
Evaluating Knee Pain: The Latest in Diagnosis and Management
Introduction
The evaluation of knee pain can be challenging. In part, this stems from the fact that knee pain may arise secondary to disease within the joint, around the joint (periarticular structures, such as tendons, ligaments, and bursae), and distant to the joint (conditions affecting the hips or feet). Defining the location of pathology is critical in order to separate true articular disease from periarticular or referred pain. In this series, we will focus on conditions localized to the joint—specifically, the nontraumatic swollen knee—while featuring the latest news and research on arthritic conditions and pain in the knee, based primarily on Medscape Medical News coverage.
Evaluating Knee Pain: The Latest in Diagnosis and Management
The Swollen Knee
A patient may report swelling in a knee as a sensation of the knee being larger than usual, or a feeling of tightness or stiffness. On physical examination, swelling can be identified by visual appearance of enlargement or loss of physical landmarks, especially in comparison to the contralateral knee (although these may be difficult to identify if both knees are swollen). Palpation of the knee can show a fluid wave (demonstrated in later slides). In addition, posterior movement of the patella of more than a few millimeters with the leg extended often indicates joint effusion (patellar ballottement). Occasionally, a patient's habitus may make detection of swelling difficult. Joint swelling is typically due to joint effusion; however, it also can be due to synovial hypertrophy, with minimal excess joint effusion. In these cases, imaging studies may allow for better identification of joint swelling.[1]
Evaluating Knee Pain: The Latest in Diagnosis and Management
More on Swelling
Once swelling is confirmed, the next step is to establish whether the cause is inflammatory or noninflammatory. History and physical exam features suggestive of an inflammatory etiology include the cardinal signs of inflammation: rubor, calor, tumor, and dolor. Pain with neither apparent swelling nor stiffness is called arthralgia; the work-up and differential diagnosis for knee arthralgia may differ from the evaluation of a swollen knee that is described in the slides ahead.
Determining the underlying etiology of knee swelling often requires close examination of other joints; a detailed nonmusculoskeletal exam; and, as always, a good history. Because the knee is an isolated joint, there are no pathognomonic patterns of disease, as seen in the hands; thus, the astute clinician needs to garner important clues from the history and exam. These include age and sex of the patient, timing of onset, pattern of arthritis (number of joints involved, symmetrical vs nonsymmetrical, axial vs nonaxial, small vs large joint), extra-articular symptoms, and exposure history.
Evaluating Knee Pain: The Latest in Diagnosis and Management
The Swollen Knee Differential Diagnosis
Typically, joint pain, stiffness, and swelling over hours to a few days is related to trauma, infection, or crystalline disease—although in rare cases, autoimmune diseases, such as rheumatoid arthritis and seronegative spondyloarthropathies (SpAs), may present with acute knee symptoms. With an acutely painful, stiff, and swollen joint, especially if monoarticular, aspiration to evaluate for infection and crystals is indicated; internal derangement may cause a similar presentation, but is a diagnosis of exclusion in this setting. Chronic causes of monoarticular joint swelling include autoimmune diseases; chronic infection; sarcoidosis; foreign body synovitis; avascular necrosis; sickle cell disease; hemophilia; Charcot joint; and joint tumors, such as pigmented villonodular synovitis (PVNS). In patients without a diagnosis, synovial biopsy should be considered to rule out infection (low sensitivity of synovial aspirate), foreign body synovitis, or neoplasm.
Evaluating Knee Pain: The Latest in Diagnosis and Management
The Swollen Knee Differential Diagnosis (cont.)
Crystalline disease: Typically acute in onset, but may be chronic; aspiration to confirm diagnosis.
Gout: Very uncommon in premenopausal females, probably because of the protective effect of estrogen on uric acid secretion at the kidney. Physical examination may identify tophi in multiple areas, including the ears, and patients may have a history of articular symptoms, especially in the first metatarsophalangeal articulation (MTP), even if such symptoms are not currently present.
Pseudogout: More common in advanced age, and may occur in the setting of metabolic stress (eg, pneumonia, recent surgery); chondrocalcinosis on radiography (common sites include the triangular fibrocartilage of the wrist, knee, and symphysis pubis) may provide a clue to this diagnosis, but joint aspiration with careful evaluation for crystals is typically needed to confirm the diagnosis.
Evaluating Knee Pain: The Latest in Diagnosis and Management
And Still More Differential Diagnosis
Skin disease: Often a window to the diagnosis of a unifying systemic disease; look for pathognomonic patterns or characteristic biopsy findings. In particular, psoriasis may indicate psoriatic arthropathy, bruising may indicate bleeding diathesis, and pustular rash may indicate an infectious process (eg, disseminated gonorrhea).
