Rheumatology (Week 2--Weinreb) Flashcards
Autoimmunity
Tolerance (normal mechanisms that prevent immune activity against self-antigens) is lost
Abnormal response by immune system against individuals own tissues resulting in tissue damage
Due to genetic, environmental and immune/cellular factors
Innate immune system produces which key inflammatory cytokines?
TNF
IFN (interferon)
IL-1beta
Does this by neutrophils and APCs recognizing PAMPs
Pathologic complement activation
Mechanism for autoimmunity
Antigen-antibody (immune) complexes deposited on tissues then bound to complement and Fc receptors –> immune dysregulation and complement activation
Results in localized tissue injury
Antigen presenting cells (APCs)
Process foreign antigens for presentation to immune cells as part of adaptive immune system
Present self-antigens during development to generate immune tolerance
MHC/HLA
HLA antigens expressed on cell surface (MHC I on all cells and MHC II on immune cells) and function to present antigens to immune system as peptides that were processed intracellularly
T and B cell receptors recognize these and activate an immune response
HLA genes
Highly polymorphic (many alleles for each gene encoding different HLA chain)
Lots of genetic diversity in HLA at the population level
Peptide, MHC, type of T cell
CD4 helper T cell = MHC II = intracellular organisms and cellular proteins
CD8 cytotoxic T cell = MHC I = extracellular organisms and antigens
T helper cells
Activate specific B cells through specific T cell receptor and MHC II/peptide antigen binding
B cells
Produce antibody
Contribute to T cell activation via specific MHC II/peptide antigen and T cell receptor interaction
Cytokines
Dysregulation of cytokines can contribute to autoimmunity
TNF-alpha
IL-1alpha
IL-1beta
IL-17A
IL-17F
Remember these because we have drugs to interfere with them!
Tolerance
To prevent a response to self antigens (prevent autoimmunity)
Double signaling/costimulation, regulatory T cells, regulatory B cells, clearance of self-antigens (apoptosis)
Also, see “mechanisms of tolerance”
Two signal immune cell activation
Two signals required for B cell and T cell activation to ensure only activation when threat by foreign antigen
Foreign antigen activates innate immune system to produce cytokines which cause increased costimulatory B7 family (CD80/86) ligand expression and likelihood of second signal (costimulatory) binding
Regulatory T cells
5-10% of CD4 T cells
Downregulate effector T cells with similar specificity
Downregulate autoreactive lymphocytes
Regulatory B cells
Population of B cells found in mice, suggested in humans
Suppresses intestinal inflammation, may be defective in lupus
Apoptosis
Controlled, regulated cell death
Cell and nuclear condensation, membrane bleb, DNA fragmentation, activated capsase, nuclear condensation, crescents, fragmentation
No inflammatory cytokines produced, anti-inflammatory
Mechanisms of tolerance
1) Clonal deletion
2) Anergy (if no second signal)
3) Inhibition/suppression
Factors contributing to tolerance failure
1) Genetic susceptibility genes (innate and adaptive immune systems) can cause: altered cytokine production/response, immune cell function/interactions, apoptosis (leading to secondary necrosis with autoantigen exposure/inflammation)
2) Environmental triggers that affect immune responses: toxins, UV light, infection, alterations in microbiome (dysbiosis)
How does necrosis cause autoimmunity?
