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Flashcards in (I) General Concepts Deck (80):

ACR choosing wisely

1. Do not test antinuclear antibody (ANA) subserologies (anti-dsDNA, anti-Sm, anti-RNP, anti-SS-B,
anti-Scl-70) without a positive ANA and clinical suspicion of immune-mediated disease. Anti-SS-A
may be an exception to this recommendation.
2. Do not test for Lyme disease as a cause of musculoskeletal symptoms without an exposure history and
appropriate examination findings.
3. Do not perform an MRI of the peripheral joints to routinely monitor inflammatory arthritis.
4. Do not prescribe biologics for RA before a trial of methotrexate (or other conventional nonbiologic
disease-modifying antirheumatic drugs [DMARDs]).
5. Do not routinely repeat dual-energy X-ray absorptiometry (DXA) scans more often than once every 2 years.


ACR peds choosing wisely

1. Do not order autoantibody panels without a positive ANA and evidence of a rheumatic disease.
2. Do not test for Lyme disease as a cause of musculoskeletal symptoms without an exposure history and
appropriate examination findings.
3. Do not routinely perform surveillance joint radiographs to monitor juvenile idiopathic arthritis (JIA)
disease activity.
4. Do not perform methotrexate toxicity laboratory tests more than every 12 weeks on stable doses.
5. Do not repeat a confirmed positive ANA in patients with established JIA or SLE.


NASS choosing wisely

• Do not order MRI of the spine within the first 6 weeks in patients with nonspecific low back pain in the
absence of red flags (trauma, use of corticosteroids, unexplained weight loss, progressive neurologic signs,
age >50 years or



• Except for anti-dsDNA, do not repeat ANA subserologies in patients with an established connective
tissue disease (CTD) diagnosis.
• Do not perform serial measurements of rheumatoid factor and anti-cyclic citrullinated peptide (CCP) in
patients with documented seropositive RA or serial ANAs in patients with a documented positive ANA
and a CTD diagnosis (e.g., SLE).
• Do not order a human leukocyte antigen (HLA)-B27 unless you suspect an undifferentiated spondyloarthropathy
based on history and examination but have nondiagnostic radiographs.
• Do not check CH50 to follow lupus disease activity.
• Do not order an MRI before ordering plain films in a patient presenting with joint or back pain.
• Do not use intraarticular hyaluronic acid injections for advanced knee OA (i.e., bone on bone).
• Do not treat low bone mass in patients at low risk for fracture (T score > –2.5, no history of fragility
fracture, no steroids, low FRAX).
• Do not order serial yearly plain radiographs in a patient with good clinical (symptoms, examination,
laboratory tests) control of their arthritis unless you are willing to change therapy for minor radiographic
disease progression.


Soft tissue rheumatism.

• Most shoulder pain is periarticular (i.e., a bursitis or tendinitis). Rule out impingement in patients with recurrent
shoulder tendinitis.
• Causes of olecranon or prepatellar bursitis: trauma, infection, gout, rheumatoid arthritis (RA).
• Recalcitrant trochanteric bursitis: rule out leg length discrepancy, hallux rigidus with an abnormal gait,
and lumbar radiculopathy.
• Recalcitrant medial knee pain: rule out anserine bursitis.
• Recalcitrant patellofemoral syndrome: rule out pes planus/hypermobility causing patellar maltracking.
• Due to risk of rupture, do not inject corticosteroids for therapy of Achilles tendinitis/enthesitis.
Use iontophoresis.


3. Back pain.

• Patients with significant low back pain cannot do a sit-up.
• Most back pain is nonsurgical.
• Magnetic resonance imaging (MRI)/computed tomography (CT) scans of lumbar spine are abnormal in
30% of patients with no symptoms. Do not attribute a patient’s symptoms to an abnormal radiograph.
• Spinal Phalen’s test is useful to diagnose spinal stenosis. Patients with spinal stenosis have more pain
walking uphill due to spinal extension making the spinal canal smaller. Straight leg raise test and
electromyography/nerve conduction velocities (EMG/NCV) are often normal or nonspecific.



