Remember that patient you thought had gout?
Your first patient of the day is a 22-year-old woman who presents with right knee pain for one week. She has no past medical history and says, “The knee just keeps hurting. I don’t know what to do. Even ibuprofen isn’t helping.” Her vital signs are normal, and you quickly order an X-ray, fully expecting it to be normal.
The next patient is a 63-year-old man with a history of diabetes, gout, and hypertension. His temperature is 100.5oC, and he is presenting with right knee pain for two days. He regularly experiences gout attacks, with his last gout episode six months ago. You again order an X-ray.
Joint pain is a common chief complaint in emergency departments and common cause of disability. Arthritis has a multitude of etiologies, ranging from benign to life threatening. Unfortunately, septic arthritis is not always easy to diagnose and may be subtle, lacking the classic signs, symptoms, or laboratory markers [1-3].
The red, hot, swollen joint may have several etiologies and requires emergent evaluation. Emergency physicians are most concerned with septic arthritis, which can cause rapid joint destruction within days, as well as death in 15% of cases [2,3]. Septic arthritis is due to bacterial infection of the joint space. The disease has a bimodal incidence, which peaks in young children and adults over age 55 years [4-7]. The incidence approaches 10 cases per 100,000 patients, but in patients with a prosthetic joint or immunocompromised state, this rate increases to 70 per 100,000 patients per year [8-10].
Septic arthritis most commonly affects one joint, but in 20% of cases, it is polyarticular (especially in immunosuppressed patients) [9-11]. A large joint is most commonly affected. The most common is the knee (50% of cases), followed by the hip, shoulder, and elbow [9-12]. Interestingly, injection drug abusers may have sternoclavicular and sternomanubrial joint involvement . The most common source is hematogenous from bacteremia (70% of cases), as joint linings lack a basement membrane, allowing easy passage of bacteria into synovial fluid. Other causes include direct inoculation from trauma or procedure. Contiguous spread from osteomyelitis, septic bursitis, and abscess is another cause [6,8-10,14].
Risk factors for septic arthritis must be carefully sought. Each of these relates to the cause of the infection, whether hematogenous (IV drug user), direct inoculation (trauma), or contiguous spread. Each risk factor has a modest impact alone on the risk of septic arthritis. As the number of risk factors increase, the risk of septic arthritis increases. Risk factors that cause joint damage lead to greater risk for infection [6-8,12,14].
As with many conditions, the history provides key clues to the diagnosis. Patients often present with a constellation of symptoms including joint pain, tenderness to palpation, swelling, erythema, warmth, and painful/limited range of motion [6,7,14]. The most common is joint pain, endorsed by 85% of patients (leaving 15% not endorsing pain). Joint swelling occurs in 78% of cases. Joint tenderness has sensitivity approaching 100% [6,7,15]. Less common findings include rigors (19%) and sweats (27%) [6,7,15]. Patients will have fever half the time, making fever a poor indicator of septic arthritis [6,7]. Sudden onset of pain is more suggestive of intrinsic joint pathology, such as septic arthritis.
Careful examination of the joint can assist with differentiating intra-articular pathology versus peri-articular pathology, such as bursitis or tendonitis. The classic examination includes a joint with generalized tenderness and painful limitation of both active and passive range of motion [6,7,16]. Focal tenderness and/or pain with specific movements suggests periarticular inflammation. No combination of exam findings can definitively diagnose septic arthritis .
Extra-articular physical examination findings may provide clues to diagnose. The presence of urethritis and pustular rash (usually less than 20 pustules are present) may suggest N. gonorrhea. Joint pain can also be referred from other structures .
Back to our patients…You dive deeper into the history and exam of both patients. The young woman says she has had four sexual partners in the last two weeks and has noticed a change in vaginal discharge with dysuria. Her knee is swollen. You notice a pustular rash, with approximately 18 lesions. The older man has been on steroids for one month. He has never had an episode of gout affecting the knee, as it usually affects his lower bilateral ankles and toes. His knee is erythematous and swollen, and his range of motion is extremely limited. He is in a sexually monogamous relationship with his wife. You question what other tests are needed for these patients.