Extracellular exposure of autoantigens and a release of DAMPs (danger associated molecular patterns) that can promote an inflammatory response
Working hypothesis for loss of tolerance to self-antigens
Autoimmune predisposing alleles and environmental factors (cross-reactive infectious antigens or exposure of hidden self-antigens) contribute to abnormal apoptosis and altered immune function; this leads to exposure of self intracellular antigens and release of inflammatory cytokines that generate pathologic cellular and autoantibody responses
Subchondral bone
Bone right beneath cartilage and there may be changes there that will help you diagnose different conditions
Pannus
Proliferative synovium which may cause erosions to bone
(inflamed synovium, hypertrophy, kind of like aggressive benign tumor)
Joint space narrowing
Decrease in distance between articulating bones due to loss of cartilage
Erosions
Areas of bone loss within or around a joint
(can be caused by crystals)
Subluxation
Partial dislocation of a joint
Arthritis vs. arthralgia
Arthritis: symptoms due to abnormalities in structure and/or inflammation directly involving the structures within the joint capsule
Arthralgia: pain involving a joint not associated with any obvious joint abnormality
Periarthritis
Symptoms due to abnormalities in structure and/or function of the structures around a joint (tendons, bursae, nerves)
Synovitis
Inflammation and proliferation of the tissue layer lining the inside of a joint (consists of synovial lining cells and underlying connective tissue)
Tenosynovitis
Inflammation and proliferation of the tissue layer lining the inside of a tendon sheath
(joints won’t be painful but around tendon will be)
Enthesitis
Inflammation of the sites of tendon or ligament insertion (entheses) into bone
Arthroscopy
Imaging used to look in a joint
What can you see on an X-ray regarding arthritis?
Periarticular osteopenia (bone loss around joint)
Subluxation
Joint space narrowing
Erosion
Additive sequence of involvement
Involvement of a joint or joints followed by an increasing number of affected joints
More typical of chronic polyarticular types of arthritis (rheumatoid arthritis)
Migratory sequence of involvement
Involvement of one joint, followed by resolution then shortly after get involvement of another joint (arthritis “jumps” from joint to joint over hours or a few days)
Less common presentation
Intermittent sequence of involvement
Involvement of a joint or joints, followed by resolution then recurrence in same or different joint usually time between is weeks to months
Typical of crystal arthropathies
Extraarticular involvement in arthritis
Eye symptoms: pain, redness, dryness
Mucocutaneous: oral ulcers, rashes, photosensitivity, skin ulcers, skin thickening
Respiratory: cough, shortness of breath, dyspnea on exertion, hemoptysis, pleuritic chest pain
Gastrointestinal: dysphagia, GERD, post-prandial pain, GI bleeding
Lab abnormalities suggesting organ involvement: hematuria, proteinuria, renal failure, hematologic abnormalities, liver function abnormalities, etc
Exam findings suggesting inflammatory articular source of symptoms
Joint swelling
Increased warmth and/or erythema
Joint tenderness to palpation
Joint effusion
Pain on passive range of motion
Monoarticular arthritis
Septic arthritis
Crystal arthropathy
Other monoarthritis
2 classes of polyarticular arthritis
Inflammatory (symmetric/small joint or asymmetric/large joint)
Noninflammatory (degenerative/osteoarthritis)
Inflammatory symmetric/small joint arthritis
Rheumatoid arthritis
SLE
Systemic sclerosis/scleroderma
Sjogren’s syndrome
Other collagen-vascular diseases
Inflammatory asymmetric/large joint arthritis
Seronegative spondyloarthropathy (oligoarticular, 2-4 joints)
Ankylosing spondylitis
Reactive arthritis/Reiter’s syndrome
Psoriasis
Inflammatory bowel disease
Indications for arthrocentesis (joint aspiration)
To rule out a septic joint
To evaluate for crystal arthropathy
To determine whether an effusion is inflammatory or noninflammatory
Therapeutic drainage (to remove joint damaging enzymes; pain relief)
Tests for synovial fluid analysis
Appearance: clear (noninflammatory) vs. cloudy (inflammatory or hemorrhagic)
Cell count and differential: WBC, neutrophil %, RBC
Gram stain: gram positive vs. gram negative organism
Culture and sensitivities: aerobic organisms, special cultures and/or testing for fungi or mycobacteria when suspected
Polarizing microscopy for crystals: negatively vs. positively birefringent crystals
Types of joint effusions
Normal: clear, colorless, viscous; <200 WBC
Noninflammatory: clear, yellow, viscous; 200-2000 WBC, <25% PMNs
Inflammatory: cloudy, yellow, decreased viscosity; 2,000-100,000 WBC, <50% PMNs
Pyarthrosis (subset of inflammatory): purulent, markedly decreased viscosity; usually >50,000 WBC, >95% PMNs
Hemarthrosis: grossly bloody (trauma vs. coagulopathy); similar to CBC (?)
