboratory indicators of inflamma with sickle cell anemia may become infected with tion may be only slightly abnormal, synovial fluid findings Salmonella species. Gram negative anaerobes account fbr can be nonspecific, and radiographic abnormalities can be only 5'7, to 7'7, of bacterial arthritis cases, most commonly in delayed. Synovial biopsy is usually necessary for diagnosis prosthetic joint infections and/or immunocompromised because the yield of synovial fluid stain and culture is less hosts. than 50'1,. Atypical mycobacteria can occasionally infect joints. Lyme Arthritis Mycobacterium marinum is acquired through skin breaks Although arthralgia and myalgia often occur at the earlier exposed to fresh or salt water (seen in fishermen and stages of Lyme disease, Lyme afthritis is a late-stage manifesta aquarium hobbyists), and usually causes skin nodules and tion. It is typically monoarticular, most commonly in the knee arthritis. (Figure 5l). It should be suspected in patients who may have had untreated or incompletely treated Lyme disease, although Fungal tnfections not all patients will have a history compatible with prior Lyme Fungi are uncommon but important causes of bone and joint disease. All patients with Lyme arthritis, however, shriuld have infections. Risk factors include immunosuppression and FTGURE 51, Unilateral kneeeffusion in Lyme arthritis. 75

lnfectious Arthritis exposure to the fungi in endemic areas. Fungal joint infection oligoarthritis. Chronic HCV infection is often associated with may be indolent and more difficult to diagnose than other circulating immune complexes, which may produce the clini bone and joint infections. Fungal causes of osteomyelitis and cal syndrome of mixed cryoglobulinemia (purpura, weakness, arthritis include coccidioidomycosis, blastomycosis, crypto- and arthralgia). coccosis, candidiasis, and sporotrichosis. Fungal arthritis is Both HBV and HCV infections may be accompanied by usually a result of hematogenous dissemination but can occur the presence of rheumatoid factor, which can cause diagnostic after direct inoculation of the joint. Some fungal inlections confusion. (e.g., blastomycosis and sporotrichosis) can be diagnosed by synovial fluid examination and culture, whereas serologic Parvovirus B19 testing and synovial biopsy may be needed for other organ- Up to 60% of adults with parvovirus B19 experience arthritis. isms (such as Coccidioides species). Synovial fluid leukocy.te It often presents acutely, is symmetric and polyarticular, and counts vary. typically involves the proximal small joints of the hands. Parvovirus B19 arthritis should be suspected when appropri Viral tnfections ate clinical features are present in someone who has exposure

exposure to the fungi in endemic areas. Fungal joint infection oligoarthritis. Chronic HCV infection is often associated with may be indolent and more difficult to diagnose than other circulating immune complexes, which may produce the clini bone and joint infections. Fungal causes of osteomyelitis and cal syndrome of mixed cryoglobulinemia (purpura, weakness, arthritis include coccidioidomycosis, blastomycosis, crypto- and arthralgia). coccosis, candidiasis, and sporotrichosis. Fungal arthritis is Both HBV and HCV infections may be accompanied by usually a result of hematogenous dissemination but can occur the presence of rheumatoid factor, which can cause diagnostic after direct inoculation of the joint. Some fungal inlections confusion. (e.g., blastomycosis and sporotrichosis) can be diagnosed by synovial fluid examination and culture, whereas serologic Parvovirus B19 testing and synovial biopsy may be needed for other organ- Up to 60% of adults with parvovirus B19 experience arthritis. isms (such as Coccidioides species). Synovial fluid leukocy.te It often presents acutely, is symmetric and polyarticular, and counts vary. typically involves the proximal small joints of the hands. Parvovirus B19 arthritis should be suspected when appropri Viral tnfections ate clinical features are present in someone who has exposure HTV to children, such as teachers and caregivers. (In contrast to HIV infection is associated with