Gout and Suspected Joint Infection: Initial Treatment Approach

1. Rheumatology Summer Board Review Session 1 Mashkur Husain

2. Question 1 • A 47-year-old man is evaluated in the emergency department for a 5-day history of acute swelling and pain of the right knee. He has a 15-year history of gout, with multiple attacks annually; he also has diabetes mellitus and chronic kidney disease. Medications are enalapril, glipizide, and allopurinol. • On physical examination, temperature is 38.2 °C (100.8 °F), blood pressure is 146/88 mm Hg, pulse rate is 96/min, and respiration rate is 15/min. BMI is 27. Several nodules are noted on the metacarpophalangeal and proximal interphalangeal joints and within the olecranon bursa. The right knee is swollen, erythematous, warm, tender, and fluctuant.

3. Question 1 Laboratory studies: • Hemoglobin 10.1 g/dL (101 g/L) • Leukocyte count 13,000/µL ([13 × 109/L], 85% neutrophils) • Serum creatinine 2.8 mg/dL (247.5 µmol/L) • Serum uric acid 9.2 mg/dL (0.54 mmol/L) • Radiographs of the knee reveal soft-tissue swelling. • Aspiration drainage of the right knee is performed. Synovial fluid leukocyte count is 110,000/µL ([110 × 109/L], 88% neutrophils). Polarized light microscopy of the fluid demonstrates extracellular and intracellular negatively birefringent crystals. Gram stain is negative for bacteria. Culture results are pending.

4. Answer Choice Which of the following is the most appropriate initial treatment? A Intra-articular methylprednisolone B prednisone C Surgical debridement and drainage D Vancomycin plus piperacillin-tazobactam

5. Answer Choice Which of the following is the most appropriate initial treatment? A Intra-articular methylprednisolone B prednisone C Surgical debridement and drainage D Vancomycin plus piperacillin-tazobactam

6. Explanation • This patient requires empiric therapy with vancomycin plus piperacillin-tazobactam, pending the results of synovial fluid cultures. Based on his history of gout as well as the presence of tophi and intracellular and extracellular negatively birefringent (urate) crystals, the patient is currently having a gout attack. However, an excessively high synovial fluid leukocyte count of the joint (>50,000/µL [50 × 109/L]) requires that the acute joint process be presumed infectious until proved otherwise. In this setting, a negative Gram stain is of insufficient sensitivity to rule out infection. Patients with chronic joint damage such as that seen in gout and other arthritides are at greater risk for joint infection. This patient also has diabetes mellitus and is presumed to be immunocompromised and susceptible not only to gram-positive, but also to gram-negative and anaerobic, organisms. Therefore, empiric combination therapy with vancomycin and piperacillin-tazobactam is an appropriate approach. • Although intra-articular methylprednisolone is an appropriate approach to treat an acute gout attack while minimizing systemic corticosteroid effects, corticosteroids should never be injected into potentially infected joints.

7. Explanation • Prednisone is also an effective treatment for acute gout, particularly if polyarticular; however, use in this patient with diabetes and a potential joint infection would not be justifiable unless and until infection were ruled out. • In this patient, infection is empirically assumed but not proved, and the joint has been adequately drained percutaneously for the time being. Surgical debridement and drainage can be considered for a definitively infected joint, particularly if the percutaneous approach is inadequate to fully drain the entire joint, but is premature at this time.

8. Key Points • Manage infectious arthritis in a patient with concurrent gout. • Bacterial infectious arthritis and gout can occur concomitantly in the same joint and should be suspected when there is a very high (>50,000/µL [50 × 109/L]) synovial fluid leukocyte count.

9. Septic Arthritis Diagnosis Septic arthritis should be considered in any patient who presents with: • sudden onset of monoarthritis • acute worsening of chronic joint disease • previously painless joint prosthesis that is now painful • radiographic loosening or migration of a cemented prosthetic device • The risk for infection is increased in persons with previously damaged joints (e.g., patients with rheumatoid arthritis), in older adults, and in immunosuppressed patients. In patients with underlying rheumatologic disorders, a sudden joint flare that is not accompanied by other features of the preexisting disorder and is unresponsive to usual therapy suggests a diagnosis of infectious arthritis.

