The goal of the musculoskeletal evaluation: To formulate a differential diagnosis that leads to

an accurate diagnosis and time therapy, while avoiding excessive diagnostic testing and
unnecessary treatment.

Red flag diagnosis:

●​ Septic arthritis
●​ Acute crystal-induced arthritis (e.g., gout)
●​ Fracture

The majority of individuals with musculoskeletal complaints can be diagnosed with a

thorough history and a comprehensive physical and musculoskeletal examination.

Many musculoskeletal disorders resemble each other at the outset, and some may take
weeks or months (but not years) to evolve in a recognizable diagnostic entity.

The evaluation should ascertain if the complaint is:

1.​ Articular or nonarticular
2.​ Inflammatory or noninflammatory
3.​ Acute or chronic
4.​ Localized (monoarticular) or widespread (polyarticular)

Articular structures:
●​ Synovium
●​ Synovial fluid
●​ Articular cartilage
●​ Intraarticular ligaments
●​ Joint capsule
●​ Juxtaarticular bone

Nonarticular (or periarticular) structures:

●​ Supportive extraarticular ligaments
●​ Tendons
●​ Bursae
●​ Muscle
●​ Fascia
●​ Bone
●​ Nerve
●​ Overlying skin
-​ More frequent and often confused with arthritis.

Articular disorders characters:

-​ Deep or diffuse pain
-​ Limited range of motion on active and passive movement
-​ Swelling (caused by synovial proliferation, effusion, or bony enlargement)
-​ Crepitation
-​ Instability
-​ Locking
-​ Deformity
Nonarticular disorders:
-​ Painful on active, but not passive (or assisted) range of motion.

Periarticular conditions
-​ focal tenderness in regions adjacent to articular structures
-​ may radiate or be elicited with a specific movement or position
-​ physical findings remote from the joint capsule.

Inflammatory disorders:
-​ ​may be infectious:
-​ (Neisseria gonorrhoeae or Mycobacterium tuberculosis)
-​ Crystal-induced (gout, pseudogout)
-​ Immune-related (rheumatoid arthritis [RA], systemic lupus erythematosus
[SLE]), reactive (rheumatic fever, reactive arthritis)
-​ Idiopathic.

4 Cardinal signs of Inflammation:

1.​ Swelling
2.​ Warmth
3.​ Redness
4.​ Pain
-​ Systemic symptoms: (fatigue, fever, rash, weight loss)
-​ Laboratory evidence of inflammation (elevated erythrocyte sedimentation rate [ESR]
or C-reactive protein [CRP]
-​ Thrombocytosis
-​ Anemia of chronic disease, or
-​ Hypoalbuminemia).

●​ Articular stiffness - commonly accompanies chronic musculoskeletal disorders. The

duration of stiffness may be prolonged (hours) with inflammatory disorders (such as
RA or polymyalgia rheumatica [PMR]) and improves with activity.
●​ Intermittent stiffness (also known as gel phenomenon) - typical of noninflammatory
conditions (such as osteoarthritis [OA]), is shorter in duration (<60 min) and is
exacerbated by activity.

Noninflammatory disorders:
-​ trauma (rotator cuff tear),
-​ repetitive use (bursitis, tendinitis),
-​ degeneration or ineffective repair (OA),
-​ neoplasm (pigmented villonodular synovitis), or
-​ pain amplification (fibromyalgia).

Noninflammatory disorders are often characterized by pain without synovial swelling or

warmth, absence of inflammatory or systemic features, intermittent gel phenomena rather
than prolonged morning stiffness, and normal (for age) or negative laboratory investigations.

Common cause of musculoskeletal pain:

-​ Trauma
 -​ Fracture
-​ Overuse syndromes
-​ Fibromyalgia

Aged <60 years:

-​ repetitive use/strain disorders
-​ gout (men only)
-​ RA
-​ spondyloarthritis, and
-​ uncommonly, infectious arthritis.

Aged >60 years:

-​ OA,
-​ crystal (gout and pseudogout) arthritis,
-​ PMR
-​ osteoporotic fracture
-​ uncommonly, septic arthritis.