several musculoskeletal adults, children frequently experience parvovirus B19 infec- disorders, including painful articular syndrome, HIV- tion as a fever accompanied by a facial rash [slapped cheek associated arthritis, reactive arthritis, infectious arthritis, appearancel, so-called fi flth disease.) Acute parvovirus B19 infection is diagnosed by detecting and diffuse infiltrative lymphocytosis syndrome. Painful articular syndrome consists of bone and joint pain, espe- anti-parvovirus IgM antibodies in the serum. Anti parvovirus cially in the lower extremities in an asymmetric pattern, IgG antibodies are highly prevalent in the general population lasting less than 24 hours. HIV associated arthritis is a non- and indicate prior infection. Joint symptoms may persist for destructive arthritis that involves joints of the lower extrem- weeks to months, and treatment is symptomatic (including NSAIDs). ity in an oligoarticular pattern and usually lasts less than 6 weeks. Reactive arthritis is the primary form of spondy loarthritis seen in patients with HIV infection and is more Rubella likely due to a response to other sexually transmitted or Arthritis is uncommon in childhood rubella infection, but up enteric infections than to the HIV infection itself. Reactive to 60% of adults with rubella develop joint symptoms, mainly arthritis in HIV may take a chronic relapsing course and may arthralgia, with the onset of rash. Joint involvement is usually be accompanied by enthesopathy and mucocutaneous man- symmetric and migratory and most symptoms resolve within ifestations. Psoriatic arthritis may be more common and is 2 weeks. The small joints of the hands, wrists, elbows, ankles,

HTV to children, such as teachers and caregivers. (In contrast to HIV infection is associated with several musculoskeletal adults, children frequently experience parvovirus B19 infec- disorders, including painful articular syndrome, HIV- tion as a fever accompanied by a facial rash [slapped cheek associated arthritis, reactive arthritis, infectious arthritis, appearancel, so-called fi flth disease.) Acute parvovirus B19 infection is diagnosed by detecting and diffuse infiltrative lymphocytosis syndrome. Painful articular syndrome consists of bone and joint pain, espe- anti-parvovirus IgM antibodies in the serum. Anti parvovirus cially in the lower extremities in an asymmetric pattern, IgG antibodies are highly prevalent in the general population lasting less than 24 hours. HIV associated arthritis is a non- and indicate prior infection. Joint symptoms may persist for destructive arthritis that involves joints of the lower extrem- weeks to months, and treatment is symptomatic (including NSAIDs). ity in an oligoarticular pattern and usually lasts less than 6 weeks. Reactive arthritis is the primary form of spondy loarthritis seen in patients with HIV infection and is more Rubella likely due to a response to other sexually transmitted or Arthritis is uncommon in childhood rubella infection, but up enteric infections than to the HIV infection itself. Reactive to 60% of adults with rubella develop joint symptoms, mainly arthritis in HIV may take a chronic relapsing course and may arthralgia, with the onset of rash. Joint involvement is usually be accompanied by enthesopathy and mucocutaneous man- symmetric and migratory and most symptoms resolve within ifestations. Psoriatic arthritis may be more common and is 2 weeks. The small joints of the hands, wrists, elbows, ankles, often more severe in patients with HIV infection, with disa- and knees are most commonly affected. The pathogenesis of bling enthesitis and joint erosion as well as axial involve- rubella arthritis is thought to be due to immune complexes ment (including sacroiliitis). Diffuse infiltrative lymphocy and/or persistence of the virus in synovial cells or joint mac- tosis syndrome is a rare condition that resembles Sjogren rophages. Diagnosis is usually made by detection of IgM syndrome, but with CDB rather than CD4 cell infiltration of antirubella antibodies; the virus may also be cultured from the exocrine glands. the nasopharynx or joint tissues. Joint fluid findings are inflammatory.

