Acute Monoarticular Arthritis—Gout Case File
Eugene C. Toy, MD, Gabriel M. Aisenberg, MD
Case 33
A 48-year-old man comes to your office complaining of severe right knee pain for 8 hours. He states that the pain started abruptly at 2 am and woke him from his sleep. The pain is so severe that even the weight of the bed sheets on his knee was unbearable. By the morning, the knee had become warm, swollen, and tender. He prefers to keep his knee bent since straightening the knee causes the pain to worsen. He has never had pain, surgery, or injury to his knees. A year ago, he did have some pain and swelling at the base of his great toe on the left foot, which was not as severe as this episode, and the previous pain resolved in 2 or 3 days after taking ibuprofen. His only medical history is hypertension, which is controlled with hydrochlorothiazide. He is a nonsmoker and reports moderate social alcohol use.
On examination, his temperature is 99.4 °F, heart rate is 104 beats per minute (bpm), blood pressure (BP) is 136/78 mm Hg, weight is 212 lb, and height is 5’11”. His head and neck examinations are unremarkable, his chest is clear to auscultation, and his heart is tachycardic but regular, with no gallops or murmurs. His right knee is swollen, with a moderate effusion, and appears erythematous, warm, and very tender to palpation. He is unable to fully extend the knee because of pain. He has no other joint swelling, pain, or deformity and no skin rashes.
▶ What is the most likely diagnosis?
▶ What is your next step?
▶ What is the best initial treatment?
▶ What are the most important risk factors for this condition?
▶ What is the most effective way to prevent this condition?
ANSWERS TO CASE 33:
Acute Monoarticular Arthritis—Gout
Summary: A 48-year-old man presents with
- Acute onset of severe right knee pain
- Swollen, erythematous right knee with effusion and limited range of motion that is tender to palpation
- No previous surgery or injury to his knees
- Previous episode of pain and swelling at the base of his great toe that resolved with ibuprofen
- History of hypertension, for which he takes hydrochlorothiazide
Most likely diagnosis: Acute monoarticular arthritis, likely crystalline or infectious. Most likely to be gout due to history of pain in the great toe and hydrochlorothiazide use.
Next step: Aspiration of the knee joint to send fluid for cell count, culture, and crystal analysis.
Best initial treatment: If the joint fluid analysis is consistent with infection, he needs drainage of the infected fluid by aspiration and administration of antibiotics. If analysis is suggestive of crystal-induced arthritis, he can be treated with colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), or corticosteroids.
Most important risk factors: Hyperuricemia (obesity, idiopathic, renal failure, thiazide diuretics, tumor lysis syndrome).
Most effective prevention: Diet modification, allopurinol, febuxostat.
ANALYSIS
Objectives
- Differentiate synovial fluid features to determine the etiology of arthritis. (EPA 3)
- Describe the stages of gout and the appropriate treatment for each stage. (EPA 1, 4)
- Describe the similarities and differences between different types of crystalline arthritis. (EPA 2)
Considerations
A middle-aged man presents with an acute attack of monoarticular arthritis, as evidenced by knee effusion, limited range of motion, and signs of inflammation (low-grade fever, erythema, warmth, tenderness). The two most likely causes are infection (eg, Staphylococcus aureus) and crystalline arthritis. If the patient is at risk, gonococcal arthritis is also a possibility. The previous less severe episode involving his first metatarsophalangeal (MTP) joint sounds like podagra, the most common presentation of gout. The rapid onset of severe symptoms during the current attack is consistent with acute gouty arthritis. In this patient, the attack could have been precipitated by the use of alcohol, which increases uric acid production, and his use of thiazide diuretics, which decrease renal excretion of uric acid.
Although the first attack was typical of gout, which makes this episode very likely to also be acute gouty arthritis, the current presentation could also be consistent with bacterial infection. Untreated septic arthritis could lead to rapid destruction of the joint, so joint aspiration and empiric antibiotic therapy are appropriate until his cultures and crystal analysis are available.