5. Laboratory tests
• Laboratory tests should be used to confirm your clinical diagnosis not make it.
• All patients with a positive rheumatoid factor do not have RA, and all patients with a positive antinuclear
antibody do not have systemic lupus erythematosus (SLE).
• Low complement (C3, C4) levels in a patient with systemic symptoms suggest an immune complexmediated
disease and narrows your diagnosis: SLE, cryoglobulinemia (types II and III), urticarial vasculitis
(HepB and C1q autoantibodies), subacute bacterial endocarditis (SBE), poststreptococcal or membranoproliferative
• An undetectable (not just low) CH50 activity may indicate a disease associated with a hereditary complement
component deficiency: autoimmune (C1, C4, C2), infection (C3), Neisseria infection (C5 to C8).
• Separating iron deficiency from anemia of chronic disease is best done by measuring the ferritin level. In a
patient with elevated C-reactive protein, a ferritin level of >100 ng/mL rules out iron deficiency.


chronic inflammatory monoarticular arthritis of >8 weeks’ duration

synovial biopsy to rule out
an unusual cause (indolent infection, etc.).


Feel both knees with the back of your hand for temperature differences and compare it to the
lower extremity.

The knee should be cooler than the skin over the tibia. If the knee is warmer then there is ongoing knee



• Cracking knuckles does not cause OA.
• Patients with arthritis can predict the weather due to changes in barometric pressure as weather fronts
move in and out of an area.
• Obesity is the major modifiable risk factor for OA.
• The joints typically involved in primary OA are: distal interphalangeal joints (DIPs) (Heberden’s nodes),
proximal interphalangeal joints (PIPs) (Bouchard’s nodes), first carpometacarpal (CMC), hips, knees, first
metatarsophalangeal joint (MTP), the cervical and lumbosacral spine.
• Patients with OA affecting joints not normally affected by primary OA (i.e., metacarpophalangeals,
wrists, elbows, shoulder, ankles) need to be evaluated for secondary causes of OA (i.e., calcium pyrophosphate
disease [CPPD], metabolic diseases, others).
• Erosive OA is an inflammatory subset of OA (10% of patients) primarily affecting the hands (DIPs, PIPs,
first CMC) and causing the “seagull” sign on radiographs. It is more disabling than primary OA


Knee and hip osteoarthritis

• Over 50% of patients over 65 years have radiographic knee OA but only 25% have symptoms. Do not rely
on the radiograph to make the diagnosis of the cause of knee pain.
• Recurrent, large, noninflammatory knee effusions are frequently due to an internal derangement
(e.g., meniscal tear).
• Nonsteroidal antiinflammatory drugs (NSAIDs) are better than acetaminophen if a patient has an
effusion, which indicates more inflammation (wet OA).
• Intraarticular corticosteroids also work and are cheaper than viscosupplementation (hyaluronic acid),
especially in patients with a knee effusion.
• Drain any knee effusion before giving viscosupplementation or corticosteroids.
• Incidental and asymptomatic meniscal tears are common (>20%) in patients with knee OA. Meniscal
repair and/or arthroscopic debridement and washout are not helpful unless there are signs of locking.
• Femoroacetabular impingement is a common cause of hip pain in young patients who develop early OA.


Seronegative RA is a difficult diagnosis in patients without erosions on radiographs

Always consider CPPD in these patients.


Treat to target

Early therapy with the goal of low disease activity is essential to RA (and psoriatic arthritis) therapy.
• It does not matter which disease activity measure you use (e.g., Clinical Disease Activity Index [CDAI],
Routine Assessment of Patient Index Data 3 [RAPID3], etc.), just pick one and use it to document if your
therapy is achieving low disease activity or remission.


Systemic sclerosis.

• New onset hypertension and schistocytes on blood smear in a diffuse systemic sclerosis patient heralds
the onset of scleroderma renal crisis, especially in a patient who is anti-RNA polymerase III positive.
Angiotensin-converting enzyme (ACE) inhibitors work better than angiotensin receptor blockers (ARBs).
• A %forced vital capacity (FVC)/%DLCO ratio of >1.6 predicts pulmonary hypertension.
• An FVC <70% and a high resolution CT scan of the lung showing >20% fibrosis predicts progression of
scleroderma-related interstitial lung disease.


36. Statins can cause myalgias without an elevated CPK, myalgias with an elevated CPK, and a
necrotizing myopathy with anti-HMGCoA reductase antibodies.