often more severe in patients with HIV infection, with disa- and knees are most commonly affected. The pathogenesis of bling enthesitis and joint erosion as well as axial involve- rubella arthritis is thought to be due to immune complexes ment (including sacroiliitis). Diffuse infiltrative lymphocy and/or persistence of the virus in synovial cells or joint mac- tosis syndrome is a rare condition that resembles Sjogren rophages. Diagnosis is usually made by detection of IgM syndrome, but with CDB rather than CD4 cell infiltration of antirubella antibodies; the virus may also be cultured from the exocrine glands. the nasopharynx or joint tissues. Joint fluid findings are inflammatory. Hepatitis Viruses Hepatitis B virus (HBV) infection causes a self-limited arthri Mosquito-Borne Viruses tis in up to 25% of infected patients during a prodromal stage Zika, dengue, and chikungunya viruses are transmitted by before the onset ofjaundice. Joint involvement can be sudden Aedes mosquitos in tropical areas. Zika also can be vertically and severe, with a pattern that is usually symmetric but can and sexually transmitted, and localized transmission in the be migratory or additive. Hand and knee joints are most often southern United States has been reported. Zika infection is affected; wrists, ankles, elbows, shoulders, and other large symptomatic in 2O"1, of infected individuals and causes joints may be involved as well. Morning stiffness is common. arthralgia along with fever, rash, and conjunctivitis. Fusiform swelling of the small joints of the hand may be Symptoms tend to be mild and last a week or less. Dengue found on physical examination. Patients with chronic HBV fever causes arthralgia, fever, and rash but may be associated infection may have recurrent but self limited polyarthralgia with severe muscle and bone pain, headache, and hemor- or polyarthritis; it is not known to progress or cause joint rhagic complications. In chikungunya infection, arthritis is a damage. predominant feature; patients may experience synovial Acute hepatitis C virus (HCV) infection can cause acute thickening and tenosynovitis, often involving the hands and onset polyarthritis, including the small hand joints, wrists, feet, in addition to fever and rash. The musculoskeletal symp shoulders, knees, and hips. One third of patients have toms of Zika and dengue infections tend to subside within

Hepatitis Viruses Hepatitis B virus (HBV) infection causes a self-limited arthri Mosquito-Borne Viruses tis in up to 25% of infected patients during a prodromal stage Zika, dengue, and chikungunya viruses are transmitted by before the onset ofjaundice. Joint involvement can be sudden Aedes mosquitos in tropical areas. Zika also can be vertically and severe, with a pattern that is usually symmetric but can and sexually transmitted, and localized transmission in the be migratory or additive. Hand and knee joints are most often southern United States has been reported. Zika infection is affected; wrists, ankles, elbows, shoulders, and other large symptomatic in 2O"1, of infected individuals and causes joints may be involved as well. Morning stiffness is common. arthralgia along with fever, rash, and conjunctivitis. Fusiform swelling of the small joints of the hand may be Symptoms tend to be mild and last a week or less. Dengue found on physical examination. Patients with chronic HBV fever causes arthralgia, fever, and rash but may be associated infection may have recurrent but self limited polyarthralgia with severe muscle and bone pain, headache, and hemor- or polyarthritis; it is not known to progress or cause joint rhagic complications. In chikungunya infection, arthritis is a damage. predominant feature; patients may experience synovial Acute hepatitis C virus (HCV) infection can cause acute thickening and tenosynovitis, often involving the hands and onset polyarthritis, including the small hand joints, wrists, feet, in addition to fever and rash. The musculoskeletal symp shoulders, knees, and hips. One third of patients have toms of Zika and dengue infections tend to subside within 75

lnfectious Arthritis days to weeks, whereas those ofchikungunya infection usu ally last longer, resembling rheumatoid arthritis (without Management rheumatoid factor or anti-cyclic citrullinated peptide anti ln patients suspected of having infectious arthritis, blood and bodies) in some cases. Diagnosis of these mosquito-borne synovial cultures (and any other cultures appropriate to the diseases is based on clinical features and serologic testing. clinical scenario) must be obtained before treatment. but Polymerase chain reaction testing on blood samples is also empiric antibiotic therapy should be started pending culture available. results (Table 37). In suspected bacterial arthritis, the initial antimicrobial coverage should be broad and account for host factors, such as immunosuppression, as well as likely causa Prosthetic Joint