Imaging tests are often ordered but offer little assistance in the diagnosis of septic arthritis. Radiographs may demonstrate effusion or soft tissue swelling. In later stages of disease, joint inflammation may result in chronic changes and calcium deposits. Computed tomography (CT) has greater sensitivity for effusions and edema but is unreliable early in the disease course to evaluate for septic arthritis. Magnetic resonance imaging (MRI) can be used to evaluate soft tissue, but will also be normal early in disease . However, radiographs can be used in the workup of osteomyelitis. Ultrasound (US) can be used to localize joint swelling and target the site for optimal aspiration. Effusions found on US will often be hypoechoic in septic arthritis [19,20].
One pitfall in the management of septic arthritis is the use of serum tests to exclude the need for joint aspiration. Synovial fluid is key to diagnosis. Serum blood tests do not rule out septic arthritis. If concern for septic arthritis exists, synovial fluid is required.
Having said that, serum tests should be obtained, as your consultants will use them for management. Consultants may need reminding that leukocytosis cannot be relied on to diagnose septic arthritis. Studies report sensitivities between 42% to 90% with a cutoff of 10 x 109/L.6 [21-23], A WBC count above this level has a positive likelihood ratio (LR) of just 1.4. When 14 x109/L is used, sensitivity is 23% [6,7,24,25].
What about using erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)? ESR sensitivity differs based on the level used, with a sensitivity of 66% for 15 mm/hr and greater than 90% for 30 mm/hr [6,25-29]. CRP greater than 10 mg/L has a sensitivity approaching 90% [6,27]. Of course these tests are not very specific, and while an elevated ESR and CRP may suggest the septic arthritis, no threshold value can rule it out. Septic arthritis can present with normal ESR and CRP . No cutoff level provides diagnostic accuracy; however, if CRP and ESR is elevated and no other cause is found, strongly consider aspiration.
Blood cultures possess a sensitivity of 23% to 36%, but these will not return while the patient is in the ED [6,23,25,30]. These should be obtained if concern exists for septic arthritis or for sepsis to assist the inpatient team.
Other tests include uric acid levels, procalcitonin, cytokines, and tumor necrosis factor. Procalcitonin may elevate if the patient has systemic illness with sepsis, rather than just localized infection [6,14,31]. Importantly, these tests do not assist the diagnostic decision and do not have the needed sensitivity or specificity for diagnosis.
Synovial fluid aspiration is needed for definitive diagnosis of septic arthritis. Typically, joint aspiration results are broken down into several types, demonstrated in Table 2. Notice that the majority overlap, creating problems when relying on these test values [6,14,27,29].
Synovial white blood cell count (sWBC) is classically taught to be greater than 100 x 109/L in septic arthritis; however, this does not always occur. It is true that as sWBC rises, the likelihood of septic arthritics increases. At sWBC counts > 50 x 109/L, a likelihood ratio (LR) of 4.7-7.7 is present (95% CI = 2.5 to 85), and for a sWBC count > 100 x 109/L, a LR of 13.2-28.0 is present (95% CI = 3.6 to 51). Counts less than 25 x 109/L demonstrate a negative LR of 0.32 (95% CI 0.23-0.43), while counts less than 50 x 109/L but greater than 25 x 109/L have a LR of 2.9 [6,7]. Synovial polymorphonuclear cells (sPMN) is also commonly quoted to be greater than 90% consistently. However, this test does not significantly alter probability of septic arthritis. Sensitivity ranges from 54% to 70%, with a + LR of 2.7-3.4, while a sPMN below 90% possesses a negative LR of 0.34 [6,7]. Providers must remember that these fluid results may overlap, and several organisms such as MRSA may present with sWBC below 25 x 109/L.
Other tests include synovial Gram stain, glucose, protein, lactate dehydrogenase (LDH), culture, and lactate. Synovial glucose and protein do not increase or decrease the likelihood of septic arthritis and do not require measurement. Synovial Gram stain has sensitivity ranging from 29% to 65% and cannot be used to rule out septic arthritis [6,15,22,23,32-36]. Synovial LDH less than 250 U/L may rule out septic arthritis, but this is based on one study [6,36]. Do not rely on crystals to rule in gout and rule out septic arthritis, as they can coexist [6,14,37]. Synovial culture is considered the gold standard laboratory test. In all cases of aspiration, ensure a culture is obtained [6,7,14].