APPROACH TO:
Monoarticular Arthritis
DEFINITIONS
ACUTE CALCIUM PYROPHOSPHATE (CPP) CRYSTAL ARTHRITIS: Arthritis caused by deposition of calcium pyrophosphate dihydrate (CPPD) crystals. Previously known as “pseudogout.”
GOUT: A disturbance of uric acid metabolism occurring mainly in men, characterized by hyperuricemia and the deposition of monosodium urate crystals in the joints and connective tissue.
MONOARTHRITIS: Inflammation of a single joint.
CLINICAL APPROACH
Pathophysiology
Almost any joint disorder may begin as monoarthritis; however, the primary concern is always infectious arthritis because it may lead to joint destruction and resultant severe morbidity. For that reason, acute monoarthritis should be considered a medical emergency and investigated and treated aggressively
Accurate diagnosis starts with a good history and physical examination supplemented by additional diagnostic testing, such as synovial fluid analysis, radiography, and occasionally synovial biopsy. Patients with crystal-induced arthritis may give a history of recurrent, self-limited episodes. Precipitation of an attack by surgery or some other stress can occur with both crystalline disorders, but gout is far more common than acute CPP crystal arthritis. The clinical course can provide some clues to the etiology: Septic arthritis usually worsens unless treated; osteoarthritis worsens with physical activity. Gout classically progresses through four stages (Table 33–1). Interestingly, the presence of completely asymptomatic periods (intercritical gout) between monoarthritic attacks is so uncommon, except in crystalline arthritis, that it is often used as a diagnostic criterion for gout.
Clinical Presentation
History and Physical Examination. Affected patients complain of the spontaneous onset of severe pain, edema, and redness of the joint. There is often a family history. Triggers can include dietary consumption of high purine foods, dehydration, or medications that increase uric acid levels.
Gout most commonly involves the first MTP joint (podagra), ankle, midfoot, or knee. Acute CPP crystal arthritis most commonly affects the large joints, such as the knee; it may also affect the wrist or the first MTP joint. In gonococcal arthritis, there are often migratory arthralgias and tenosynovitis, often involving the wrist and hands, associated with pustular skin lesions. These may progress to purulent monoarthritis or oligoarthritis. Nongonococcal causes of septic arthritis often involve large weight-bearing joints, such as the knee and hip. The most common bacterial pathogen comes from skin flora, such as S. aureus.
The basic approach in physical examination is to differentiate arthritis from inflammatory conditions adjacent to the joint, such as cellulitis or bursitis. True arthritis is characterized by swelling and redness around the joint and painful limitation of motion in all planes during active and passive motion. Joint movement that is not limited by passive motion suggests a soft tissue disorder such as bursitis rather than arthritis.
Laboratory Tests/Imaging. Synovial fluid analysis helps to differentiate between inflammatory and noninflammatory causes of arthritis. Diagnostic arthrocentesis is usually necessary when evaluating an acute monoarthritis and is essential when infection is suspected. Fluid analysis typically includes gross examination, cell count and differential, Gram stain and culture, and crystal analysis. Figure 33–1 shows the typical results that can help one distinguish between noninflammatory conditions such as osteoarthritis, inflammatory arthritis such as crystalline disease, and septic arthritis, which is most often a bacterial infection.
Normal joints contain a small amount of fluid that is essentially acellular. Noninflammatory effusions should have a white blood cell (WBC) count less than 1000 to 2000/mm3 with less than 25% to 50% polymorphonuclear (PMN) cells. If the fluid is inflammatory, the joint should be considered infected until proven otherwise, especially if the patient is febrile.