10. Septic Arthritis • The hallmark of a septic joint is pain on passive range of motion in the absence of trauma, and an infected joint typically appears swollen and warm with overlying erythema. • Gonococcal arthritis is the most common form of bacterial arthritis in young sexually active persons in the United States. This condition manifests as either a purulent arthritis or a syndrome of disseminated gonococcemia. The arthritis usually involves one or two joints sequentially, most commonly the knees, wrists, ankles, or elbows. Disseminated gonococcemia is characterized by a prodrome of tenosynovitis, polyarthralgia, and cutaneous lesions that progress from papules or macules to pustules and usually are sterile on culture. Fever and rigors are common

11. Septic Arthritis Most patients with purulent gonococcal arthritis do not have systemic features or cutaneous involvement; therefore, gonococcal arthritis should be considered in all sexually active patients. Blood cultures for Neisseria gonorrhoeae are positive in 50% of infected patients. Obtaining culture specimens from the pharynx, genitals, and rectum in addition to synovial fluid cultures increases the diagnostic yield. • Other less common causes of septic arthritis: • Gram-negative infections are more common in older, immunosuppressed, and postoperative patients and those with IV catheters. • Tuberculous arthritis typically is indolent, does not cause systemic features, and is not associated with positive TST; synovial fluid is usually inflammatory with a predominance of polymorphonuclear cells and a negative Gram stain. • Fungal arthritis typically manifests as subacute monoarthritis in patients with a systemic fungal infection.

14. Question 2 • A 36-year-old man is evaluated for a 5-month history of left knee pain and swelling. He is a gardener and frequently scrapes his knees while working in the soil. He has mild but chronic discomfort when walking and at rest. The patient reports no diarrhea or urethral discharge and has been sexually inactive for 2 years. He has a 10-year history of type 2 diabetes mellitus that is managed with insulin. • On physical examination, temperature is 38.0 °C (100.4 °F), blood pressure is 135/77 mm Hg, pulse rate is 78/min, and respiration rate is 12/min. BMI is 20. The left knee is warm and swollen with a palpable effusion. The knee has decreased flexion, and increasing discomfort is noted at the limits of range of motion. • Laboratory studies reveal a leukocyte count of 11,000/µL ([11 × 109/L], 35% lymphocytes) and an erythrocyte sedimentation rate of 48 mm/h.

15. Question 2 • Radiographs of the left knee reveal soft-tissue swelling and diffuse joint-space narrowing, with periarticular osteopenia. Aspiration of the knee is performed. Synovial fluid leukocyte count is 6500/µL ([6.5 × 109/L], 65% lymphocytes). Polarized light microscopy reveals no crystals. Gram stain is negative. • Subsequent bacterial cultures, Lyme disease titers, rheumatoid factor, and anti–cyclic citrullinated peptide antibody titers are negative. Tuberculin skin test results are negative.

16. Answer Choice Which of the following is the most appropriate diagnostic test to perform next? A Alizarin red staining of synovial fluid B Anti–streptolysin O antibody titers C MRI of the knee D Synovial biopsy

17. Answer Choice Which of the following is the most appropriate diagnostic test to perform next? A Alizarin red staining of synovial fluid B Anti–streptolysin O antibody titers C MRI of the knee D Synovial biopsy

18. Explanation • Synovial biopsy is indicated for this patient with probable fungal arthritis. Fungal arthritis is rare, typically occurs in patients who are immunocompromised, and manifests as subacute monoarthritis. This patient has long-standing, indolent, chronic monoarticular arthritis; a history of diabetes mellitus; and recurrent skin breaks with likely soil exposure. In this setting, infection with a fungus, particularly Sporothrix schenckii, is the likely cause. S. schenckii is associated with plant litter and other organic materials. S. schenckii arthritis usually manifests as progressive joint pain, swelling, and loss of range of motion. The diagnosis of fungal arthritis requires a high degree of suspicion and is most commonly made by synovial biopsy and/or culture of joint fluid. Because joint fluid culture may take weeks, obtaining a synovial biopsy is appropriate at this time. • Alizarin red staining of synovial fluid is not done routinely but is theoretically helpful for identifying basic calcium phosphate (BCP) crystals, which are invisible under polarized light microscopy. However, the chronic nature of the patient's condition, along with his relatively young age and an absence of calcification seen on radiographs, makes a diagnosis of BCP arthritis unlikely.