Other medical history: Many diseases may be associated with joint pathology. A detailed review of the patient's medical history and review of systems, as well as travel history and exposures (eg, tick bites), may provide clues to the knee pathology, especially if the cause of knee swelling is not otherwise readily apparent. For example, lower spine involvement is not typical of rheumatic disease outside the setting of an SpA. As such, the report of low back pain in a young patient (< 40 years) with knee swelling may help to uncover a unifying diagnosis of an SpA. In contrast, new-onset back pain in patients older than 50 years probably represents a separate issue of degenerative spine disease.
Evaluating Knee Pain: The Latest in Diagnosis and Management
Case 1: Inflammation
A 62-year-old woman presents with right knee swelling that has been present for 4-5 weeks (slide 2 and above). A dotted line outlines the Hoffa fat pad, a structure commonly mistaken for knee swelling. Directly superior to this structure lies the inferior pole of the patella, with an additional pen line marking the superior patellar pole. A large effusion is present, which may be best appreciated when comparing to the contralateral side (slide 2). Joint aspirate from the superolateral knee revealed a white blood cell (WBC) count of 29,000, confirming an inflammatory fluid. Crystal analysis, Gram stain, and culture were negative.
Key point: Defining the location of abnormality is critical in differentiating disease within the joint from periarticular conditions, such as patellofemoral syndrome, prepatellar bursitis, and pes anserine bursitis.
Evaluating Knee Pain: The Latest in Diagnosis and Management
A Knee May Not Tell All
The hands above belong to the same patient. In discussion, she admits to several years of joint discomfort and loss of range of motion that she attributed to "wear and tear." The following clues of a chronic inflammatory arthritis were present: ulnar deviation of the digits, muscular wasting of the dorsal interosseous muscles, and mild synovitis of several metacarpophalangeal joints (MCPs) and proximal interphalangeal joints (PIPs) bilaterally. Testing identified rheumatoid factor and anti-cyclic citrullinated peptide antibody; radiography showed classic periarticular osteopenia and marginal erosions, confirming the diagnosis of RA.
Key point: As outlined in this case, the outward appearance of a knee effusion often fails to define the underlying etiology; additional clues from the examination and history are necessary.
Evaluating Knee Pain: The Latest in Diagnosis and Management
Rheumatoid Arthritis: The Latest
In recent years, new treatments for RA have employed mechanisms of action biosimilar to already FDA-approved agents. The lack of novel treatment concepts has led some to question whether the field was in a rut. Nonetheless, important new data have recently appeared that allow rheumatologists to refine their use of existing RA therapies. One of the most promising new developments is in identifying which patients with RA may be able to taper their therapy. Ideal candidates for tapering include those who have had sustained remission for ≥ 6 months on stable disease-modifying antirheumatic drugs (DMARDs), low disease activity scores, negative autoantibody tests, and other factors.[2] Other recent data from the ongoing Dutch PRAIRI trial have shown that RA can be targeted preclinically with a single infusion of the anti-CD20 antibody rituximab, which can delay its onset by up to a year in high-risk individuals.[3] This approach may be of particular value, in light of results from a recent study showing that early intervention leads to lesser disability rates than later treatment.[4]
Evaluating Knee Pain: The Latest in Diagnosis and Management
Case 2: Evaluate Other Joints
A 29-year-old man presents with 12 months of stiffness and swelling of the right knee. He denies trauma. Prior joint aspirations revealed a mild inflammatory fluid (WBCs in the 4000-6000 range), without crystals. Past prednisone use improved the swelling, with recurrence on taper. He was then prescribed allopurinol (despite the absence of urate crystals from aspirate), without improvement. In the past 6 months, he has developed swelling in the left heel. On history, he mentions low back stiffness that he attributes to his job. He denies a history of recent genitourinary or gastrointestinal infection, and has no history of psoriasis or inflammatory eye disease. On exam, he has swelling of his right knee and at the insertion of the left Achilles tendon. Radiography revealed an erosive enthesopathy at the heel (break in cortical bone; arrow above) as well as left-sided sacroiliitis, confirming a diagnosis of undifferentiated SpA.
Key point: Evaluating other sites of musculoskeletal symptoms may reveal the cause of knee pathology.