• Myalgias can be improved with coenzyme Q.
• Hydrophilic statins (pravachol, rosuvastatin) cause less myopathy than lipophilic statins (simvastatin, etc.).


Hydrophilic statins

pravachol, rosuvastatin


lipophilic statins

simvastatin, etc


APL labs:

lupus anticoagulant,
anticardiolipin antibodies,
anti-β2glycoprotein I antibodies


All patients with significantly positive aPLabs should have prophylactic anticoagulation if they
undergo a surgical procedure and/or following pregnancy delivery even if they have never had
a clot.

Surgical release of tissue factor is the second hit in the “two hit” hypothesis for clots in aPLab positive patients.
• Always have placenta assessed (clinically and/or pathologically) for evidence of damage in patients with
aPLab regardless of pregnancy outcome. If placental damage is present, the patient needs anticoagulation
during any future pregnancy.


Still’s disease should be considered in any patient with a quotidian fever (decreases to normal
or below once a day), rash, and joint pain.

A ferritin level >1000 ng/mL supports the diagnosis.


(PMR) patients should respond completely to 20 mg daily of
and normalize their erythrocyte sedimentation rate (ESR) within a month

The presence of fever or failure to respond to prednisone clinically and serologically suggests giant cell
arteritis or another diagnosis such as lymphoma.


After ruling out infection and malignancy, consider vasculitis in any patient with multisystem
disease who has an ESR >100 mm/hour and a C-reactive protein >10 times the upper limit of

• The primary vasculitides (i.e., not due to another disease) are not associated with positive serologies
(ANA, rheumatoid factor (RF), low complements), neutropenia, or thrombocytopenia. If one of these are
present, consider another diagnosis.


Listen for subclavian bruits in all patients suspected of having GCA as it may be their only

Large vessel involvement puts them at increased (17×) risk for aortic dissections and aneurysms.


Do not delay starting prednisone in a patient suspected to have GCA

It will not affect the temporal artery biopsy results for at least a week.


When the suspected diagnosis is primary vasculitis of the central nervous system (CNS), it
probably is incorrect

Rule out other diseases with a brain biopsy


GPA or Wegener’s) should be considered in any adult who
develops otitis media.

GPA predominantly affects the upper and lower respiratory tracts and kidneys and is associated with
proteinase 3-antineutrophil cytoplasmic antibody (PR3-ANCA).


Skin biopsy in Henoch–Schonlein purpura (HSP) shows leukocytoclastic vasculitis with IgA
deposition in vessel walls on direct immunofluorescence

HSP is the most common small vessel vasculitis in childhood.


Most patients with mixed cryoglobulinemia will present with palpable purpura, arthralgia, and
weakness/myalgias (Meltzer’s triad).

A positive rheumatoid factor and low C4 (“poor man’s cryo”) level supports the diagnosis before the
screen has returned.


Meltzer’s triad

palpable purpura, arthralgia, and

(ptx with mixed cryo)


Even though HLA-B27 increases a person’s risk of developing a spondyloarthropathy 50 times,
only 1 out of every 50 (2%) HLA-B27 positive individuals without a family history will develop
ankylosing spondylitis during their lifetime

If the person has a family history the risk increases to one in five (20%).
• Nearly 50% of HLA-B27 positive patients with recurrent unilateral anterior uveitis have or will develop
an underlying spondyloarthropathy


A patient less than 40 years old with three out of four of the following has a high likelihood of
having inflammatory back pain:

(1) morning stiffness of at least 30 minutes; (2) improvement of
back pain with exercise but not rest;
(3) awakening because of back pain and stiffness during
second half of the night only;
(4) alternating buttock pain.


60. Inflammatory arthritis is most likely to occur in Crohn’s disease patients with extensive colonic

These patients may present with prominent arthritis but few gastrointestinal symptoms


62. Reactive arthritis is a sterile, inflammatory arthritis that is typically preceded by a gastrointestinal
or genitourinary infection occurring 1 to 4 weeks previously.

The arthritis can improve with prolonged antibiotics only if it is due to chlamydia


Inflammation of the DIP joints and finger dactylitis are highly characteristic of psoriatic arthritis.

• Differential diagnosis of DIP arthritis: psoraitic, OA, multicentric reticulohistiocytosis, and primary biliary
cirrhosis. In a patient with OA who gets inflamed DIP–R/O gout.