Synovial lactate has the best diagnostic accuracy in septic arthritis, based on several studies. Levels above 10 mmol/L demonstrate +LRs ranging from 20 to infinity [6,34,38-40]. Of note, studies have differentiated D-lactate, produced by bacteria, and L-lactate, produced by humans. Some laboratories can differentiate these two forms; however, not all laboratories can analyze synovial lactate tests.
Interestingly, the serum WBC is normal for the young woman and slightly elevated for the older man. Your patients both receive joint aspiration, and you send the samples for synovial WBC, Gram stain, culture, and lactate. The tests return with a sWBC of greater than 70 x 109/L and synovial lactate > 10 mmol/L for both. You diagnose septic arthritis and think about what your next steps should include.
Bacteria able to enter the affected joint produce an inflammatory cell response. As no basement membrane is present in the synovial tissue, rapid access is common with acute symptoms and purulence. Several mechanisms exist for joint destruction: 1) Cytokines and proteases released at the site, 2) Increased pressure from effusion formation, and 3) Bacterial DNA and toxin release [14,15,32].
There are many pathogens capable of causing bacterial arthritis; however, the infection is usually monomicrobial. Polymicrobial infections typically occur with penetrating trauma. S. aureus, including the notorious MRSA species, is the most common affecting joints. Of note, septic arthritis due to MRSA can have lower synovial WBC counts, with an average of approximately 15,000 cells/microliter (range of 3,400 to 34,075 cells/microliter) . Always inquire about sexual activity in patients, as N. gonorrhea is the most common agent in adults of reproductive years. This species can present with migratory polyarthritis, pustular rash, urethritis, and tenosynovitis. Table 3 demonstrates likely pathogens based on clinical risks and population [6,8,11,14-16].
The key to management includes early recognition and treatment, with 1) joint aspiration, 2) antibiotics, and 3) orthopedic surgery consultation. Most published treatment recommendations follow Gram stain and culture results. Emergency physicians do not have this data, and empiric coverage is warranted after joint aspiration. If the patient presents with sepsis and concern for septic arthritis, provide broad-spectrum antibiotics first and then obtain synovial fluid [14,42,43].
Antibiotics should provide gram-positive and gram-negative coverage with 1) vancomycin at 20 mg/kg IV and 2) ceftriaxone 2g IV or cefotaxime 2g IV, respectively. If the patient is allergic to vancomycin, then daptomycin, clindamycin, or linezolid can be utilized [14,42,43]. Currently, no role for intraarticular antibiotics or intraarticular steroids exists in the ED.
An important aspect of management includes orthopedic surgery consultation and inpatient admission. Many patients will resolve with antibiotics alone; however, if the condition does not improve with several days of antibiotic therapy, orthopedic intervention may be required. Surgeons may utilize needle aspiration alone, arthroscopic drainage, open surgical drainage, or a combination of techniques for joint clean out. Needle aspiration is often able to decompress the joint, though knee, shoulder, or wrist infections may need arthroscopy for joint visualization and full decompression [42,44].
Almost all emergency providers have evaluated and managed that patient who presents with a high pretest probability of septic arthritis, but the aspiration results are not supportive, or in the patient who has an effusion that appears to not be septic on history and exam, but aspiration results suggest otherwise. Management is not always clear in these circumstances. If pretest probability is high and aspiration results are not clear cut for one etiology, admission is likely needed for antibiotics, orthopedic evaluation, and repeat assessments. For patients with low likelihood based on history and exam, but whose aspiration results are more suggestive of septic arthritis, admission is again likely warranted for antibiotics, orthopedic consultation, and repeat assessment. If the possibility for rapid follow-up is available, this may be an option after discussing the plan with the patient in a shared-decision making model. This will be dependent on your center and practice.
You speak with the orthopedic surgeon on call and start ceftriaxone and vancomycin for both patients, as you suspect gonococcal septic arthritis. The adult male most likely has S. aureus septic arthritis. The orthopedic surgeon states he will see them while they are in the ED. He feels both patients will likely receive appropriate treatment with antibiotics alone. You speak with your hospitalist as well, who states she will admit both patients for IV antibiotics.