●​ SLE and reactive arthritis occur more frequently in the young,

●​ Fibromyalgia and RA are frequent in middle age, and
●​ OA and PMR are more prevalent among the elderly.
●​ Men:
○​ Gout
○​ Spondyloarthritis
○​ Ankylosing spondylitis are more common whereas
●​ Women:
○​ RA
○​ Fibromyalgia
○​ Osteoporosis
○​ Lupus
●​ The chronology of the complaint is an important diagnostic feature and can be
divided into:
○​ Onset,
○​ evolution, and
○​ duration.
●​ The onset of disorders such as septic arthritis or gout tends to be abrupt, whereas
OA, RA, and fibromyalgia may have more indolent presentations.
●​ Certain comorbidities may have musculoskeletal consequences. This is especially so
for diabetes mellitus (carpal tunnel syndrome), renal insufficiency (gout), depression
or insomnia (fibromyalgia), myeloma (spinal pain), cancer (myositis), and
osteoporosis (fracture) or when using certain drugs such as glucocorticoids
(osteonecrosis, septic arthritis), diuretics, or chemotherapy (gout).
●​ Patients with febrile, multisystem disorders require exclusion of crystal, infectious, or
neoplastic etiologies and an evaluation driven by the dominant symptom/finding with
the greatest specificity.
●​ Certain conditions, such as acute gout, can be precipitated in hospitalized patients
by:
○​ surgery,
○​ dehydration, or
○​ medications
●​ The musculoskeletal examination depends largely on careful inspection, palpation,
contralateral comparison, and a variety of specific physical maneuvers to elicit
diagnostic signs.
●​ Small to moderate knee effusions may be identified by the “bulge sign” or
“ballottement" of the patellae.
●​ Active and passive range of motion should be assessed in all planes, with
contralateral comparison.
●​ A goniometer may be used to quantify the arc of movement.
●​ Extreme range of motion and connective tissue laxity:
○​ Hypermobility syndrome
○​ Ehlers-Danlos syndrome
○​ Marfan’s syndrome.
●​ Limitation of motion or contractures are frequently caused by:
○​ Inflammation
○​ Effusion
○​ Pain
○​ Deformity
○​ Neuromyopathic causes.
●​ The most common malalignment in the knee is genu varum (bowlegs) or genu
valgum (knock-knees) resulting from asymmetric cartilage loss medially or laterally,
respectively.