• Differential diagnosis of DIP arthritis:

multicentric reticulohistiocytosis,
primary biliary cirrhosis.
In a patient with OA who gets inflamed DIP–R/O gout.


64. Any patient with fever, arthralgias, and tenosynovitis should be evaluated for a disseminated
gonococcal infection (DGI).

The majority of females develop DGI within 1 week of onset of menses.


66. The chest radiograph is normal in 50% of patients who have tuberculous septic arthritis, which
most commonly presents as chronic inflammatory monoarticular arthritis involving the knee

diagnosis of tuberculous arthritis is best confirmed by synovial biopsy and culture because synovial fluid
acid fast bacilli (AFB) stain is positive in only 20%


68. Hepatitis C is the most common cause of cryoglobulinemia

Overall, 50% of hepatitis C patients have cryoglobulins, but only 5% develop cryoglobulinemic vasculitis


69. Gout is the most common cause of inflammatory arthritis in men over age 40 years

It should not occur in premenopausal females


Uric acid is less soluble in the cold.

Consequently, gout occurs in the cooler distal joints and not in the spine or joints near the spine. If you do
not get any fluid when you tap the first MTP joint, blow out the end of the needle onto a slide and examine
the blood speck for uric acid crystals.


CPPD disease is a disease of the elderly with onset and increasing frequency after the age of
55 years.

Only patients with familial mutations or metabolic abnormalities (e.g., hemochromatosis, hypophosphatasia,
etc.) get CPPD before age 55 years.


CPPD before age 55 years.

familial mutations or metabolic abnormalities (e.g., hemochromatosis, hypophosphatasia,


73. CPPD should be considered in any elderly patient with a seronegative inflammatory or degenerative
arthritis involving the MCPs, wrists, and shoulders.

CPPD can mimic seronegative RA, PMR, and OA involving atypical joints.



major risk factors for fragility fractures are low bone mass, advancing age, previous fragility fractures,
corticosteroid use, and the propensity to fall. The best predictor of a future fall is a fall within the previous
6 months. Screen the patient with the “get up and go” test.
• Each decrease of –1.0 T-score on DXA correlates with a 12% loss of bone. At a T-score of –2.5, the patient
has lost 30% of their bone mass, which is when osteopenia can reliably be detected on plain radiographs.
• Rule out vitamin D insufficiency in all patients with a low bone mass. Consider celiac disease in any Caucasian
patient with a low vitamin D level even if they do not have diarrhea.
• Pharmacological therapy should be initiated in patients who have had a fragility fracture, a bone
mineral density T-score ≤–2.5, or a FRAX-derived 10-year risk of ≥3% for hip fractures and ≥20%
for other major osteoporosis fractures.
• Vertebroplasty and kyphoplasty are most effective when done within 6 months of onset of a severely
symptomatic vertebral compression fracture and in patients with vertebral edema pattern on MRI.
• Stress fracture should be considered when new onset lower extremity bone pain (tibia, fibula, metatarsal)
is increased by the vibration of a tuning fork (128 Hz) (sensitivity and specificity >80%).


80. Musculoskeletal manifestations can be the presenting manifestation in up to 33% of patients
with hemochromatosis.

Consider in any Caucasian male under age 40 years with “seronegative RA,” degenerative changes of the
second and third MCP joints, and/or hypogonadotrophic hypogonadism with low bone mass


Fibromyalgia is a chronic noninflammatory, nonautoimmune central afferent processing disorder
leading to a diffuse pain syndrome as well as other symptoms.

Narcotics and corticosteroids should not be used for treatment.


Obstructive sleep apnea (ask if they snore even if they are nonobese), hypothyroidism, and
vitamin D deficiency (25 OH vitamin D <5 ng/mL) should be ruled out in all fibromyalgia patients
regardless of body size.

In patients with severe and refractory symptoms, ask about physical and/or sexual abuse.


Growing pains do not occur during the daytime.

A limp in a child is pathologic until proven otherwise.


Consider Kawasaki disease in any child under age 5 years presenting with prolonged high
fevers and conjunctivitis.

Intravenous immunoglobulin (IVIG) within 10 days of disease onset is the treatment of choice


Muscle cramps, pain, or myoglobinuria brought on by exercise suggests a metabolic myopathy.