It has long been espoused that aspiration should not be conducted through a site of cellulitis. However, one recent review suggests no harm from this, with the only direct definitive contraindications including frank abscess or purulence . Anticoagulation is not a contraindication . Prosthetic joints can be aspirated in association with an orthopedic surgery consultation . If unable to obtain fluid on the initial aspiration, several techniques can be used to augment success. First, use a larger gauge needle and a smaller syringe, which increases the pulling force. Compression of the contralateral side of the joint with gentle rotation of the needle while aspirating may also improve your ability to obtain synovial fluid . For more on optimizing fluid aspiration, please see these videos: Video 1 and Video 2.
Several patient populations can present emergency physicians with challenges. These include patients with gout, HIV, prosthetic joint, and hemophilia.
Special Populations: Gout
The patient with gout can present emergency physicians with a challenge: joints affected by gout often have signs and symptoms similar to septic arthritis, and patients can be predisposed to septic arthritis due to chronic joint damage. Joint fluid should be assessed for the presence of uric acid or calcium pyrophosphate crystals; however, the presence of crystals does not rule out septic arthritis, as the pathologies may coexist in 1.5% of cases [37,49]. Of note, these patients with concurrent disease more commonly display sWBC counts greater than 50 x 109/L.37,49 Despite the majority of patients with concurrent disease displaying elevated sWBC counts, 10% of patients will display sWBC < 6 x 109/L . The patient must be asked about prior incidences of gout and joints affected. If the current presentation is any different than prior gout episodes, septic arthritis should be assumed and synovial fluid obtained [14,37,49].
Special Populations: HIV
The immunocompromised state predisposes HIV patients to a multitude of orthopedic diseases including myopathy, joint disease, bone disorders, and disseminated diseases. Septic arthritis is most commonly caused by MRSA, but tuberculosis and fungal species can also result in infection . Empiric treatment should not be modified, but infectious disease consultation will be needed for these patients.
Special Populations: Prosthetic Joint
Evaluation for septic arthritis in a prosthetic joint requires radiographs, and per a recent review, ESR and CRP . If the physician suspects septic arthritis, the joint should be aspirated. Of note, the optimal thresholds for septic arthritis are sWBC 3 x 109/L and sPMN > 80%. In the first six weeks postoperatively, these thresholds change to sWBC 10 x 109/L and sPMN > 90%. Per this review, a CRP greater than 100 mg/L requires joint aspiration .
Special Populations: Hemophilia
Hemarthrosis is common in hemophilia A and B. It is a hallmark of severe hemophilia and is associated with disability and reduced quality of life in these patients. If a patient with hemophilia presents with joint pain, swelling, and redness, the patient must be asked about prior joint bleeds, prophylactic medications, known factor levels, and if any recent factor was taken. In the majority of circumstances, joint aspiration should be avoided, as it will not assist in diagnosis or management. However, if the patient presents within two days of onset with extreme swelling, pain, and bleeding, joint aspiration can be completed in association with hematology and orthopedic surgery after factor concentrate is provided [51,52]. Most references recommend correcting factor to 100% concentration before aspiration. In cases of rapid intra-articular accumulation of blood, aspiration may improve pain control and rehabilitation, though this is controversial and should only be completed in association with hematology consultation [51,52].
Septic arthritis is a potentially deadly condition, and unfortunately does not always present classically. The red, hot, swollen joint mandates consideration of septic arthritis. No physical examination finding can rule out the condition, and serum blood tests should not be used to decrease your concern. Diagnostic aspiration is required, with the sample sent for synovial WBC, Gram stain, culture, and lactate. Synovial lactate and culture are the best laboratory tests, as some patients can present with normal synovial WBC and Gram stain. Management requires orthopedic surgery consultation and antibiotics.
- Prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation — United States, 2007-2009. MMWR Morb Mortal Wkly Rep. 2010;59(39):1261-1265.
- Cisternas MG, Yelin EH, Foreman AJ, Pasta DJ, Helmick CG. Trends in medical care expenditures of US adults with arthritis and other rheumatic conditions 1997 to 2005. J Rheumatol. 2009;36(11):2531-2538.
- Gupta MN, Sturrock RD, Field M. A prospective 2-year study of 75 patients with adult-onset septic arthritis. Rheumatology. 2001;40:24–30.
- Jay GD TJ, Warman ML, Laderer MC, Breuer KS. The role of lubricin in the mechanical behavior of synovial fluid. Proc Natl Acad Sci USA. 2007;104(15):6194-6199.