Evaluating Knee Pain: The Latest in Diagnosis and Management
Spondyloarthritis: The Latest
New research has focused on the role of the gut microbiome as a potential trigger for ankylosing spondylitis (AS).[5] This may one day extend the efficacy of treatments directed at the gut microbiome to AS. Additional research has shown that effective treatment of very early peripheral spondyloarthritis can be provided with the tumor necrosis factor (TNF) inhibitor golimumab. Results presented at the 2016 International Congress on Spondyloarthritides showed that it produced significantly higher rates of clinical remission at 12 weeks when compared with placebo (70% vs 15%; P<.001).[6] Other research presented at this meeting indicated that a combination of TNF inhibitors and nonsteroidal anti-inflammatory drugs may work in a synergistic fashion to slow the progression of AS.[7] Elsewhere, the oral Janus kinase (JAK) inhibitor tofacitinib outperformed placebo at 12 weeks in a phase 2 trial.[8]
Evaluating Knee Pain: The Latest in Diagnosis and Management
Case 3: Dermatologic Findings
A 55-year-old woman presents with right knee swelling and increasing discomfort at the right index finger for 6 months. A rash developed on the back of her neck and ocular region starting 18 months earlier (diagnosed as "dermatitis"), and now includes her nasal alae in the past 4 weeks. From this brief history and exam, we identified a chronic, nonmigratory oligoarthritis. A rheumatic review of systems should be performed to rule out infectious exposure, recent travel, such exposures as tick bites and sexual contacts, and presence of other organ involvement. The review of systems was negative other than skin disease, which eluded diagnosis to date.
Key point: Identifying a concurrent skin condition may offer a window to establishing the cause of an underlying arthritis. In this setting, recognition of characteristic or classic presentations of skin disease, or performing a formal biopsy, is crucial.
Evaluating Knee Pain: The Latest in Diagnosis and Management
More on the Skin
This patient's rash has several distinctive features: a reddish-purple color, its raised nature, and preferential involvement of the nasal alae. These findings are characteristic of lupus pernio, a cutaneous manifestation of sarcoidosis. A subsequent chest radiograph confirmed hilar lymphadenopathy. Hand radiographs show underlying bony changes that correspond to digit swelling seen on examination. Bony changes in sarcoidosis often preserve the cortical margins (differentiating it from erosive disease as seen in rheumatoid arthritis, for example); instead, the cortex of the involved finger has been "tunneled out," resulting in a reticular or lace-like appearance of the proximal phalange. Patients with sarcoidosis who have lupus pernio have a higher incidence of pulmonary and bone involvement.
Evaluating Knee Pain: The Latest in Diagnosis and Management
Arthritis and the Skin: The Latest
In the past few years, a number of new treatment options have become available for psoriatic arthritis (PsA). A 2016 systematic review of randomized controlled trials of these new agents concluded that those with the most robust safety and efficacy data were the biological DMARDs ustekinumab and secukinumab, the targeted synthetic DMARD apremilast, and the TNF inhibitors golimumab and certolizumab pegol.[9] The European League Against Rheumatism used this systematic review to revise its recommendations on the pharmacologic treatment of PsA.[10] These recommendations and other research have placed increasing emphasis on treating to target in PsA, though additional study is needed to determine the optimal treatment targets and their use in subgroups of PsA.[11]Recently published phase 3 trial results have shown the new interleukin 17A (IL-17A) inhibitor ixekizumab to improve disease activity and physical function, and reduce progression of structural damage, in patients with PsA.[12] Participants had not previously received biologics, so it is unclear where this agent, if ultimately deemed safe and effective, would sit in the treatment continuum for PsA.
Evaluating Knee Pain: The Latest in Diagnosis and Management
Case 4: Consider Crystals
A 68-year-old man recovering from abdominal surgery developed an acutely painful, swollen left knee. Exam revealed swelling superior to the knee that was tender and warm, consistent with a suprapatellar effusion. The effusion was aspirated from a superolateral patellar approach (next slide) and yielded cloudy yellow fluid with numerous intracellular gout crystals. Gram stain and culture were negative. If a suprapatellar effusion is present, the simplest way to obtain fluid may be through a superolateral patellar approach (next slide), rather than a medial or lateral midpatellar approach.[13]
Key point: Postsurgical gout flares are common, although pseudogout is possible as well. Of note, infection needs to be ruled out; septic arthritis can occur concurrently in patients with active crystalline disease.