Muscle symptoms with short bursts of high-intensity exercise and the second wind phenomenon are characteristic
of a glycogen storage disease. McArdle’s disease and acid maltase deficiency are most common.
• Muscle symptoms with prolonged low-intensity exercise and/or prolonged fasting suggests a defect in fatty
acid oxidation. Carnitine palmitoyltransferase II (CPT II) deficiency is most common.
• The most common metabolic myopathies associated with myoglobinuria are CPT II deficiency and
McArdle’s disease.
• The most common myopathies that are confused with polymyositis are acid maltase deficiency and
limb-girdle muscular dystrophy.
• Children presenting with a muscle disease without rash almost always have a metabolic or genetic myopathy
and not primary polymyositis.


of a glycogen storage disease

Muscle symptoms with short bursts of high-intensity exercise and the second wind phenomenon
McArdle’s disease and acid maltase deficiency are most common.


acid oxidation

Muscle symptoms with prolonged low-intensity exercise and/or prolonged fasting

Carnitine palmitoyltransferase II (CPT II) deficiency is most common


A patient with acute, inflammatory arthritis involving bilateral ankles should always be evaluated
for sarcoidosis.

Erythema nodosum typically affects the anterior aspect of lower legs and never ulcerates. Subcutaneous
nodules on the posterior aspect of calf or any that ulcerate should raise concern for vasculitis or infection.


Autoinflammatory syndromes are characterized by episodes of fever, rash, arthritis, peritonitis,
eye inflammation, lack of autoantibodies, and elevated acute phase reactants in various combinations
that normalize between flares.

The duration of flares differs between diseases:

Inhibition of
interleukin-1 is the treatment of choice.


• Always rule out a medication as the cause of musculoskeletal symptoms.

— pANCA vasculitis:
cocaine (levamisole).

— Achilles tendinitis and rupture.

— Drug-induced lupus:
anti-TNF agents,


• All NSAIDs should be used with caution (if at all) in patients with:

underlying renal or cardiovascular


All NSAIDs can cause:

photosensitivity. Piroxicam is most likely to cause small bowel webs

AND can interfere with conception


AVN from corticosteroids is the most common reason a physician is sued for a medication
adverse effect.
Record in the chart that you counseled the patient on the following risk:

for each 20mg of prednisone taken for over a month, the risk of AVN is 5% (e.g., a 60-mg dose for a month confers
a risk of 15% for AVN).
Patients with SLE, those that have aPLabs, and those that rapidly become cushingoid
are most at risk.


Methotrexate is the most effective anchor drug for all combination therapies. An increase of the:

mean corpuscular volume by 5 fL correlates with a good methotrexate effect.


Azathioprine is better used for maintenance of remission than for induction of remission. It should NOT be used in patients:

on allopurinol,
ampicillin (rash).

It can cause resistance to coumadin


HLA-B*5801 gene.

Allopurinol hypersensitivity syndrome is more common in Asian patients with kidney disease


Do not use colchicine:

Do not use in patients on clarithromycin who have renal

in ptx who are on
-cyclosporine/tacrolimus (causes myopathy),
-antifungals(e.g., ketoconazole),
-HIV protease inhibitors.

in patients on clarithromycin who have renal


check what before Pegloticase ??

G6PD status


Stop ACE inhibitors in patients with:

chronic regional pain syndrome


stop calcium channel blockers in:

patients with erythromelalgia.


Voriconazole can cause:

nodular hypertrophic osteoarthropathy.


A properly fitted cane

used in the contralateral hand can unweight a diseased hip by 25% to 40%.


Up to heaven, down to hell

When a patient has a painful lower extremity joint, tell him/her to use the
good leg to step up a stair (up to heaven) and use the painful leg to step down a stair (down to hell).


two indications for joint replacement surgery

(1) pain unresponsive to medical therapy and
(2) loss of joint function. Therefore, inability to walk more than one block, stand longer than 20 to 30
minutes due to pain, or walk up stairs are indications for total hip and total knee replacement


Lumbar spine surgery is most successful in patients

Lumbar spine surgery is most successful in patients with radicular symptoms confirmed by clinical examination,
EMG, and MRI findings who have failed conservative therapy. Success of surgery decreases by
33% for each one that does not confirm the other.


1. what is the most abundant protein in the body?