- Dubost JJ, Soubrier M, De Champs C, Ristori JM, Bussiere JL, Sauvezie B. No changes in the distribution of organisms responsible for septic arthritis over a 20 year period. Ann Rheum Dis. 2002;61(3):267-269.
- Carpenter CR, Schuur JD, Everett WW, Pines JM. Evidence-based Diagnostics: Adult Septic Arthritis. Academic emergency medicine: official journal of the Society for Academic Emergency Medicine. 2011;18(8):781-796.
- Margaretten ME, Kohlwes J, Moore D, Bent S. Does this adult patient have septic arthritis? JAMA 2007; 297:1478.
- Kaandorp CJ, Van Schaardenburg D, Krijnen P, Habbema JD, van de Laar MA. Risk factors for septic arthritis in patients with joint disease. A prospective study. Arthritis Rheum. 1995 Dec; 38(12):1819-25.
- Morgan DS, Fisher D, Merianos A, Currie BJ. An 18 year clinical review of septic arthritis from tropical Australia. Epidemiol Infect 1996; 117:423.
- Gavet F, Tournadre A, Soubrier M, et al. Septic arthritis in patients aged 80 and older: a comparison with younger adults. J Am Geriatr Soc 2005; 53:1210.
- Dubost JJ, Fis I, Denis P, et al. Polyarticular septic arthritis. Medicine (Baltimore) 1993; 72:296.
- Kaandorp CJ, Dinant HJ, van de Laar MA, Moens HJ, Prins AP, Dijkmans BA. Incidence and sources of native and prosthetic joint infection: a community based prospective survey. Ann Rheum Dis. 1997 Aug; 56(8):470-5.
- Ross JJ, Shamsuddin H. Sternoclavicular septic arthritis: review of 180 cases. Medicine (Baltimore) 2004; 83:139.
- Mathews CJ, Coakley G. Septic arthritis: current diagnostic and therapeutic algorithm. Curr Opin Rheumatol 2008; 20:457.
- Goldenberg DL, Cohen AS. Acute infectious arthritis. A review of patients with nongonococcal joint infections (with emphasis on therapy and prognosis) Am J Med. 1976;60:369–377.
- Robinson E-G. Evaluation of the Patient: History and Physical Examination. Primer on the Rheumatic Diseases, 13th ed. 2008:6.
- Cucurull E, Espinoza LR. Gonococcal arthritis. Rheum Dis Clin North Am. 1998 May. 24(2):305-22.
- Shirtliff ME, Mader JT. Acute septic arthritis. Clin Microbiol Rev. 2002;15(4):527-544.
- Zieger MM, Dörr U, Schulz RD. Ultrasonography of hip joint effusions. Skeletal Radiol. 1987;16(8):607-11.
- Valley VT, Stahmer SA. Targeted musculoarticular sonography in the detection of joint effusions. Acad Emerg Med. 2001 Apr;8(4):361-7.
- Deesomchok U, Tumrasvin T. Clinical study of culture-proven cases of non-gonococcal arthritis. J Med Assoc Thai. 1990;73:615–623.
- McCutchan HJ, Fisher RC. Synovial leukocytosis in infectious arthritis. Clin Orthop Relat Res. 1990;257:226–230.
- Schlapbach P, Ambord C, Blochlinger AM, Gerber NJ. Bacterial arthritis: are fever, rigors, leucocytosis and blood cultures of diagnostic value? Clin Rheumatol. 1990;9:69–72.
- Jeng GW, Wang CR, Liu ST, et al. Measurement of synovial tumor necrosis factor-alpha in diagnosing emergency patients with bacterial arthritis. Am J Emerg Med. 1997;15:626–629.
- Cooper C, Cawley MI. Bacterial arthritis in an English health district: a 10 year review. Ann Rheum Dis. 1986;45:458–463.
- Ernst AA, Weiss SJ, Tracy LA, Weiss NR. Usefulness of CRP and ESR in predicting septic joints. South Med J. 2010;103:522–526.
- Li SF, Henderson J, Dickman E, Darzynkiewicz R. Laboratory tests in adults with monoarticular arthritis: can they rule out a septic joint. Acad Emerg Med. 2004;11:276–280.