Polarizing microscopy for detection of birefringent crystals
Put crystal between two filters that are perpendicular to each other
Plane of polarized light is rotated by a birefringent crystal
Orientation of second filter is the plane of polarized light and is used to orient long axis of crystals
Gout crystals on polarizing microscopy
Yellow parallel and blue perpendicular crystals = negatively birefringent = urate crystals (gout)
Intracellular crystals are highly indicative of an acute gouty flare (usually not seen between attacks)
Calcium pyrophosphate (pseudogout) crystals on polarizing microscopy
Blue parallel and yellow perpendicular crystals = positively birefringent = calcium pyrophosphate (pseudogout) crystals
Noninflammatory effusion could mean which diseases?
Osteoarthritis
Internal derangements (tendon/ligament/meniscal injuries)
Inflammatory effusion could mean which diseases
Infection
Crystal disease
Rheymatoid arthritis
Seronegative spondyloarthropathy
SLE
Pyarthrosis effusion could mean which dieseases?
Infection
Intense inflammation: crystal disease, psoriatic arthritis
Hemarthrosis effusion could mean which diseases?
Trauma (intraarticular fracture)
Coagulopathy (hemophilia, anticoagulant related)
Acute phase response
Increase in liver-synthesized proteins and immunoglobulins that occurs in response to trauma/tissue injury or a variety of inflammatory/immunologic stimuli
Acute phase proteins: fibrinogen (major contributor), C-reactive protein, haptoglobin, ceruloplasmin, alpha-1-antitrypsin, complement C3 and C4, serum amyloid A protein, immunoglobulins
Testing for systemic inflammation
Use ESR and CRP
Sensitive for inflammation, but not specific enough to be used to make diagnosis of specific disease
Erythrocyte sedimentation rate (ESR)
Measures distance in mm that RBCs fall over 1h
Normal range: 0-20mm/h
Age adjustment (>50yrs) for upper limit of normal: Males = age/2; females = age+10/2
Indirect measure of acute phase proteins because acute phase proteins are anionic (fibrinogen) so allow RBCs to pack together more closely, decrease surface area and sediment more rapidly
High sensitivity for many inflammatory conditions
Not very specific: many diseases and non-disease states can result in increased ESR
Slow decay time (weeks) so can’t follow changes over short periods of time
C-reactive protein (CRP)
Increased specificity because is a directly measured protein level so less affected by non-disease factors than the ESR
Increases within 24h of inflammatory stimulus, peaks within 24-48h and rapidly normalizes with resolution of stimulus
More useful measure for changes over shorter periods of time (days) than ESR
Why shouldn’t you measure ESR every day?
ESR won’t change every day because is affected by anionic acute phase proteins, which stick around for weeks!
Ex: fibrinogen stays around for 2 weeks after initial inflammatory stimulus
Points about using ESR and CRP
Nonspecific: these tests should NOT be used as general screening test for any disease; limited role in diagnosis and prognosis; most useful for monitoring disease activity and response to therapy
False-positives: most are of short duration and spontaneously normalize
False-negatives: ESR and CRP can be normal with many conditions, so a normal result alone cannot rule out a specific disease
Rheumatoid factor
Rheumatoid factor (RF) is an IgM, IgG, or IgA antibody which binds to Fc portion of an IgG immunoglobulin
IgM RFs are clinically measured
Not specific for any given condition: reflects a state of chronic immune activation
Increased RF occurs normally in older individuals with chronic infections and other autoimmune diseases
Helps to make diagnosis of RA, but is NOT diagnostic of RA (could mean many other things)
Antinuclear antibody (ANA)
ANA test detects antibodies directed against different nuclear antigens
Antinuclear antibody in plasma caused LE cells (PMN) to phagocytose nuclei, which happened a lot in people with SLE (not specific for SLE though)
ANA titer is highest dilution giving positive signal (immunofluorescence); abnormal result is titer >1:40
Approach to diagnosing arthritis
1) Determine if complaints due to true arthritis or periarticular
2) Monoarticular or polyarticular arthritis?