Evaluating Knee Pain: The Latest in Diagnosis and Management
Effusions
Occasionally, much of a knee effusion resides in the suprapatellar region. While this space is contiguous with the more inferior aspects of the knee, if on exam a predominately suprapatellar effusion is present, aspiration from the superolateral approach may be the simplest way to obtain synovial fluid. A patient should lie down with the knee as flat as possible, and the pitch of the needle should be roughly parallel to the floor and inserted 1 cm superior and 1 cm lateral to the upper lateral corner of the patella (black outline), in the 2-o'clock position. The needle can be directed parallel to the top of the patella with care to avoid the quadriceps tendon (yellow arrow), or at a 45° angle under the patella (black dashed arrow). Because the suprapatellar space is contiguous with the lower knee, medial and lateral midpatellar approaches (white arrows) can also be used.[14]
Evaluating Knee Pain: The Latest in Diagnosis and Management
A Closer Look at Crystals
Under polarized microscopy, there is a needle-shaped, negatively birefringent, intracellular crystal (left image). The crystal appears yellow when its long axis is aligned with the first-order red compensator (right image); this is in contrast to calcium pyrophosphate crystals, which appear blue in this setting and are typically rhomboid in shape. A quick estimate of the nucleated cell count can be obtained by the clinician at the bedside: 1 WBC per high-power field (40×) equals 500 cells/μL.[15]
Evaluating Knee Pain: The Latest in Diagnosis and Management
Gout: The Latest
New gout treatment guidelines from the American College of Physicians[16] have been greeted skeptically by some, as they recommend that clinicians move away from controlling serum uric acid levels to instead concentrating on relieving acute symptoms. Regardless, effective interventions for gout have become increasingly important, as US hospitalizations for this condition have noticeably increased in past two decades and now outpace those for RA.[17] It is thought that the majority of patients with gout could be at an elevated risk for cardiovascular events,[18] though recent hypothesis-generating data found that the common medication colchicine may reduce this somewhat.[19]Randomized study data indicate that when it comes to their analgesic qualities in treating acute gout symptoms, both oral prednisolone and indomethacin can be considered similarly effective first-line options.[20] In May, the journal BMJ published a study indicating that the low-salt, fruit- and vegetable-rich Dietary Approaches to Stop Hypertension (DASH) diet may lower the risk for gout.[21] Moving beyond diet to surgical interventions, a 2016 study from Sweden found that bariatric surgery prevents gout and hyperuricemia in obese persons.[22]
Evaluating Knee Pain: The Latest in Diagnosis and Management
Case 5: Comorbid Arthritides
A 63-year-old man presents with about 5 years of right knee pain, but over the past 2 days he has had marked worsening, with swelling, pain, and redness. He has a history of knee injury and surgery where "cartilage" was removed. He drinks 12 beers daily. On exam, the right knee is warm, swollen, and tender, with a tender, golf-ball-sized nodule on the upper right side. Synovial fluid shows 22,000 nucleated cells/μL (87% neutrophils) and negatively birefringent intracellular crystals that are consistent with gout; Gram stain and culture were negative. Plain films revealed severe medial joint-space narrowing and osteophyte formation, and a calcified mass on the right (yellow arrow) that correlated with a nodule on examination. This patient has chronic osteoarthritis and tophaceous gout, with an acute gout flare.
Key points: This case illustrates the important point that multiple forms of arthritis can exist in one joint. In addition, gouty exacerbations often involve peripheral joints with chronic damage or degenerative disease.
Evaluating Knee Pain: The Latest in Diagnosis and Management
Case 6: Rice Bodies
A 63-year-old woman presents with about 2 years of widespread joint pain, stiffness, and swelling. On exam, she has synovitis in multiple small joints of her hands and feet, and bilateral warm knee effusions. Plain films demonstrate multiple small erosions in her MCPs and MTPs, and serology is positive for rheumatoid factor and anti-cyclic citrullinated peptide antibody. Aspiration of the right knee reveals the synovial fluid seen above. The whitish material in the fluid is "rice bodies": fibrinous exudates, or fibrinous exudate surrounding collagenous nuclei. These can be seen in long-standing rheumatoid arthritis (as in this patient) or other causes of chronic inflammation, including infection with tuberculosis. As such, Gram stain and culture for typical organisms, as well as acid-fast bacilli, is important.[23]
Evaluating Knee Pain: The Latest in Diagnosis and Management
Case 7: Understand the History
A 24-year-old black man presents with diffuse bone pain thought to be due to an acute sickle cell crisis, and bilateral knee effusions. On exam, both knees are mildly warm and tender, with moderate effusions. Aspiration of the left knee revealed greenish-yellow synovial fluid (image above), with a count of 600 nucleated cells/μL, and negative crystals, Gram stain, and culture. The color is due to the presence of bilirubin from hemolytic anemia. Joint symptoms in sickle cell disease can be from many causes, including acute crisis that can be associated with noninflammatory effusions (as seen here), bone infarction, crystalline disease, chronic synovitis, and degenerative changes.[24]
Key points: Understanding the patient's medical history can aid in diagnosis of knee pathology. In addition, septic joints or osteomyelitis can be seen in sickle cell disease and often involve gram-negative species, such as Salmonella and Escherichia. If joint symptoms and effusion are present, it is important to evaluate for infection.