- Weston VC, Jones AC, Bradbury N, Fawthrop F, Doherty M. Clinical features and outcome of septic arthritis in a single UK Health District 1982-1991. Ann Rheum Dis. 1999;58(4):214-219.
- Li SF, Cassidy C, Chang C, Gharib S, Torres J. Diagnostic utility of laboratory tests in septic arthritis. Emerg Med J. 2007;24:75–77.
- Söderquist B, Jones I, Fredlund H, Vikerfors T. Bacterial or crystal-associated arthritis? Discriminating ability of serum inflammatory markers. Scan J Infect Dis. 1998;30:591–596.
- Martinot M, Sordet C, Soubrier M, et al. Diagnostic value of serum and synovial procalcitonin in acute arthritis: a prospective study of 42 patients. Clin Exp Rheumatol. 2005;23:303–310.
- Argen RJ, Wilson CH, Wood P. Suppurative arthritis. Arch Intern Med. 1966;117:661–666.
- Rosenthal J, Bole GG, Robinson WD. Acute nongonococcal infectious arthritis. Evaluation of risk factors, therapy, and outcome. Arthritis Rheum. 1980;23:889–897.
- Riordan T, Doyle D, Tabaqchali S. Synovial fluid lactic acid measurement in the diagnosis and management of septic arthritis. J Clin Pathol. 1982;35:390–394.
- Faraj AA, Omonbude OD, Godwin P. Gram staining in the diagnosis of acute septic arthritis. Acta Orthop Belgica. 2002;68:388–391.
- Schmerling RH, Delbanco TL, Tosteson AN, Trentham DE. Synovial fluid tests: what should be ordered? JAMA. 1990; 264:1009–1014.
- Yu KH, Luo SF, Liou LB, et al. Concomitant septic and gouty arthritis–an analysis of 30 cases. Rheumatology (Oxford). 2003;42(9):1062-1066.
- Brook I, Reza MJ, Bricknell KS, Bluestone R, Finegold SM. Synovial fluid lactic acid. A diagnostic aid in septic arthritis. Arthritis Rheum. 1978; 21:774–779.
- Mossman SS, Coleman JM, Gow PJ. Synovial fluid lactic acid in septic arthritis. N Z Med J. 1981; 93:115–117.
- Gratacós J, Vila J, Moyá F, et al. D-lactic acid in synovial fluid. A rapid diagnostic test for bacterial synovitis. J Rheumatol. 1995; 22:1504–1508.
- Frazee BW, Fee C, Lambert L. How common is MRSA in adult septic arthritis? Ann Emerg Med. 2009;54(5):695-700.
- Sharff KA, Richards EP, Townes JM. Clinical management of septic arthritis. Curr Rheumatol Rep 2013; 15:332.
- Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011; 52:e18.
- Hunter JG, Gross JM, Dahl JD, et al. Risk factors for failure of a single surgical debridement in adults with acute septic arthritis. J Bone Joint Surg Am 2015; 97:558.
- Dooley DP. Aspiration of the possibly septic joint through potential cellulitis: just do it! J Emerg Med. 2002;23(2):210.
- Ahmed I, Gertner E. Safety of arthrocentesis and joint injection in patients receiving anticoagulation at therapeutic levels. Am J Med. 2012;125(3):265-269.
- Luthringer TA, Fillingham YA, Okroi K, Ward EJ, Della Valle C. Periprosthetic Joint Infection After Hip and Knee Arthroplasty: A Review for Emergency Care Providers. Ann Emerg Med. Article in Press. DOI: http://dx.doi.org/10.1016/j.annemergmed.2016.03.004.
- Roberts WN. Primer: pitfalls of aspiration and injection. Nat Clin Pract Rheumatol. 2007;3(8):464-472.
- Shah K, Spear J, Nathanson LA, McCauley J, Edlow JA. Does the presence of crystal arthritis rule out septic arthritis? J Emerg Med. 2007; 32:23–26.
- Takhar SS, Hendey GW. Orthopedic illnesses in patients with HIV. Emerg Med Clin North Am. 2010 May;28(2):335-42.
- Rodriguez-Merchan EC, Jimenez-Yuste V, Aznar JA, et al. Joint protection in haemophilia. Haemophilia. 2011; 17(2):1–23.
- Simpson ML, Valentino LA. Management of joint bleeding in hemophilia. Expert Rev Hematol. 2012;5(4):459–468.