3) Inflammatory or non-inflammatory?
4) Symmetric of asymmetric?
5) Is there axial joint involvement?
Now in the right diagnostic “neighborhood”
6) Modify hypotheses based on mode of onset, duration, sequence of involvement, presence of extraarticular findings
7) Rule out or confirm diagnoses with appropriate lab, radiologic and other testing
Monoarticular arthritis
Most common types are acute septic arthritis and crystal arthritis…and they present identically!
Septic arthritis
Inflammatory arthritis caused by an infectious process involving the synovium and joint space
Most commonly a single joint, but polyarticular presentation 10-20% of the time
Infections can be acute or chronic
Considered a medical emergency because: (1) marker for underlying systemic infection with increased morbidity and mortality, and (2) can result in irreversible damage to the joint in just a few days resulting in impaired joint function and/or chronic pain
Two most common causes of septic joint are nongonococcal bacterial arthritis and gonococcal bacterial arthritis (disseminated gonococcal infection)
Mechanisms of entry of nongonococcal bacterial arthritis into the joint
1) Hematogenous spread: most common; bacteremia (bacteria in the blood) results in seeding of joint
2) Direct innoculation: following procedures or penetrating trauma
3) Direct spread from an adjacent tissue infection: cellulitis (skin infection), bursitis, or osteomyelitis (bone infection)
Progression and pathology of nongonococcal bacterial arthritis
Bacterial seeding results in acute inflammation with migration of neutrophils into synovium, synovial hyperplasia, and development of joint effusion
Over next 5-7 days, release of various inflammatory cytokines, host proteolytic enzymes and bacterial toxins contribute to cartilage and bone degradation (bones look mushed together on x-ray: irregular bony margins, joint space narrowing, osteopenia)
What is the most common cause of nongonococcal bacterial arthritis?
Staphylococcus aureus (gram positive coccus)
Gram negative bacterial joint infections are much less common and associated with older age, GI infections, GU infections, and IV drug use
Clinical presentation of nongonococcal bacterial arthritis
Acute onset of inflamed joint
Typically monoarthritis (polyarticular 10-20% and usually with immunosupression or marked bacteremia)
Most commonly large (shoulder, hip, knee (50%, most common)) or intermediate (wrist, ankle) joints; small or fibrous joints (sacroiliac, sternoclavicular) much less common
Constitutional symptoms: fever, chills, rigors (bacteremia)
Signs of infection in other organ systems
Physical exam: erythema and warmth, tenderness to palpation, pain on passive range of motion, swelling and effusion
Risk factors for nongonococcal bacterial arthritis
Anything contributing to increased risk of bacteremia, joint seeding, or decreased ability to clear infection from joint
Local factors: prior joint damage, surgery/arthrocentesis, prosthetic joint
Systemic factors: younger/older age, immunosuppression, comorbid disease
Social factors: IV drug abuse, homelessness, animal exposures
Gonococcal bacterial arthritis
Neisseria gonorrhea (gram negative) enters into joint via hematogenous spread from its mucosal site of infection (urethra, cervix, rectum, pharynx)
Develops in only 1-3% of people infected with Neisseria gonorrhea
Most common form of septic arthritis in youg sexually active adults in the US but can occur in older adults too
3x more common in women and more common in homo/bisexual men
Two types of clinical presentation of gonococcal bacterial arthritis
1) Purulent arthritis: mono or oligoarticular arthritis (wrist, knee, and/or ankles); purulent joint effusion present from which organism can be cultured; may not be associated with other signs of gonococcal infection
2) Triad: macular or vesicopustular skin lesions; tenosynovitis involving tendon sheaths of wrists, fingers, ankles, toes (important distinguishing feature); blood and mucosal cultures usually positive but synovial fluid cultures negative
Risk factors for gonococcal bacterial arthritis
Local factors: female, previous gonococcal infection (increased risk of asymptomatic infection)
Systemic factors: bacterial factors, complement deficiencies that impair the formation of the attack complex (C5-8)
Social factors: unprotected sexual activity, IV drug abuse, lower educational status, urban residence
Diagnosis of septic arthritis
Clinical: monoarthritis is considered a septic joint until proven otherwise!