Crystal analysis requires the use of a polarizing light microscope. Monosodium urate crystals, the cause of gout, are needle shaped, typically intracellular within a PMN cell, and are negatively birefringent, appearing yellow under the polarizing microscope as seen in Figure 33–2. CPPD crystals, the cause of acute CPP crystalline arthritis, are short and rhomboid and are weakly positively birefringent, appearing blue under polarized light. Even if crystals are seen, infection must be excluded when the synovial fluid is inflammatory. Crystals and infection may coexist in the same joint, and chronic arthritis or previous joint damage, such as occurs in gout, may predispose that joint to hematogenous infection.
In septic arthritis, Gram stain and culture of the synovial fluid is positive in 60% to 80% of cases. False-negative results may be related to prior antibiotic use or fastidious microorganisms. For example, in gonococcal arthritis, joint fluid cultures typically are negative, whereas cultures of blood or the pustular skin lesions may be positive. Sometimes the diagnosis rests on demonstration of gonococcal infection in another site, such as urethritis, with the typical arthritis-dermatitis syndrome. Synovial biopsy may be required when the cause of monoarthritis remains unclear, and it is usually necessary to diagnose arthritis caused by tuberculosis or hemochromatosis.
Plain radiographs usually are unremarkable in cases of inflammatory arthritis; the typical finding is soft tissue swelling. Chondrocalcinosis or linear calcium deposition in joint cartilage as seen in Figure 33–3 suggests acute CPP arthritis.
Treatment
Generally, patients require initiation of treatment before all test results are available. When septic arthritis is suspected, the clinician should culture the joint fluid and start antibiotic therapy; the antibiotic choice should be initially based on the Gram stain and, when available, the culture results. If the Gram stain is negative, the clinical picture should dictate antimicrobial selection. For example, if the patient has the typical presentation of gonococcal arthritis, intravenous ceftriaxone is the usual initial therapy, usually with rapid improvement in symptoms. Nongonococcal septic arthritis usually is caused by gram-positive organisms, most often S. aureus, so treatment would involve an antistaphylococcal antibiotic such as vancomycin, daptomycin, or linezolid. If cultures demonstrate organisms that are sensitive to beta-lactams, antibiotic therapy can be guided by the culture and susceptibility results. It is essential to drain the purulent joint fluid, usually by repeated percutaneous aspiration. Open surgical drainage or arthroscopy is required when joint fluid is loculated or when shoulders, hips, or sacroiliac joints are involved.
Figure 33–2. Synovial fluid microscopy showing negatively birefringent crystals. Reproduced with permission, from Strasinger SK, Di Lorenzo MS. Urinalysis and Body Fluids. 5th ed. 2008. Copyright © F.A. Davis Company. All rights reserved.
Figure 33–3. X-ray of knee showing chondrocalcinosis. Arrows point to the calcification of the menisci with calcium pyrophosphate dehydrate crystal deposition. Reproduced with permission, from McKean SC, Ross JJ, Dressler DD, et al., eds. Principles and Practice of Hospital Medicine, 2nd ed. 2017. Copyright © McGraw Hill LLC. All rights reserved.
In general, asymptomatic hyperuricemia requires no specific treatment. Lowering the urate level does not necessarily prevent the development of gout, and most of these patients will never develop any symptoms.
In patients with symptomatic hyperuricemia (patients who have uric acid kidney stones, more than two acute gout attacks per year, or tophi), recommended treatment is with urate-lowering therapy, which is discussed in the material that follows. Acute gouty arthritis is treated with therapies to reduce the inflammatory reaction to the presence of the crystals, all of which are most effective if started early in the attack. Potent NSAIDs, such as indomethacin, are the mainstay of therapy during an acute attack. Alternatively, oral colchicine can be taken three times daily until the joint symptoms abate, but dosing is limited by gastrointestinal side effects such as nausea and diarrhea. For individuals affected by acute joint pain with renal insufficiency (for which an NSAID or colchicine is relatively contraindicated), intra-articular glucocorticoid injection or oral steroid therapy is usually beneficial. Steroids should be used only if infection has been excluded. Treatment to lower uric acid levels is inappropriate during an acute episode because any sudden increase or decrease in urate levels may precipitate further attacks.