lnfections tive microorganisms and regional antibiotic sensitivity data. Bacterial infection complicates I"l, to 3"/,, of total knee and hip Antibiotics should initially be given parenterally. Given the replacements; rot€S are higher in immunocompromised high prevalence of methicillin-resistant S. oureus, vancomycin patients and those with rheumatoid arthritis. lnfection with is often included initially. The duration of treatment depends gram positive organisms, such as S. oureus, is most common. on the causative organism and patient response and comor Prosthetic joint infections are divided into early onset bidities, but bacterial arthritis usually requires 3 to 6 weeks of (<3 months after placement), delayed (: to z+ months after treatment. surgery), and late onset (>24 months after placement). These An infected joint must also be adequately drained. Needle definitions are controversial, with some sources defining aspiration is an acceptable approach and should be performed delayed infection as occurring 3 to 12 months after surgery. regularly (usually daily) as long as there is an effusion. Early and delayed infections are usually related to surgical Ultrasound guidance may improve the ability to fully drain the contamination at the time of the implantation, whereas late joint. Surgical drainage is an equally good alternative and is infections result from hematogenous seeding of the joint. more immediately definitive. Additionally, surgical drainage is Early and late prosthetic joint infections typically present with required for joints that are not easily accessible for needle pain, warmth, effusion, and fever. Peripheral leukocyte count aspiration (e.g., sternoclavicular, sternomanubrial, shoulder, and inflammatory markers are usually elevated. Delayed and hip joints), if there is evidence of soft-tissue extension of infections, however, may be more dif'ficult to recognize infection, or if the clinical response to antimicrobial therapy is because symptoms are less severe, and they are often caused inadequate. The goal of surgery is to remove all purulent mate by less virulent microorganisms, such as coagulase negative rial and nonviable tissue and, in some cases, to perform syno- staphylococci and other skin organisms. vial biopsy or synovectomy. rEY POI]IIS Antibiotic treatment is recommended fbr all patients o Approximately 75'/" of cases of nongonococcal infectious with Lyme arthritis. Approximately 90"/,, of patients will respond to a28 day course of oral doxycycline, amoxicillin, or arthritis in adults are caused by gram positive cocci, cefuroxime axetil. Patients with incomplete responses may wlth Staphylococcus qureus the most frequent micro need treatment with a second course or a more aggressive organism in both native and prosthetic joints. drug regimen, usually intravenous ceftriaxone. Treatment o Disseminated gonococcal infection may present as the beyond 1 month of ceftriaxone offers no benefit and should arthritis dermatitis syndrome (tenosynovitis, dermati not be used. Antibiotic refractory Lyme arthritis occurs in 107, tis, and polyarthralgia) or as purulent arthritis that pre- ofpatients or less, probably represents a progression to sterile sents with mono- or oligoarthritis but usually without autoimmune arthritis, and responds to synovectomy or treat skin lesions or fever. ment with disease modifying antirheumatic drugs (such as . Lyme arthritis is a late-stage manifestation of the dis- hydroxychloroquine or methotrexate). ease and is typically monoarticular (most commonly in Mycobacterial joint infections require at least 6 to the knee) and inflammatory; diagnosis should be sus- 9 months of multidrug therapy. Treatment of arthritis associ pected in patients who may have had untreated or ated with viral infections is largely supportive, although spe incompletely treated Lyme disease. cific viral therapy is appropriate for HIV and HCV infections; . MAcobacterium tuberculosis arthritis typically presents immunosuppressive therapy with glucocorticoids and rituxi as chronic pain in a single weight-bearing joint, such as mab may be needed in refractory HCV related disease or severe the knee; concurrent pulmonary tuberculosis is present mixed cryoglobulinemia. in only a minority of patients. Treatment of prosthetic joint infections is challenging and requires early surgical consultation. Orthopedic implants . Early and late prosthetic joint infections usually present serve as a nidus for microorganisms, and the avascularity of with pain, warmth, effusion of the joint, and fever; the infected hardware limits antibiotic penetrance. Many delayed infections may be more difficult to recognize patients require removal ofthe orthopedic device as part ofa because they are often caused by less virulent micro- two-stage procedure, with reimplantation of a new device organisms, and symptoms may be less severe. after an appropriate course of intravenous antibiotics.