●​ Laboratory tests should be used to confirm a specific clinical diagnosis and not be
used to screen or evaluate patients with vague rheumatic complaints.
●​ Besides a complete blood count, including a white blood cell (WBC) and differential
count, the routine evaluation should include a determination of an acute-phase
reactant such as the ESR or CRP, which can be useful in discriminating
inflammatory from noninflammatory disorders. Both are inexpensive, easily obtained,
and may be elevated with infection, inflammation, autoimmune disorders,
neoplasia, pregnancy, renal insufficiency, advanced age, or hyperlipidemia.
●​ Serum uric acid determinations are useful in the diagnosis of gout and in monitoring
the response to urate-lowering therapy. Uric acid, the end product of purine
metabolism, is primarily excreted in the urine.
●​ Serum values range from 238 to 516 μmol/L (4.0–8.6 mg/dL) in men; the lower
values (178–351 μmol/L [3.0–5.9 mg/dL]) seen in women are caused by the
uricosuric effects of estrogen.
●​ Urinary uric acid levels are normally <750 mg per 24 h. Although hyperuricemia is
associated with an increased incidence of gout and nephrolithiasis, levels may not
correlate with the severity of articular disease.
●​ Uric acid levels (and the risk of gout) may be increased by inborn errors of
metabolism (Lesch-Nyhan syndrome), disease states (renal insufficiency,
myeloproliferative disease, psoriasis), or drugs (alcohol, cytotoxic therapy,
thiazides).
●​ Although nearly all patients with gout will demonstrate hyperuricemia at some time
during their illness, up to 50% of patients with an acute gouty attack will have
normal serum uric acid levels. Monitoring serum uric acid is useful in assessing the
response to urate-lowering therapy or chemotherapy, with the target goal being a
serum urate <6 mg/dL.
●​ Aspiration and analysis of synovial fluid are always indicated in acute monoarthritis or
when an infectious or crystal-induced arthropathy is suspected. Synovial fluid may
distinguish between noninflammatory and inflammatory processes by analysis of the
appearance, viscosity, and cell count.
●​ Tests for synovial fluid glucose, protein, lactate dehydrogenase, lactic acid, or
autoantibodies are not recommended as they have no diagnostic value.
●​ Normal synovial fluid is clear or a pale straw color and is viscous, primarily
because of the high levels of hyaluronate. Noninflammatory synovial fluid is clear,
viscous, and amber-colored, with a WBC count of <2000/μL and a predominance of
mononuclear cells.
●​ The viscosity of synovial fluid is assessed by expressing fluid from the syringe
one drop at a time. Normally, there is a stringing effect, with a long tail behind
each synovial drop.
●​ Effusions caused by OA or trauma will have normal viscosity. Inflammatory fluid is
turbid and yellow, with an increased WBC count (2000–50,000/μL) and a
polymorphonuclear leukocyte predominance. Inflammatory fluid has reduced
viscosity (no stringing), diminished hyaluronate, and little or no tail following each
drop of synovial fluid. Such effusions are found in RA, gout, and other inflammatory
arthritides.
●​ Septic fluid is opaque and purulent, with a WBC count usually >50,000/μL, a pre-
dominance of polymorphonuclear leukocytes (>75%), and low viscosity. Such
effusions are typical of septic arthritis but may also occur with RA or gout.
●​ Monosodium urate crystals (observed in gout) are seen by polarized microscopy
and are long, needle-shaped, negatively birefringent, and usually intracellular.
●​ In chondrocalcinosis and pseudogout, calcium pyrophosphate dihydrate
crystals are usually short, rhomboid-shaped, and positively birefringent.
●​ Whenever infection is suspected, synovial fluid should be Gram stained and
cultured appropriately.
●​ It should be noted that crystal-induced arthritis and septic arthritis occasionally
occur together in the same joint.
●​ Conventional radiography has been a valuable tool in the diagnosis and staging of
articular disorders.
●​ Plain x-rays are most appropriate and cost effective when there is a history of
trauma, suspected chronic infection, progressive disability, or monoarticular
involvement; when therapeutic alterations are considered; or when a baseline
assessment is desired for what appears to be a chronic process. However, in acute
inflammatory arthritis, early radiography is rarely helpful in establishing a
diagnosis and may only reveal soft tissue swelling or juxtaarticular demineralization.
 ●​ Ultrasonography is useful in the detection of soft tissue abnormalities (tendinitis,
tenosynovitis, enthesitis, bursitis), crystal deposition, and entrapment neuropathies.
Wider use, lower cost, better technology, and enhanced site-specific transducers now
allow for wider use and 2853 diagnostic specificity, especially when considering
synovial (Baker’s) cysts, rotator cuff tears, tendinitis and tendon injury, and crystal
deposition on cartilage.
●​ Use of power Doppler allows for early detection of synovitis and bony erosions.
●​ MRI has largely replaced scintigraphy in diagnosing osseous infection, neoplasia,
inflammation, increased blood flow, bone remodeling, heterotopic bone formation, or
avascular necrosis.
●​ Computed tomography (CT) provides detailed visualization of the axial skeleton.
Articulations previously considered difficult to visualize by radiography (e.g.,
zygapophyseal, sacroiliac, sternoclavicular, hip joints) can be evaluated using CT.
●​ CT has been demonstrated to be useful in the diagnosis of low back pain (e.g.,
spinal stenosis vs herniated disk), sacroiliitis, osteoid osteoma, and stress
fractures.
●​ Helical or spiral CT (with or without contrast angiography) is a novel technique
that is rapid, cost effective, and sensitive in diagnosing pulmonary embolism or
obscure fractures, often in the setting of initially equivocal findings.
●​ MRI has become the preferred technique when evaluating complex
musculoskeletal disorders.
●​ MRI can image fascia, vessels, nerve, muscle, cartilage, ligaments, tendons,
pannus, synovial effusions, and bone marrow.