2.what is the major cartilage of diarthroidial joints?.

3. selective transudate of plasma?.

4. The most critical signaling pathway is a for osteoblast activation and bone mass regulation?

5. The most critical signaling pathway for osteoclast differentiation/activation and bone remodeling?

1. Collagen -Mutations of collagen types I and II can lead to musculoskeletal

2. Hyaline cartilage -It is avascular and aneural and composed mainly of type II
collagen and aggrecan.

3.Synovial fluid. It is made viscous by the secretion of hyaluronic acid by synoviocytes
into the synovial fluid.

4. Wnt/β-catenin



macromolecular “building blocks” of connective tissue.



How many types of collagen are there?

The collagens are the most abundant body proteins and account for 20% to 30% of the total body mass.

There are at least 29 different types of collagen.


definitive structural feature of all collagen molecules

triple helix.
three polypeptide chains (α-chains) twisted around each other into a right-handed major helix


major collagen classes and the types of collagen included in each class

Fibril-forming (interstitial)
Fibril-associated collagens with interrupted triple helices (FACIT

Collagens with specialized structures or functions:
Basement membrane collagen—type IV.
Nonfibrillar collagens—types VI, VII, XIII, XV, XVII, XVIII.
Short-chain collagens—types VIII, X.


How are the fibril-forming (interstitial) collagens synthesized?

Page 17

30 distinct genes that encode the various collagen chains. In adults, collagen gene expression
is subject to positive regulation (TGF-β) and negative regulation (IFN-γ and TNF-α).


Which enzymes are important in collagen degradation? How are they regulated?

important collagenolytic enzymes responsible for cleavage of type I collagen belong to the matrix
metalloproteinase (MMP) group. The collagenases are secreted in latent form and, when activated, cleave
the collagen molecule at a single specific site following a glycine residue located about three quarters of the
distance from the amino terminal end (between residues 775 and 776 of the α1[I] chain). Gelatinases and
stromelysins then degrade the unfolded fragments.Both α-macroglobulin and tissue inhibitors of metalloproteases (TIMP 1 to 4) are capable of inhibiting collagenase
activity. It is likely that other collagen types have type-specific collagenases capable of degrading them.
Serum procollagen peptides, urinary hydroxyproline, urinary pyridinoline/deoxypyridinoline cross-links, and
serum C-telopeptides and urinary N-telopeptides are used as measures of collagen turnover


What is elastin, and where is it located?

Elastin fibers are connective tissues that can stretch when hydrated and return to their original length after
being stretched. They are synthesized by smooth muscle cells and less so by fibroblasts. They comprise a significant
portion of the dry weight of ligaments (up to 70% to 80%), lungs, larger blood vessels such as aorta (30%
to 60%), and skin (2% to 5%). Elastin is a polymer of tropoelastin monomers, which contain 850 amino acids,
predominantly valine, proline, glycine, and alanine. When tropoelastin molecules associate to form a fiber,
lysine residues cross-link by forming desmosine and isodesmosine, which are unique to elastin. Mutations in
the elastin gene can cause cutis laxa and supravalvular aortic stenosis. Elastases, which are serine proteases,
are capable of degrading elastase. Elastases are located in tissues, macrophages, leukocytes, and platelets. Such
elastases may contribute to blood vessel wall damage and aneurysm formation in the vasculitides. Urinary
desmosine levels are used as a measure of elastin degradation


What are fibrillin-1 and fibrillin-2?

These fibrillins are large glycoproteins coded for by a gene located on chromosome 15 (fibrillin-1) and chromosome
5 (fibrillin-2). They function as part of the microfibrillar proteins, which are associated with an elastin
core. Fibrillin can also be found as isolated bundles of microfibrils in skin, blood vessels, and several other
tissues. Abnormalities in fibrillin-1 are thought to cause Marfan’s syndrome (see also Chapter 55), whereas
abnormalities in fibrillin-2 cause contractural arachnodactyly.


List NB adhessins (cell-binding glycoproteins) that can be present in intracellular
matrices and basement membranes.

Fibronectin—connective tissue.
Laminin—basement membrane.
These glycoproteins have specific adhesive and other important properties. They bind cells by attaching to
integrins on cells. Some have the classical arginine–glycine–aspartic acid (RGD) cell-binding sequence.