What is the next diagnostic step?A 45-year-old white man presents to your office complaining of left knee pain that started last night. He says that the pain started suddenly after dinner and was severe within a span of 3 hours. He denies any trauma, fever, systemic symptoms, or prior similar episodes. He has a history of hypertension for which he takes hydrochlorothiazide (HCTZ). He admits to consuming a great amount of wine last night with dinner.
On examination, his temperature is 98°F, his pulse is 90 beats/min, his respirations are 22 breaths/min, and his blood pressure is 129/88 mm Hg. Heart and lung examinations are unremarkable. The patient is reluctant to flex the left knee, wincing in pain at touch, and has passive range of motion. The knee is edematous, hot to touch, and has erythema of the overlying skin. No crepitation or deformity is apparent. No other joints are involved. Inguinal lymph nodes are not enlarged. Complete blood count reveals a white blood cell count of 10,900 cells/mm3 and is otherwise normal.
What is the next diagnostic step?
What is the most likely diagnosis?
What is the next step in therapy?
Summary: This is a 45-year-old man who presents with the sudden onset of monoarticular, nontraumatic joint pain. Evolution from onset to severe pain was rapid. The patient denies any trauma, systemic signs of illness, or any prior episodes. The history that he took HCTZ and drank a lot of alcohol the night that his symptoms started is important. His vital signs are stable, and he does not appear to be systemically ill. There is pain to movement and touch of the left knee, with evident edema, erythema, and warmth of the joint. No other joints are involved. His white blood cell count is not indicative of an acute infectious process.
• Next diagnostic step: Joint aspiration for examination of joint fluid to identify crystals and exclude infection
• Most likely diagnosis: Crystal-induced gout of the left knee
• Next step in therapy: Nonsteroidal anti-inflammatory drug (NSAID) and provide analgesia; may consider using colchicine
1. Have a differential diagnosis for nontraumatic joint pain, based on clinical presentation.
2. Be familiar with the most common diagnostic tests for the above conditions, and have a rationale when ordering these tests.
3. Know the most common treatment options in the acute onset of gout and infectious arthritis, as well as the chronic management of rheumatoid arthritis and osteoarthritis.
This 45-year-old man presents with the sudden onset of monoarticular joint pain. The first diagnosis that needs to be excluded is an infected joint. A joint becomes septic by blood inoculation, by contiguous infection (such as from bone or soft tissue), or from direct inoculation from trauma or surgery. Exclusion of an infectious etiology is paramount as cartilage can be destroyed within the first 24 hours of infection. In this case, the patient’s history and clinical scenario do not favor an infectious cause, although it cannot be excluded by history and physical examination alone.
There are several additional pieces of information that guide the diagnosis in this case. Most gout attacks occur between the ages of 30 and 50 years in men, with a later onset in postmenopausal women (50-70 years of age). The patient’s recent increase in alcohol consumption can be considered an exacerbating factor. Other factors that may also increase the risk of a gout attack include trauma, surgery, or a large meal (especially one high in purines such as red meat, liver, or seafood) that induces hyperuricemia. Finally, the patient’s history of taking a thiazide diuretic is also important, as these drugs may induce hyperuricemia.
The examination of a joint aspirate is essential for the diagnosis. The gross appearance of fluid is not very specific, as both a septic aspirate and a heavily condensed crystal-induced arthritis may have a thick, yellowish/chalky appearance. To diagnose crystal-induced arthritis, polarizing microscopy has to reveal monosodium urate (MSU) crystals, which will look like needles and have a strong negative birefringence. Other crystals that may be seen are calcium pyrophosphate dehydrate, calcium hydroxyapatite, and calcium oxalate.
• Calcium pyrophosphate dehydrate: Rod-shaped, rhomboid, weakly positive birefringence
• Calcium hydroxyapatite: Seen by electron microscopy, cytoplasmic inclusions that are nonbirefringent
• Calcium oxalate: Bipyramidal appearance, strongly positive birefringence; seen mostly in end-stage renal disease patients
In crystal-induced arthritis, the white blood cell count of the joint aspirate is on average 2000 to 60,000/μL, with less than 90% neutrophils, while a septic joint will have an average of 100,000 WBC/μL (25,000-250,000 cells) with more than 90% neutrophils. Aspirate that has been determined to be crystal-induced must also be cultured so as to rule out a coexisting infection.
GOUTY ARTHRITIS: Condition of excess uric acid leading to deposition of MSU crystals in joints, especially the great toe.
PSEUDOGOUT: Condition of joint pain and inflammation due to calcium pyrophosphate dehydrate crystals in the joints, which can be diagnosed by noting rod-shaped, rhomboid, weakly positive birefringence by crystal analysis.
Depending on the etiology, pain may be present in one, two, or more joints. Considering the patient’s age, medical history, and medication profile is important. The patient’s lifestyle and social history should also be considered, as certain activities may predispose a patient to specific infections. Among the major diagnoses that have to be considered in a nontraumatic swollen joint are gout (or any crystal-induced arthritis), infectious arthritis, osteoarthritis, and rheumatoid arthritis. For acute monoarticular arthritis in adults, the most common causes include trauma, crystals, and infection.