days to weeks, whereas those ofchikungunya infection usu ally last longer, resembling rheumatoid arthritis (without Management rheumatoid factor or anti-cyclic citrullinated peptide anti ln patients suspected of having infectious arthritis, blood and bodies) in some cases. Diagnosis of these mosquito-borne synovial cultures (and any other cultures appropriate to the diseases is based on clinical features and serologic testing. clinical scenario) must be obtained before treatment. but Polymerase chain reaction testing on blood samples is also empiric antibiotic therapy should be started pending culture available. results (Table 37). In suspected bacterial arthritis, the initial antimicrobial coverage should be broad and account for host factors, such as immunosuppression, as well as likely causa Prosthetic Joint lnfections tive microorganisms and regional antibiotic sensitivity data. Bacterial infection complicates I"l, to 3"/,, of total knee and hip Antibiotics should initially be given parenterally. Given the replacements; rot€S are higher in immunocompromised high prevalence of methicillin-resistant S. oureus, vancomycin patients and those with rheumatoid arthritis. lnfection with is often included initially. The duration of treatment depends gram positive organisms, such as S. oureus, is most common. on the causative organism and patient response and comor Prosthetic joint infections are divided into early onset bidities, but bacterial arthritis usually requires 3 to 6 weeks of (<3 months after placement), delayed (: to z+ months after treatment. surgery), and late onset (>24 months after placement). These An infected joint must also be adequately drained. Needle definitions are controversial, with some sources defining aspiration is an acceptable approach and should be performed delayed infection as occurring 3 to 12 months after surgery. regularly (usually daily) as long as there is an effusion. Early and delayed infections are usually related to surgical Ultrasound guidance may improve the ability to fully drain the contamination at the time of the implantation, whereas late joint. Surgical drainage is an equally good alternative and is infections result from hematogenous seeding of the joint. more immediately definitive. Additionally, surgical drainage is Early and late prosthetic joint infections typically present with required for joints that are not easily accessible for needle pain, warmth, effusion, and fever. Peripheral leukocyte count aspiration (e.g., sternoclavicular, sternomanubrial, shoulder, and inflammatory markers are usually elevated. Delayed and hip joints), if there is evidence of soft-tissue extension of infections, however, may be more dif'ficult to recognize infection, or if the clinical response to antimicrobial therapy is because symptoms are less severe, and they are often caused inadequate. The goal of surgery is to remove all purulent mate by less virulent microorganisms, such as coagulase negative rial and nonviable tissue and, in some cases, to perform syno- staphylococci and other skin organisms. vial biopsy or synovectomy. rEY POI]IIS Antibiotic treatment is recommended fbr all patients o Approximately 75'/" of cases of nongonococcal infectious with Lyme arthritis. Approximately 90"/,, of patients will respond to a28 day course of oral doxycycline, amoxicillin, or arthritis in adults are caused by gram positive cocci, cefuroxime axetil. Patients with incomplete responses may wlth Staphylococcus qureus the most frequent micro need treatment with a second course or a more aggressive organism in both native and prosthetic joints. drug regimen, usually intravenous ceftriaxone. Treatment o Disseminated gonococcal infection may present as the beyond 1 month of ceftriaxone offers no benefit and should arthritis dermatitis syndrome (tenosynovitis, dermati not be used. Antibiotic refractory Lyme arthritis occurs in 107, tis, and polyarthralgia) or as purulent arthritis that pre- ofpatients or less, probably represents a progression to sterile sents with mono- or oligoarthritis but usually without autoimmune arthritis, and responds to synovectomy or treat skin lesions or fever. ment with disease modifying antirheumatic drugs (such as . Lyme arthritis is a late-stage manifestation of the dis- hydroxychloroquine or methotrexate). ease and is typically monoarticular (most commonly in Mycobacterial joint infections require at least 6 to the knee) and inflammatory; diagnosis should be sus- 9 months of multidrug therapy. Treatment of arthritis associ pected in patients who may have had untreated or ated with viral infections is largely supportive, although spe incompletely treated Lyme disease. cific viral therapy is appropriate for HIV and HCV infections; . MAcobacterium tuberculosis arthritis typically presents immunosuppressive therapy with glucocorticoids and rituxi as chronic pain in a single weight-bearing joint, such as mab may be needed in refractory HCV related disease or severe the knee; concurrent pulmonary tuberculosis is present mixed cryoglobulinemia. in only a minority of patients. Treatment of prosthetic joint infections is challenging and requires early surgical consultation. Orthopedic implants . Early and late prosthetic joint infections usually present serve as a nidus for microorganisms, and the avascularity of with pain, warmth, effusion of the joint, and fever; the infected hardware limits antibiotic penetrance. Many delayed infections may be more difficult to recognize patients require removal ofthe orthopedic device as part ofa because they are often caused by less virulent micro- two-stage procedure, with reimplantation of a new device organisms, and symptoms may be less severe. after an appropriate course of intravenous antibiotics. 77