19. Explanation • Obtaining anti–streptolysin O antibody titers aids in the diagnosis of rheumatic fever; however, this patient lacks the systemic signs (such as cardiac and/or neurologic involvement) that warrant consideration of rheumatic fever. • MRI of the knee would help delineate the extent of the joint damage but would not provide insight into the nature of the infectious process. Key Point • Fungal arthritis is rare, typically occurs in patients who are immunocompromised, and manifests as subacute monoarthritis

20. Question 3 • A 52-year-old man is evaluated for a 5-year history of gradually progressive left knee pain. He has 20 minutes of morning stiffness, which returns after prolonged inactivity. He has minimal to no pain at rest. He reports no clicking or locking of the knee. Over the past several months, the pain has limited his ambulation to no more than a few blocks. • On physical examination, vital signs are normal. BMI is 25. The left knee has a small effusion and some fullness at the back of the knee; the knee is not erythematous or warm. Range of motion of the knee elicits crepitus. There is medial joint line tenderness to palpation, bony hypertrophy, and a moderate varus deformity. There is no evidence of joint instability on stress testing. • Radiographs of the knee reveal bone-on-bone joint-space loss and numerous osteophytes

21. Answer Choice Which of the following is the most appropriate next diagnostic step for this patient? A CT of the knee B Joint aspiration C MRI of the knee D No diagnostic testing

22. Answer Choice Which of the following is the most appropriate next diagnostic step for this patient? A CT of the knee B Joint aspiration C MRI of the knee D No diagnostic testing

23. Explanation • No additional diagnostic testing is indicated for this patient who has osteoarthritis, which is a clinical diagnosis. According to the American College of Rheumatology's clinical criteria, knee osteoarthritis can be diagnosed if knee pain is accompanied by at least three of the following features: age greater than 50 years, stiffness lasting less than 30 minutes, crepitus, bony tenderness, bony enlargement, and no palpable warmth. These criteria are 95% sensitive and 69% specific but have not been validated for clinical practice. Additional diagnostic testing is not appropriate, because it has no impact on the management of advanced disease. • CT of the knee is very sensitive for pathologic findings in bone and can be used to look for evidence of an occult fracture, osteomyelitis, or bone erosions. However, none of these are suspected in this patient. • Small- to moderate-sized effusions can occur in patients with osteoarthritis, and the fluid is typically noninflammatory. Joint aspiration in this patient without evidence of joint inflammation and evident osteoarthritis is not useful diagnostically but is often done in the context of intra-articular corticosteroid injection or viscosupplementation.

24. Explanation • MRI is useful to evaluate soft-tissue structures in the knee such as meniscal tears. Patients with meniscal tears may report a clicking or locking of the knee secondary to loose cartilage but often have pain only on walking, particularly going up or down stairs. Patients with degenerative arthritis often have MRI findings that indicate meniscus tears. These tears are part of the degenerative process but do not impact management; arthroscopic knee surgery for patients with osteoarthritis provides no clinical benefit. The one exception may be in patients with meniscal tears that result in a free flap or loose body, producing painful locking of the joint. These symptoms are not present in this patient. Key Point • Osteoarthritis is diagnosed clinically and does not require advanced imaging to establish the diagnosis.

25. Question 4 • A 76-year-old woman is evaluated for a 3-month history of left knee pain of moderate intensity that worsens with ambulation. She reports minimal pain at rest and no nocturnal pain. There are no clicking or locking symptoms. She has tried naproxen and ibuprofen but developed dyspepsia; acetaminophen provides mild to moderate relief. The patient has hypertension, hypercholesterolemia, and chronic stable angina. Medications are lisinopril, metoprolol, simvastatin, low-dose aspirin, and nitroglycerin as needed. • On physical examination, vital signs are normal. BMI is 32. Range of motion of the left knee elicits crepitus. There is a small effusion without redness or warmth and tenderness to palpation along the medial joint line. Testing for meniscal or ligamentous injury is negative.