Patients with tophaceous gout are managed as previously described during acute attacks and subsequently treated with allopurinol to help tophaceous deposits resolve. A new agent, pegloticase, is an intravenous medication that is a recombinant form of urate-oxidase enzyme that will rapidly dissolve tophi in patients with treatment-resistant tophaceous gout. Surgery may be indicated if the mass effect of tophi causes nerve compression, joint deformity, or chronic skin ulceration with resultant infection.
Prognosis and Prevention. During intercritical gout, the focus shifts to preventing further attacks by lowering uric acid levels to less than 6 mg/dL. Dietary restriction is mainly aimed at avoiding organ-rich foods, such as liver, and alcohol. Patients taking thiazide diuretics should be switched to another antihypertensive if possible. Urate lowering can be accomplished by therapy to increase uric acid excretion by the kidney, such as with probenecid. Uricosuric agents such as probenecid are ineffective in patients with renal failure, however, and are contraindicated in patients with a history of uric acid kidney stones. In these patients, allopurinol can be used to diminish uric acid production, but it must be given at a lower dose in patients with renal disease. Febuxostat is a new xanthine oxidase inhibitor that does not require dose adjustment in renal insufficiency.
Patients with acute CPP arthritis are treated similarly for acute attacks (NSAIDs, colchicine, and systemic or intra-articular steroids). Prophylaxis with colchicine may be helpful in patients with chronic recurrent attacks, but there is no effective therapy for preventing CPPD crystal formation or deposition.
CASE CORRELATION
- See also Case 31 (Osteoarthritis/Degenerative Joint Disease), Case 32 (Low Back Pain), and Case 34 (Rheumatoid Arthritis).
COMPREHENSION QUESTIONS
33.1 A previously healthy 18-year-old college freshman presents to the student health clinic complaining of pain on the dorsum of her left wrist and in her right ankle, fever, and a pustular rash on the extensor surfaces of both her forearms. She has mild swelling and erythema of her ankle and pain on passive flexion of her wrist. Less than 1 mL of joint fluid is aspirated from her ankle and shows 8000 PMN cells per high-power field (hpf) but no organisms on Gram stain. Which of the following is the best initial treatment?
A. Indomethacin orally
B. Intravenous nafcillin
C. Colchicine orally
D. Intra-articular prednisone
E. Intravenous ceftriaxone
33.2 Which of the following laboratory tests is most likely to confirm the diagnosis for the case in Question 33.1?
A. Crystal analysis of the joint fluid
B. Culture of joint fluid
C. Blood culture
D. Cervical samples for DNA amplification tests
33.3 A 30-year-old man is seen in the emergency department for complaints of severe right knee pain of 1 day ‘s duration that has worsened throughout the day. He denies trauma, prior joint pain, skin rash, or penile discharge. On examination, his BP is 140/80 mm Hg, heart rate is 100 bpm, and temperature is 98 °F. He has no skin rashes. The right knee is swollen, red, and very painful to the touch and to move. Joint aspirate reveals 55,000 leukocytes/mm3 with a predominance of PMN leukocytes, but no organisms on Gram stain. Analysis shows few negatively birefringent crystals. Which of the following is the best initial treatment for this patient?
A. Oral corticosteroids
B. Intra-articular corticosteroids
C. Intravenous antibiotic therapy
D. Oral colchicine
ANSWERS
33.1 E. The patient described best fits the picture of disseminated gonococcal infection. She has the corresponding pustular rash, which typically is located on extensor surfaces of distal extremities. Pain on passive flexion of her wrist indicates likely tenosynovitis of that area. The fluid is inflammatory (high number of leukocytes), but gonococci are typically not seen on Gram stain; if they are seen, they are gram-negative intracellular diplococci. Intravenous ceftriaxone is the usual treatment of choice for gonococcal infection and because of the possibility of resistance, oral zithromycin is added. Treatment is usually at least for 1 week. Gonococcal arthritis is the most common cause of infectious arthritis in patients younger than 40 years. Nafcillin (answer B) would be useful for staphylococcal arthritis and would be the more likely choice if she were older, had some chronic joint disease such as rheumatoid arthritis, or were immunocompromised. Indomethacin (answer A) or colchicine (answer C) would be useful if she had a crystalline arthritis, but that is unlikely in this clinical picture. Intra-articular prednisone (answer D) is contraindicated until infectious arthritis is ruled out.