Lab: WBC possibly elevated but normal 40% of the time; positive blood cultures indicate bacteremia; culture mucosal sites if suspect disseminated gonococcal infection
Joint aspiration: inflammatory fluid (WBCs > 2,000mm3, increased neutrophils); gram stain of fluid may be positive (but sensitivity only 20-45%); synovial fluid culture to confirm infection is gold standard (allow culture to grow for 72 hours)
Management of septic arthritis
If you suspect septic joint, start IV antibiotics right after joint aspiration/sent for culture/blood culture taken
Evaluate other organ systems for infection
Joint should be serially drained to remove damaging inflammatory and toxic mediators and to monitor cell count and if cell count > 50,000mm3, call orthopedics to perform washout of joint (using big tube to wash w/saline)
After clinical improvement, low level rehab starte
Treatment delay increases the risk of chronic joint damage
Crystal arthropathy (gout)
Purines metabolized to uric acid but uric acid exists in ionic urate form in plasma, which is excreted by the kidney
Physiologic saturation of plasma causes monosodium urate crystals (gout crystals) to form in tissues
Inflammatory response to urate crystals via innate immune system (same as rsponse to septic joint, which is why they present identically!)
Causes of hyperuricemia
Increased production: increased cell turnover (some tumors/chemotherapy, psoriasis), increased intake of purine rich food (shellfish, organ meat, beer), increased alcohol intake (binging causes increased breakdown of ATP/ADP), genetic predisposition (mutations in purine metabolizing genes)
Decreased excretion: acute/chronic renal failure, drugs that interfere w/excretion (thiazide diuretics), diabetes (increased insulin interferes with excretion), genetic predisposition (polymorphisms in renal urate transporters)
Pathophysiology of gout
Not completely known
Not just urate crystal deposition, because extracellular crystals found in non-inflamed joints
Changes in serum uric acid concentrations (increases AND decreases) associated with flare ups
3 phases of gout
1) Acute arthritis: acute monoarthritis
2) Intercritical gout: asymptomatic period between attacks, but extracellular MSUM crystals may still be present in synovial fluid
3) Chronic tophaceous gout: increasing frequency and severity of attacks with formation of tophic and erosive polyarticular arthritis
Can cycle through phases 1 and 2 or 2 and 3
Clinical presentation of gout
History of hyperuricemia or condition associated with hyperuricemia
Sudden onset of monoarthritis
Inflammation 3-10 days, spontaneous resolution 3-7 days
Most common at 1st metarsalphalangeal, ankle, knee, wrist
Tenosynovitis and bursitis bc urate crystals in synovium of tendon sheaths and bursae
With longstanding hyperuricemia, chronic gout can develop
Low grade fever, inflamed joint, tophi in soft tissues (skin, bursae, tenosynovium)
Chronic gout
Develop with longstanding hyperuricemia
Flares can become more frequent, more prolonged, polyarticular
Associated with nodular collections of monosodium urate crystals (tophi)
Chronic low to moderate joint inflammation that doesn’t spontaneously resolve and is poorly responsive to treatment
Tophi formation can cause bony erosions
Can cause renal precipitation of urate crystals and thus kidney damage
Diagnosis of gout
Should be suspected in acute monoarthritis or tenosynovitis, especially if there are risk factors
Since identical to septic joint on appearance, synovial fluid must be obtained for cell count, gram stain, culture, crystal analysis
Definitive diagnosis of gouty arthritis made by finding negatively birefringent (yellow parallel) needle-shaped crystals (and intracellular crystals mean acute gouty flare)
Can sometimes have septic joint at same time
Management of gout
First treat inflammation (colchicine, steroids, NSAIDs, intraarticular steroid injection)
Avoid anything that would change serum uric acid concentration (don’t give allopurinol bc that would decrease uric acid concentration and don’t want it to change at all!)