26. Question 4 • Laboratory studies, including complete blood count and erythrocyte sedimentation rate, are normal. • Radiographs of the knee reveal medial tibiofemoral compartment joint-space narrowing and sclerosis; small medial osteophytes are present.

27. Answer Choice Which of the following is the next best step in management? A Add celecoxib B Add glucosamine sulfate C MRI of the knee D Weight loss and exercise

28. Answer Choice Which of the following is the next best step in management? A Add celecoxib B Add glucosamine sulfate C MRI of the knee D Weight loss and exercise

29. Explanation • Weight loss and exercise are indicated for this patient with knee osteoarthritis. Her knee pain, which is worse with weight bearing, is suggestive of tibiofemoral knee osteoarthritis, a diagnosis supported by the presence of medial joint line tenderness and radiographic findings of medial tibiofemoral compartment joint-space narrowing. The strongest risk factors for osteoarthritis are advancing age, obesity, female gender, joint injury (caused by occupation, repetitive use, or actual trauma), and genetic factors. Obesity, in particular, is the most important modifiable risk factor for knee osteoarthritis. Several trials have demonstrated that weight loss and/or exercise programs can offer relief of pain and improved function comparable to the benefits of NSAID use. In long-term studies, sustained weight loss of approximately 6.8 kg (15 lb) has resulted in symptomatic relief. • Celecoxib carries an increased myocardial risk and is therefore not appropriate for this patient who has coronary artery disease. Although celecoxib has a lower risk of gastrointestinal ulcers than other NSAIDs, it can still cause dyspepsia, which occurred in this patient after taking naproxen and ibuprofen.

30. Explanation • There have been several contradictory studies regarding glucosamine sulfate in the management of osteoarthritis. After several favorable smaller studies, a trial sponsored by the National Institutes of Health showed no effectiveness in reducing pain. A recently conducted meta-analysis also found negative results for the use of glucosamine sulfate. • MRI of the knee would be indicated to evaluate for meniscal or other ligamentous injuries, none of which is suggested by this patient's history (the knee locking or giving way) or examination findings (negative examination for tendinous or ligamentous injury). Key Point • Obesity is the most important modifiable risk factor for knee osteoarthritis, and weight loss and exercise are recommended to reduce pain and improve function

31. Osteoarthritis Diagnosis • Age is the most important risk factor for developing primary OA in women and men. Additional risk factors include genetics, obesity, and trauma-induced mechanical joint instability. OA most often affects the lower cervical and lumbar spine; hips; knees; DIP, PIP, and first carpometacarpal joints. Characteristic findings include: • morning joint stiffness lasting <30 minutes • gelling (brief stiffness after inactivity) • crepitus • tenderness along the joint line • reduced joint motion • bony enlargement (including Heberden and Bouchard nodes) • involvement of the first carpometacarpal joint results in “squaring” at the base of the thumb

32. Osteoarthritis • Two important variants are erosive OA of the hand and DISH. • Erosive inflammatory OA is characterized by pain and palpable swelling of the soft tissue in the PIP and DIP joints. This condition also may be associated with disease flares during which these joints become more swollen and painful. • DISH is an often asymptomatic form of OA that causes significant radiographic changes similar to those associated with degenerative spondylosis or ankylosing spondylitis. X-rays of the spine in patients with DISH reveal flowing ossification that develops along the anterolateral aspect of the vertebral bodies, particularly the anterior longitudinal ligament. However, neither disk-space narrowing nor syndesmophytes are visible in this setting, as they are in lumbar spondylosis or ankylosing spondylitis, respectively.

33. Osteoarthritis • Secondary OA results from previous joint injury or metabolic diseases such as hemochromatosis. Consider metabolic causes when OA develops in atypical joints (e.g., MCP joints, shoulder, wrist). • Be alert for an acutely painful calf mimicking a DVT, which represents a ruptured Baker cyst (herniation of fluid-filled synovium of the posterior knee) or ruptured gastrocnemius muscle. • No pathognomonic laboratory tests are available for OA. An x-ray is not helpful in the diagnosis of symptomatic hand OA (clinical examination is more specific) but is the “gold standard” for hip and knee OA. X-rays show joint-space narrowing, subchondral sclerosis, and osteophytes. Synovial fluid is usually noninflammatory, with a leukocyte count <2000/microliter. Ultrasonography is useful in the diagnosis of Baker cyst.