Chapter 372: Gout and Other Crystal-Associated Arthropathies

●​ Polarized light microscopy alone can identify most typical crystals, except for apatite.
●​ Aspiration and analysis of effusions are also important to assess the possibility of
infection.
●​ Crystal shedding from inert deposits triggered by certain factors is considered a key
process behind episodic manifestation of acute inflammation (gout or pseudogout)
involving activation of inflammasome and potent proinflammatory cytokines such as
interleukin (IL) 1β.
●​ Gout is a hyperuricemic metabolic condition, typically manifested by episodic
inflammatory arthritis with disabling pain, among middle-aged to elderly men and
postmenopausal women
●​ When someone has high levels of uric acid in their blood for a long time (a
condition called chronic hyperuricemia), the body can't get rid of it all. As a result,
there’s too much uric acid in the blood, which can turn into tiny crystals. These
crystals, called monosodium urate (MSU), can build up in joints and other tissues,
causing pain and swelling. This is what happens in gout, a type of arthritis.
●​ Risk factors:
○​ Obesity and insulin resistance syndrome,
○​ Metabolic factors (diet, alcohol)
○​ Genes
○​ Medications (diuretics, low-dose aspirin)
●​ Uricase is an enzyme present in most other mammals that breaks down uric acid
(urate) into allantoin, a compound that is highly soluble in water and easily excreted
 in urine. Without uricase, humans cannot efficiently break down uric acid, leading to a
higher baseline level of urate in the blood. This condition is called hyperuricemia.
●​ Hyperuricemia and gout are associated with multiple cardiovascular-metabolic
comorbidities, including obesity, hypertension, type 2 diabetes, myocardial infarction,
stroke, and urate nephrolithiasis modifiable risk factors include obesity, Western diet,
alcohol, sedentary lifestyle, and diuretics
●​ The metatarsophalangeal joint of the first toe is involved in 70–90% of cases
(podagra), followed by tarsal joints, ankles, and knees. Finger, wrist, and elbow
joints can also be involved, although more often in elderly patients or in advanced
disease.
●​ The gout flares often begin at night to early morning, The affected joints rapidly
become warm, red, tender, and substantially swollen with a clinical appearance
that often mimics that cellulitis
●​ Women represent only 5–20% of all patients with gout. Most women with gout are
postmenopausal and elderly; tend to have osteoarthritis, hypertension, or mild
renal insufficiency; and usually are receiving diuretics
●​ The presumptive diagnosis ideally should be confirmed by needle aspiration of
involved joints or tophaceous deposits
●​ During acute gout flares, needle-shaped MSU crystals typically are present both
intracellularly and extracellularly. Under compensated polarized light, these crystals
show bright, negative birefringence.
●​ Synovial fluid appears cloudy due to the increased numbers of leukocytes (e.g.,
from 5000–75,000/μL)
●​ Because bacterial infection can coexist with MSU crystals in synovial fluid, joint fluid
is often stained and cultured for potential septic arthritis
●​ Long-term high uric acid levels are needed for gout to develop. Over time, urate
crystals form and settle in the joints, causing inflammation and pain.
●​ During a gout attack, the body releases certain inflammatory substances (like IL-6),
which can increase the removal of uric acid through the urine. This can lower uric
acid levels in the blood temporarily, sometimes by as much as 2 mg/dL.
●​ Serum creatinine, liver function tests, hemoglobin, white blood cell (WBC) count,
hemoglobin A1c, and serum lipids are usually obtained at baseline to assess
possible risk factor and comorbidities
●​ In plain radiography, cystic changes, well-defined erosions with sclerotic margins
(often with overhanging bony edges), and soft tissue masses are characteristic
features of advanced gout with tophaceous deposits. Musculoskeletal ultrasound can
timely aid earlier diagnosis by revealing a double-contour sign overlying the articular
cartilage (signifying MSU deposition).
●​ the mainstay of acute gout care is the administration of anti-inflammatory drugs such
as nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and glucocorticoids
●​ , indomethacin, 25–50 mg tid; naproxen, 500 mg bid; ibuprofen, 800 mg tid; and
celecoxib, 800 mg followed by 400 mg 12 h later, then 400 mg bid)
●​ The goal is to keep uric acid below 300–360 μmol/L (5.0–6.0 mg/dL) to prevent
future gout attacks and dissolve tophi.
●​ Urate-lowering drugs are recommended if lifestyle changes (like losing weight, eating
healthy, drinking less alcohol, reducing sugary foods and drinks, and avoiding certain
diuretics) don’t work.
●​ The decision depends on:
 ○​ The number of gout attacks (more than two a year often justifies medication).
○​ How severe and long the attacks are.
○​ How gout affects daily life.
○​ The patient’s willingness to stick with lifelong treatment.
●​ First-Line Treatment: Allopurinol
1.​ How It Works:
○​ Allopurinol is a xanthine oxidase inhibitor that lowers uric acid levels.
2.​ Dosing:
○​ Start at a low dose (e.g., 100 mg daily).
○​ Gradually increase up to 800 mg daily to achieve a uric acid level below 5–6
mg/dL.
○​ In patients with chronic kidney disease (CKD), start even lower (e.g., 50 mg
daily) and increase slowly.
3.​ Why Start Low:
○​ Reduces risks of:
■​ Severe skin reactions (SCARs, such as Stevens-Johnson syndrome).
■​ Gout flares caused by rapid uric acid drops.
4.​ Screening for Risks:
○​ Patients with the HLA-B*5801 gene (common in Southeast Asians, Pacific
Islanders, and black populations) are at higher risk for SCARs.
○​ These patients should use alternative drugs like febuxostat, which doesn’t
require HLA-B*5801 testing or dose adjustment for kidney disease.