Evaluating Knee Pain: The Latest in Diagnosis and Management
Case 8: Look for Infection
A 26-year-old woman presents with 3 days of migratory arthritis, including current right knee pain and swelling. Her right knee is warm and tender, with an effusion. She has tenderness and swelling over the extensor tendons of her right wrist. She also has several pustular skin lesions (image above). Synovial fluid from the knee contains 18,000 nucleated cells/μL (90% neutrophils) and rare gram-negative diplococci. A diagnosis of disseminated gonococcal infection can be made from multiple sites: blood; synovial fluid; skin lesions; or mucosal surfaces. Cultures can be performed on a variety of media, including Thayer-Martin, chocolate agar, or polymerase chain reaction. Testing for other sexually transmitted diseases is also recommended.[25]
Key points: Synovial fluid analysis should be performed in cases with acute-onset inflammatory arthritis, especially if monoarticular, to rule out infection. In this case, examination of sites other than the knee that included other joints and the skin led to high suspicion of disseminated gonococcal infection.
Evaluating Knee Pain: The Latest in Diagnosis and Management
Case 9: Bursitis
A 32-year-old man presents with 1 week of worsening pain, redness, and swelling of his knee (image above), which began after working on his knees. Tenderness is worse with flexion. Aspiration of the prepatellar bursa shows 8200 nucleated cells/μL (85% neutrophils), minimal blood, and no crystals. Gram stain showed gram-positive cocci cultured as Staphylococcus aureus. This patient has infectious prepatellar bursitis, which from his history was probably induced by local trauma. Other causes of bursitis include trauma, crystalline disease, and RA. Because bursal fluid typically has few WBCs, even counts of 1-2000 should be considered infectious until proven otherwise. It is also important to note that fungal infections have been reported in otherwise immunocompetent hosts, and therefore should remain in the differential. In this case, the patient's ability to fully extend his knee while being unable to flex it helps differentiate bursitis from a true knee effusion.[26]
Evaluating Knee Pain: The Latest in Diagnosis and Management
Case 10: Pigmented Villonodular Synovitis
A 38-year-old man presented with 10 months of worsening pain and swelling of his knee, with loss of range of motion. Exam revealed a cool, largely nontender, swollen right knee. Synovial aspiration revealed a noninflammatory serosanguinous fluid. Plain films showed only mild degenerative changes, although MRI identified a synovial mass with decreased intensity on T1 and T2 imaging (see above). Biopsy led to the diagnosis of diffuse PVNS, which was subsequently treated with synovectomy. PVNS is a rare disease that typically affects males, often involving the knees. It is often monoarticular, but can occur in more than 1 joint. 2 forms exist: diffuse PVNS (involvement of the entire joint lining, as seen here) and focal nodular PVNS (often, the small joints of hands and feet; if the tendon sheath is involved, the term giant cell tumor of the tendon sheath is used).[27] The MRI findings are due to hemosiderin deposition and, when present, highly suspicious for diffuse PVNS.
Key points: A high index of suspicion is necessary to diagnose PVNS; in this case it was spurred by the finding of a chronic monoarticular arthritis not explained by initial synovial fluid analysis.
Evaluating Knee Pain: The Latest in Diagnosis and Management
Conclusion
A painful knee may represent the end result of trauma or a long list of underlying conditions, as outlined in this slideshow. Acute presentations (swelling over hours to days), especially if monoarticular, require joint aspiration to rule out crystalline disease, infection, or hemorrhage. Identifying a diagnosis may be more elusive in cases with a more chronic presentation. In such patients, uncovering the underlying etiology will require attention to medical history, exposures, and recognition of involvement of additional joints or associated extra-articular symptoms. Recent therapeutic advancements in the field of rheumatology have resulted in drug regimens specifically tailored to individual diseases. As such, the treatment of patients with knee swelling will require not only a knowledge of these cutting-edge therapies, but also reliance on the skills of the clinician to accurately arrive at the correct diagnosis.
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