34. Bony enlargement of the DIP joints and squaring of the first carpometacarpal joint characteristic of osteoarthritis.

35. Don't Be Tricked Typical OA radiographic changes do not exclude other diagnoses. Be alert for: • septic arthritis superimposed on OA • trochanteric and anserine bursitis causing hip and knee pain • de Quervain tenosynovitis mimicking carpometacarpal OA • hemochromatosis, particularly if involving the second and third metacarpophalangeal joints • gout or CPPD deposition disease

36. Therapy Medical therapy includes: • acetaminophen as first-line therapy for hip and knee OA • NSAIDs in patients who do not respond to acetaminophen or as initial therapy for severe pain • tramadol if NSAIDs are contraindicated or ineffective • intra-articular corticosteroids for acute exacerbations of knee OA • intra-articular hyaluronan injection, which has comparable efficacy to NSAID therapy for knee OA • glucosamine sulfate, although data for its use are conflicting • Patients with hip and knee OA benefit from weight loss; patients with knee OA benefit from quadriceps-strengthening exercises. Joint arthroplasty of the hip or knee is indicated for pain that does not respond to nonsurgical treatment, especially when lifestyle or activities of daily living are affected.

37. Don't Be Tricked • Patients with signs of inflammation should not undergo intra-articular corticosteroid therapy until synovial fluid analysis excludes infection. • Do not select arthroscopic lavage, debridement, or closed lavage for knee OA.

38. Medial compartment joint space-narrowing and subchondral sclerosis consistent with osteoarthritis are shown.

39. Question 5 • A 52-year-old man is evaluated for an 8-week history of pain and 2 hours of morning stiffness of the hands that improves with activity. The patient has no pertinent personal or family medical history. He takes no medications. • On physical examination, vital signs are normal. Synovitis is noted at the metacarpophalangeal joints of the second through fifth digits bilaterally with swelling, tenderness, and pain on range of motion. The remainder of the examination is normal. • Laboratory studies, including complete blood count, chemistries, liver chemistry tests, thyroid-stimulating hormone, C-reactive protein, and urinalysis, are normal; erythrocyte sedimentation rate is 13 mm/h, and rheumatoid factor is negative. Parvovirus serology results are negative. • Radiographs of the hands are normal

40. Answer Choice Which of the following antibody assays is most helpful in establishing this patient's diagnosis? A Anti–cyclic citrullinated peptide antibodies B Antimitochondrial antibodies C Antineutrophil cytoplasmic antibodies D Antinuclear antibodies

41. Answer Choice Which of the following antibody assays is most helpful in establishing this patient's diagnosis? A Anti–cyclic citrullinated peptide antibodies B Antimitochondrial antibodies C Antineutrophil cytoplasmic antibodies D Antinuclear antibodies

42. Explanation • An anti–cyclic citrullinated peptide (CCP) antibody assay is warranted for this patient in whom rheumatoid arthritis is suspected. Anti-CCP antibodies are present in approximately 40% to 60% of patients with early rheumatoid arthritis, including some patients with a negative rheumatoid factor. These antibodies are 95% specific for rheumatoid arthritis. The presence of higher titers of either rheumatoid factor or anti-CCP antibodies or the presence of both increases the likelihood of disease. Although this patient's rheumatoid factor is negative and his acute phase reactants are normal, rheumatoid arthritis remains a significant concern because he has synovitis of eight small joints and morning stiffness lasting more than 1 hour, common symptoms of rheumatoid arthritis. An anti-CCP antibody assay is therefore appropriate to determine whether this patient's symptoms are caused by rheumatoid arthritis. • Antimitochondrial antibodies are present in patients with autoimmune hepatitis. Patients with this disease can develop arthralgia and arthritis similar to this patient; however, he does not have liver chemistry test abnormalities that are characteristic of autoimmune hepatitis.