Second-Line Treatments: Uricosuric Agents

1.​ Probenecid:
○​ Helps kidneys remove uric acid.
○​ Works best in patients with good kidney function (not effective if creatinine >2
mg/dL).
○​ Start at 250 mg twice daily and increase as needed (up to 3 g daily).
2.​ Other Options:
○​ Benzbromarone (not available in the U.S.) is effective for patients with CKD.
○​ Drugs like losartan, amlodipine, fenofibrate, and SGLT2 inhibitors (used for
other conditions) also lower uric acid.
3.​ Pegloticase:
○​ A specialized drug for patients who cannot tolerate or fail other treatments.

Key Points About Starting Urate-Lowering Therapy

1.​ Avoid Starting During a Gout Flare:

○​ Lowering uric acid too quickly during an attack can worsen symptoms.
2.​ When to Start:
○​ Begin after a flare resolves or during its recovery phase.
○​ Use anti-inflammatory drugs (e.g., colchicine 0.6 mg daily or naproxen 250
mg twice daily) alongside to prevent flares triggered by urate-lowering
therapy.
3.​ Duration of Anti-Inflammatory Prophylaxis:
○​ Continue until:
 ■​ Uric acid levels are normal.
■​ No gout attacks for 3–6 months.
■​ Tophi have disappeared.