If more than 2 flares per year then lower serum uric acid concentration (hypouricemic therapy): decrease purine intake, decrease meds that would cause hyperuricemia, take hypouricemic meds
Calcium pyrophosphate deposition disease (CPPD), or pseudogout
CPPD crystals can form in cartilage and intraarticular fibrous structures and shedding of crystals can cause inflammatory response that occurs through same innate immune pathway as gout
Clinical presentation of joint inflammation, tenosynovitis, bursitis identical to gout except NO tophi
Clinical presentations of CPPD
Acute arthritis (pseudogout causes inflammation, monoarticular)
CPPD arthropathy (degenerative changes similar to osteoarthritis)
Tenosynovitis alone or with inflam arthritis
Radiologically as chondrocalcinosis (calcification of cartilage/fibrocartilage)
Common with older age but sometimes associated with metabolic disease (parathyroid, thyroid, hemachromatosis)
Diagnosis of CPPD
Positively birefringent (parallel blue) rhomboid-shaped crystals on polarizing microscopy
Treatment of CPPD
Inflammation treated same way as gout (colchicine, steroids, NSAIDs, intraarticular steroid injection)
No hypouricemic therapy (uric acid isn’t a problem!)
Consider metabolic workup
Osteoarthritis
Complex group of non-autoimmune mechanically-induced conditions due to altered joint loading that results in failure and loss of intraarticular cartilage and dysfunction of other articular components (synovium, ligaments, neural components, bone) resulting in chronic joint pain and loss of joint function
Most prevalent type of arthritis
Primary vs. Secondary osteoarthritis
Primary osteoarthritis: not associated with trauma or other medical condition; joint involved usually DIP, PIP, 1st CMC, wrists, acromioclavicular, cervical/lumbar spine, hips, knees, MTPs
Secondary osteoarthritis: associated with trauma or other metabolic conditions (such as CPPD); joint involved usually NOT the ones listed above
Pathology of osteoarthritis
In the cartilage, get fibrillations and fissures
Thinning and loss of cartilage in response to altered forces which cause osteophytes
Clinical presentation of osteoarthritis
Mechanical joint pain exacerbated by weight bearing and/or relieved by rest (can contribute to inactivity)
Stiffness less than 30 min in the morning or after not moving for a while
Decreased range of joint motion secondary to pain or severe joint damage
Muscle weakness/atrophy secondary to pain and inactivity, can result in altered gait and increased risk for fall
Non-inflammatory swelling
Characteristic presentation: bilateral DIP joint space narrowing with osteophytes
Trauma, CPPD and other metabolic conditions suggest secondary osteoarthritis
Physical exam findings of osteoarthritis
Tenderness to palpation without joint swelling
Decreased ROM with crepitus (crackling due to loss of cartilage)
Pain on passive range of motion (if disease is in advanced stage)
Osteophytes, joint malalignment
Altered gait
Bursitis and/or tendonitis due to altered gait and joint deformities
Diagnosis of osteoarthritis
History and associated joint exam findings in absence of inflammation
Secondary osteoarthritis diagnosed if joints other than those usually seen in primary, if trauma or underlying associated condition
Only do lab testing for underlying condition for secondary osteoarthritis
X-rays helpful to confirm diagnosis
X-rays in diagnosis of osteoarthritis
Only take x-ray to confirm the diagnosis
Asymmetric joint space narrowing
Osteophytes
Subchondral bony sclerosis (hardening from inflammation)
Subchondral bony cysts (looks darker)
Note: radiologic severity does not always correlate with given patient’s pain or level of joint function
Management of osteoarthritis
No therapy can restore lost cartilage
Goal of treatment is to control pain (meds, PT, weight loss), restore function (pain control, PT), prevent/minimize progression (PT, weight loss)
If pain/loss of function severe, consider joint replacement surgery