43. Explanation • Antineutrophil cytoplasmic antibodies are typically associated with vasculitis such as granulomatosis with polyangiitis (also known as Wegener granulomatosis), microscopic polyangiitis, Churg-Strauss syndrome, anti–glomerular basement membrane antibody disease, and drug-induced vasculitis. Arthritis and arthralgia can be associated with these syndromes; however, the presence of these vascular inflammatory disorders would be unusual in the absence of other system involvement. • Antinuclear antibodies (ANA) can be clinically useful when there is clinical suspicion for autoimmune conditions associated with these antibodies such as systemic lupus erythematosus (SLE). SLE may present with arthritis but, in this case, SLE is less likely than rheumatoid arthritis. SLE typically occurs in women of childbearing age, with additional clinical and/or laboratory abnormalities rather than isolated arthritis. ANA are present in some patients with rheumatoid arthritis but are not specific for this disorder. Key Point • Anti–cyclic citrullinated peptide antibodies are a highly specific marker for rheumatoid arthritis.

44. Question 6 • A 36-year-old woman is evaluated for a 5-week history of pain and swelling of the fingers accompanied by morning stiffness lasting more than 1 hour. Her only medication is ibuprofen, which provides minimal relief. • On physical examination, vital signs are normal. Musculoskeletal examination reveals tenderness and swelling of the right second, third, and fourth metacarpophalangeal joints and the left third, fourth, and fifth metacarpophalangeal joints. There is no bony enlargement, ulnar deviation, or other abnormalities. • Radiographs of the hands and wrists are normal.

45. Labs

46. Answer Choice Which of the following is the most appropriate next step in management? A Etanercept B Hydroxychloroquine C Methotrexate D Reevaluate in 6 weeks

47. Answer Choice Which of the following is the most appropriate next step in management? A Etanercept B Hydroxychloroquine C Methotrexate D Reevaluate in 6 weeks

48. Explanation • Methotrexate is indicated for this patient with early rheumatoid arthritis. Experts recommend that patients begin disease-modifying antirheumatic drug (DMARD) therapy within 3 months of onset. The sooner DMARDs are instituted, the more likely that damage will be limited. Methotrexate is the gold standard DMARD therapy for rheumatoid arthritis and is central to most treatments for the disease. This agent can be effective as initial monotherapy for patients with rheumatoid arthritis of any duration or degree of activity. This patient has synovitis of six metacarpophalangeal joints with a symmetric distribution not involving the distal interphalangeal joints, which is consistent with rheumatoid arthritis. She has swelling, prolonged morning stiffness, an elevated erythrocyte sedimentation rate (ESR), and positive rheumatoid factor, which further support the diagnosis of rheumatoid arthritis, and initial treatment with methotrexate is warranted at this time. • Etanercept is a tumor necrosis factor α inhibitor used for initial therapy in some patients with high disease activity and poor prognostic features. This agent may be necessary for this patient if her disease does not respond to methotrexate. • Hydroxychloroquine as monotherapy may be effective only in mild cases early in the disease course for patients without poor prognostic features. This patient has evidence of moderate disease activity, given the extent of her synovitis and elevated ESR; therefore, hydroxychloroquine as a single agent is unlikely to control this degree of inflammation and is more beneficial as an adjunctive agent.

49. Explanation Reevaluation in 6 weeks is not indicated for this patient whose laboratory studies reveal no evidence of acute parvovirus or hepatitis B infection. Such viral infections can cause an acute polyarthritis syndrome that mimics rheumatoid arthritis. The diagnosis of rheumatoid arthritis previously was predicated on symptoms lasting more than 6 weeks to exclude many self-limiting viral syndromes. However, classification criteria no longer require symptoms to occur for 6 weeks to avoid delays in treatment. The likelihood of rheumatoid arthritis is now calculated on the distribution of joints involved, rheumatoid factor, anti–citrullinated peptide antibodies, acute phase reactants, and duration of symptoms. Key Point • Methotrexate is the gold standard disease-modifying antirheumatic drug therapy for rheumatoid arthritis and is central to most treatments for the disease

50. Rheumatoid Arthritis Diagnosis • RA is a symmetric inflammatory polyarthritis that primarily involves the small joints of the hands and feet. Characteristic findings include: • morning stiffness lasting >1 hour • seven classic sites of symmetric joint pain (PIP, MCP, wrist, elbow, knee, ankle, and MTP joints) • synovitis characterized by soft-tissue swelling or effusion • subcutaneous nodules over bony prominences or extensor surfaces