33.2 D. Synovial fluid analysis and cultures (answers A and B) usually are sterile in gonococcal arthritis (in fact, the arthritis is more likely caused by immune complex deposition than by actual joint infection), and blood cultures (answer C) are positive less than 50% of the time. Diagnosis is more often made by finding gonococcal infection through nucleic acid amplification tests in a more typical site, such as the urethra, cervix, or pharynx.
33.3 C. This patient presents with an acute inflammatory arthritis, which should be treated as possible a septic arthritis until final cultures return. The inflammatory arthritis as shown by markedly elevated leukocyte count in the synovial fluid. The Gram stain of the joint aspirate is suspicious for infection, even with no organisms seen on Gram stain. In other words, the sensitivity of Gram stain for a septic arthritis is low; however, the positive predictive value if organisms are present is high. Although the presence of crystals may suggest a crystalline arthritis, it does not eliminate the possibility of a concurrent infection. Typically, crystalline arthritis is associated with a synovial white cell count in the range of 5000 to 40,000/mm3, and the typical cell count for infectious arthritis is > 50,000 cells/mm3. These are general tendencies and not hard and fast rules. Importantly, if intravenous antibiotics are not administered in the setting of a septic joint, then the patient may lose function of the joint or even die. Thus, antibiotics should be administered to this patient until infection is ruled out. Corticosteroids—either oral (answer A) or intra-articular (answer B)—should not be used until infection is ruled out. Answer D (colchicine) can be given for pseudogout but is not as important as antibiotics. NSAIDs, rest, ice, and pain control should be instituted in addition to intravenous antibiotics. Synovial cultures should return in 48 hours.
CLINICAL PEARLS
▶ In the absence of trauma, acute monoarthritis is most likely to be caused by septic or crystalline arthritis.
▶ In a febrile patient with a joint effusion, diagnostic arthrocentesis is mandatory. Inflammatory fluid (WBC count more than 2000/mm3) should be considered infected until proven otherwise.
▶ Gonococcal arthritis usually presents as a migratory tenosynovitis, often involving the wrists and hands, with few vesiculopustular skin lesions.
▶ Nongonococcal septic arthritis is most often caused by S. aureus and most often affects large weight-bearing joints.
▶ Monosodium urate crystals in gout are needle shaped and negatively birefringent (yellow) under the polarizing microscope. CPPD crystals in pseudogout are rhomboid and positively birefringent (blue).
▶ Treatment of gout depends on the stage: NSAIDs (specifically indomethacin), colchicine, or steroids for an acute gouty arthritis, and urate-lowering therapy with probenecid, allopurinol, or febuxostat during the intercritical period.
REFERENCES
Campion EW, Glynn RJ, DeLabray LO. Asymptomatic hyperuricemia: risk and consequences in the Normative Aging Study. Am J Med. 1987;82:421-426.
Madoff LC. Infectious arthritis. In: Kasper DL, Fauci AS, Hauser SL, et al, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw Hill; 2015:833-838.
Schumacher HR, Chen LX. Gout and other crystal-associated arthropathies. In: Kasper DL, Fauci AS, Hauser SL, et al, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw Hill; 2015:2233-2237.
Synovial fluid analyses, synovial biopsy, and synovial pathology. Musculoskeletal Key. https:// musculoskeletalkey.com/synovial-fluid-analyses-synovial-biopsy-and-synovial-pathology/.
Terkeltaub RA. Gout. N Engl J Med. 2003;349:1647-1655.
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