Chapter 371: Osteoarthritis

●​ Most common type of arthritis. Age is the most important risk factor as well as
obesity
●​ Osteoarthritis is a condition where the joint gradually fails, involving changes in all
joint structures. The hallmark of OA is the loss of hyaline cartilage, which starts in
specific areas and is uneven at first. Other key changes include:
●​ Thickening and hardening of the bone under the cartilage (subchondral
bone).
●​ Growth of bone spurs (osteophytes) at the joint edges.
●​ Stretching of the joint capsule.
●​ Varying levels of joint inflammation (synovitis).
●​ Weakening of muscles around the joint.
●​ Synovial fluid reduces friction between articulating cartilage surfaces, thereby serving
as a protector against friction-induced cartilage wear. This lubrication function
depends on hyaluronic acid and on lubricin, a mucinous glycoprotein secreted by
synovial fibroblasts whose concentration diminishes after joint injury and in the face
of synovial inflammation.
●​ In healthy cartilage, type 2 collagen traps aggrecan molecules within its network. The
negative charges on aggrecan repel each other, creating stiffness that helps cartilage
resist compression.
●​ Osteoarthritis (OA) cartilage gradually loses a key protein called aggrecan, causing
the collagen structure to loosen and type 2 collagen to be lost. These changes make
the cartilage weaker and less able to resist pressure.
●​ Joint vulnerability and joint loading are the two major factors contributing to the
development of OA
●​ In younger people, joint movement stimulates cartilage to repair itself, but in older
adults, cartilage doesn't respond as well. This leads to thinner cartilage, which is
more prone to damage. Additionally, muscles and ligaments weaken with age, and
nerve responses slow down, making joints less protected. Women, especially those
over 60, are at a higher risk of developing OA, possibly due to hormone changes
during menopause.
●​ Two types of limb malalignment in the frontal plane: varus, in which the stress is
placed across the medial compartment of the knee joint, and valgus, which places
excess stress across the lateral compartment of the knee.
●​ Pathology:
○​ Osteoarthritis (OA) affects many joint structures over time. Initially, the
cartilage surface becomes rough, and as the disease progresses, deeper
erosions develop, eventually reaching the underlying bone. Even though OA
causes patchy cartilage loss, it tends to worsen over time, leading to more
widespread cartilage damage.
○​ After cartilage is injured, chondrocytes (cartilage cells) multiply and form
clusters. These clusters are active but mostly break down proteoglycans
(proteins that help cartilage retain water), which weakens the cartilage. As
 this process continues, cartilage loses its ability to bounce back after pressure
and becomes more vulnerable to further damage. Chondrocytes at the base
of the cartilage die off, contributing to cartilage loss.
○​ The bone beneath the cartilage also changes. Stimulated by growth factors
and cytokines, bone cells (osteoclasts and osteoblasts) become active. Bone
thickens beneath the cartilage, even before it breaks down, due to healing
from microfractures. In advanced OA, small areas of bone death may occur,
often from injury to the bone's blood supply.
○​ Osteophytes, or bone spurs, form at the joint edges where cartilage is lost.
These begin as new cartilage growth and later turn to bone as blood vessels
invade. Osteophytes are a key feature seen on X-rays in OA.
○​ The synovium (lining of the joint) also changes in OA. Normally, it produces
fluids to reduce joint friction, but in OA, it can become swollen and inflamed.
This causes more damage by activating chondrocytes to break down the
cartilage. The joint capsule, which holds the joint together, also becomes
stretched and fibrotic.
●​ Healthy cartilage doesn't have nerves, so its loss alone doesn’t cause pain in
osteoarthritis (OA). Pain in OA is usually linked to other structures in the joint that are
innervated, such as the synovium, ligaments, joint capsule, muscles, and bone.
These structures aren’t visible on X-rays, and the severity of X-ray changes doesn’t
always match pain severity. However, in advanced OA, as cartilage breaks down and
blood vessels invade the area, pain can develop.
●​ MRI studies have shown that in painful osteoarthritic knees, sources of pain often
include synovial inflammation, joint effusions (fluid buildup), and bone marrow
edema. Many OA joints experience some synovitis (synovial inflammation), which is
linked to pain severity. Fluid buildup in the joint can stretch the capsule and stimulate
pain receptors. OA also causes increased pressure on bones, leading to bone
marrow edema seen on MRI, which indicates microcracks and scar tissue that can
trigger pain. Other pain sources near the joint, like bursitis or iliotibial band syndrome,
are also common.
●​ In OA, pain typically occurs during weight-bearing activities, but it can become
constant and present even at rest as the disease progresses. This suggests that
changes in nervous system signaling also contribute to pain. In OA, peripheral nerve
receptors may become overly responsive (peripheral sensitization), and there may be
increased pain signaling in the brain (central sensitization). Some people are
genetically more likely to develop this heightened pain response, and these changes
are linked to more severe pain and a higher risk of chronic pain. Additionally, obesity
can worsen joint pain, likely due to inflammatory substances produced by fat cells
(adipokines).
●​ NSAIDs are the most popular drugs to treat osteoarthritic pain. They can be
administered either topically or orally. In clinical trials, oral NSAIDs produce ~30%
greater improvement in pain
●​ The American Heart Association has identified COX-2 inhibitors as putting patients at
high risk, although low doses of celecoxib (≤200 mg/d) are not associated with an
elevation of risk. The only conventional NSAIDs that appear safe from a
cardiovascular perspective are naproxen and low-dose celecoxib, but they do have
GI toxicity
Chapter 130: Septic Arthritis

●​ Since acute bacterial infection can destroy articular cartilage rapidly, all inflamed
joints must be evaluated without delay to exclude noninfectious processes and
determine appropriate antimicrobial therapy and drainage procedures.
●​ Normal synovial fluid contains <180 cells (predominantly mononuclear cells) per
microliter. Synovial cell counts averaging 100,000/μL (range, 25,000–250,000/μL),
with >90% neutrophils, are characteristic of acute bacterial infections