Gout’s first episode can often be confused with cellulitis. It presents with swelling and pain, usually of one joint, accompanied by erythema and warmth. Classically, a gout attack involves the metatarsophalangeal joint of the first toe, called podagra, but it may involve any joint in the body. Some cases left untreated resolve spontaneously within 3 to 10 days, with no residual signs or symptoms. During an acute attack, the serum uric acid level may be normal or even low, likely as a result of the existing deposition of the urate crystals. Uric acid levels are, however, useful in monitoring hypouricemic therapy between attacks. Radiographs may show cystic changes in the joint surface, with punched-out lesions and soft-tissue calcifications. These findings are nonspecific and are also seen in osteoarthritis and rheumatoid arthritis.
An infection usually involves only one joint if it is of bacterial origin (>90% of cases). The knee, hip, and shoulder are the three most commonly involved joints. A chronic monoarticular arthritis or involvement of two to three joints may be caused by fungi or mycobacteria. In the case of acute polyarticular (more than three joints) arthritis, the etiology may be from endocarditis or a disseminated gonococcal infection.
Bacterial infections of a joint occur most commonly in persons with rheumatoid arthritis. The chronic inflammation of joints coupled with the use of steroids predisposes this group to Staphylococcus aureus infections. HIV-positive patients may develop pneumococcal, salmonella, or even Haemophilus influenzae joint infections. Intravenous drug users are most likely to get a streptococcal, staphylococcal, gram-negative, or Pseudomonas infection.
Range of motion (ROM) of the joint is an important maneuver of the physical examination. A septic joint will have a very limited ROM due to pain coupled with a joint effusion and fever. However, a nearby cellulitis, bursitis, or osteomyelitis will usually maintain the ROM of a joint. The aspirate of a septic joint will have a positive culture in more than 90% of cases.
Osteoarthritis (OA) is most commonly found in people older than 65 years of age (68% of patients) and is associated with trauma, history of repetitive joint use, and obesity (specifically for knee OA). It primarily affects the cartilage, but ends up damaging the bone surface, synovium, meniscus, and ligaments. The clinical presentation is usually that of a dull, deep, ache-type pain. The onset is usually gradual, with activity exacerbating the pain, and rest decreasing it. In the latter stages, pain is usually constant. On physical examination, a bony crepitus may be felt on passive ROM. There may be a small joint effusion and periarticular muscle atrophy. In the advanced stage, joint deformity with decreased ROM will be seen. X-rays are usually normal at first, with the gradual development of bone sclerosis, subchondral cysts, and osteophytes.
Rheumatoid arthritis (RA) is another common disorder that may affect people from any age group, but will usually present initially in those 30 to 55 years old. The presentation of RA can be varied, ranging from a monoarticular arthritis that is intermittent, to a polyarthritis that progresses gradually in intensity, leading to disability. It affects more women than men (3:1), and the treatment will usually depend on the stage at which the disease is diagnosed. Among the laboratory tests that may be abnormal in patients with RA are a positive rheumatoid factor (RF) and anti-citrullinated protein antibody (anti-CCP), an elevated erythrocyte sedimentation rate (ESR), an elevated C-reactive protein (CRP), anemia, thrombocytosis, and low albumin. The level of hypoalbuminemia usually correlates with the severity of the disease. The anti-CCP autoantibody is more specific than RF; additionally, a positive anti-CCP may precede the clinical manifestation of disease by many years.
In 2010, the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) developed a new approach to diagnose RA that focuses on features found in the earlier stages of disease. According to this new classification, RA is diagnosed if a person presents with synovitis (swelling) in at least one joint, all other diagnoses for the synovitis are excluded, and has a calculated individual score of 6 points or more (maximum of 10 points). This individual score is based upon both clinical and laboratory factors, including: the number and site of involved joints, serologic abnormalities (RF and anti-CCP), elevated acute-phase response markers (CRP and ESR), and symptom duration (Table 3–1).
Table 3–1 • ACR/EULAR CRITERIA FOR DIAGNOSIS OF RHEUMATOID ARTHRITIS
1. Synovitis (swelling) is present in at least 1 joint
2. All other diagnoses for clinical synovitis are excluded
3. Individual score >6 points is reached based on the following criteria:
a. Joint involvement: 1 largea joint (no points), 2-10 large joints (1 point), 1-3 smallb joints +/– large joint (2 points), 4-10 small joints +/– large joints (3 points), >10 joints (5 points)
b. Serology: Negative RF and anti-CCP (no points), low positive RF or anti-CCP (2 points), high positive RF or anti-CCP (3 points)
c. Acute-phase reactants: normal CRP and normal ESR (no points), abnormal CRP or abnormal ESR (1 point)
d. Duration of symptoms: <6 weeks (no point), ≥66 weeks (1 point)
aLarge joints include shoulders, elbows, hips, knees, and ankles.
bSmall joints include wrists, MCP, PIP, 2nd to 5th MTPs, and thumb interphalangeal joints.
Data from Aletaha D, Neogi T, Silman AJ, et al. Rheumatoid arthritis classification criteria. Arthritis Rheum. 2010;62(9); 2569-2581.
Analgesia is a common factor to consider in therapy for all the conditions described above. In the case of an acute gout attack, colchicines, nonsteroidal anti-inflammatory drugs (NSAIDs), and glucocorticoids are the drugs mainly used. In the elderly population, one must take into account the possibility of GI complications from the above medications. To reduce these risks, intra-articular steroids, ice packs, and low-dose colchicine are more often used. In patients with recurrent gout attacks, chronic medication therapy can be used to maintain serum uric acid levels below 5 mg/dL. The maintenance therapy is usually with either probenecid, which increases the urinary excretion of uric acid, or allopurinol, which reduces the production of uric acid.
A septic joint requires surgery for drainage of infectious material followed by IV antibiotics. Methicillin-resistant S aureus (MRSA) will usually require vancomycin, but coverage with antibiotics is dependent on the specific organisms isolated.
Degenerative joint disease treatment involves mobility exercises, maintenance of adequate range of motion, and weight loss, if appropriate. Intra-articular corticosteroid injections may provide relief for varying amounts of time, but should only be done every 4 to 6 months so as to avoid cartilage destruction. Surgery, such as joint replacement, is usually reserved for people with severe disease that affects their daily functions.
Therapy for rheumatoid arthritis involves multiple modalities. Education and counseling of the patient regarding disease progression, treatment options, and implications to lifestyle is essential. Exercises, such as those that maintain joint mobility and muscle strength, are very important, as the natural course of RA is to develop a stiff joint that becomes disabling. Physical therapy and occupational therapy are important to address specific areas in which the patient may need additional devices to perform activities of daily living.
Many different categories of medications are used in RA. These include NSAIDs, glucocorticoids, disease-modifying antirheumatic drugs (DMARDs), anticytokines, and topical analgesics. Among the DMARDs are sulfasalazine and methotrexate. Infliximab and etanercept are examples of anticytokine agents. Treatment regimens are individualized, and will often include a combination of two or three of these agents. Although effective, monitoring for hepatotoxicity must be performed.
3.1 A 26-year-old man presents with a fever, dysuria, and left knee pain. He reports being sexually active with a new partner as recently as 2 weeks ago. On physical examination, he is febrile and his left knee is erythematous, swollen, and tender. He denies a previous history of arthritis. Which of the following is the next best step?
A. CBC with differential
B. X-ray of the knee
C. Aspiration of synovial fluid
D. Serum uric acid level
3.2 A 44-year-old woman has a 5-month history of malaise and stiff hands in the morning that improve as the day goes by. She notes that both hands are involved at the wrists. Initial laboratory tests show an elevated ESR and high positive anti-CCP. Which of the following treatments is most likely to lead to the best long-term disease outcome for this patient?
B. Ibuprofen
C. Naproxen
D. Methotrexate
E. Intravenous ceftriaxone
3.3 A 52-year-old man complains of bilateral knee pain for about 1 year. He is noted to have a BMI of 40 kg/m2. Which of the following is the best therapy?
A. Allopurinol
B. Ibuprofen
C. Methotrexate
D. Intravenous ceftriaxone
E. Oral glucocorticoids
3.4 A 35-year-old man with hypertension presents with the sudden onset of right big toe pain. Which of the following is the best treatment?
A. Ibuprofen
B. Methotrexate
C. Colchicine
D. Intravenous antibiotics
3.1 C. Infectious arthritis would need to be high on the differential diagnosis because of the danger of gonococcal arthritis. The history supports this diagnosis. This patient needs a joint aspiration to look for gram-negative diplococci, crystals, and to obtain a sample for culture. He will likely require surgical drainage of the swollen joint and IV antibiotic therapy.
3.2 D. Morning stiffness, involvement of the hands, and symmetric arthritis are common features of RA. According to the ACR/EULAR, this patient meets the criteria for the diagnosis of newly presenting RA in that she has joint involvement, positive serology, elevated acute-phase reactants, and duration of symptoms more than 6 weeks. DMARD therapy, such as the use of methotrexate, would be indicated. Methotrexate as a disease-modifying agent would alter the natural history of the disease rather than just treat the symptoms.
3.3 B. Obesity is a risk factor for osteoarthritis, which is common in the knees and typically presents with a gradual onset and worsening of symptoms. Along with exercise and efforts to lose weight, an NSAID medication, such as ibuprofen, may provide symptomatic relief.
3.4 C. Gouty arthritis often initially presents in the big toe (“podagra”) and the use of HCTZ, a common treatment for hypertension, also can increase the risk. Colchicine can provide effective acute treatment.
A red, swollen joint must be aspirated to rule out a joint infection.
Trauma, infection, and crystals are the most common causes of acute monoarthritis in adults.
Aletaha D, Neogi T, Silman AJ, et. al. Rheumatoid arthritis classification criteria. Arthritis Rheum. 2010;62(9);2569-2581.
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Mochan E, Ebell MH. Predicting rheumatoid arthritis risk in adults with undifferentiated arthritis. Am Fam Physician. 2008;77:1451-1453.