RA, osteoarthritis, ankylo Flashcards
In gout - depositions of what component?
Monosodium urate crystals
What is a risk factor for hyperuricemia?
increased purine metabolism
what is a risk factor for gout?
elevated uric acid levels
What is important enzyme in purine synthesis?
phosphoribosyl pyrophosphate (PRPP) synthetase
What produces PRPP synthetase?
activated ribose
What component is needed for de novo synthesis of purine and pyrimidine nucleotides?
activated ribose
activated ribose is used in ………….. and ………… synthesis.
de novo purine and pyrimidine synthesis
What mutation in what structure leads to increased production and degradation of purines?
Activating mutation involving PRPP synthetase
activating mutation in PRPP synthetase cause …………….. activation of purine synthesis pathway.
feed-forward
What is result of feed-forward activation of the purine synthesis pathway?
More purine molecules will undergo degradation, resulting in hyperuricemia and increase risk of gout
What joints most commonly in acute gouty arthritis?
First metatarsophalangeal joint or knee
acute gouty arthritis symptoms develops within ………..
rapidly over 24h
manifestation (3) of acute gouty arthritis?
swelling, erythema and exquisite tenderness
What method is used for diagnosis of acute gouty arthritis?
Joint aspiration –> needle-shaped, negatively birefringent crystals under polarized lamp
What are primary immuno cells in acute gouty arthritis?
neutrophils
Pathophysio of acute gouty arthritis?
Neutrophils –> phagocytosis of urate crystals –> release of various cytokines and inflammatory mediators –> further neutrophils activation and chemotaxis –> positive feedback loop that amplifies the inflammatory response
What is first therapy in acute gouty arthritis?
NSAIDs
Why NSAIDs used in acute gouty arthritis as primary agent?
inhibit prostanoid biosynthesis (prostaglandins, prostacyclin, thromboxane) –> broad ant-inflammatory effect that includes INHIBITION OF NEUTROPHILS
Why patients may be contraindicated for NSAIDs?
peptic ulcers, renal impairment
What use in acute gouty arthritis if patient cannot use NSAIDs?
Colchicine
What is effect of colchicine on neutrophils?
impairs migration and phagocytosis by interfering with microtubule formation
What mechanism by colchicine decrease neutrophils activation?
Colchicine decreases tyrosine phosphorylation in response to monosodium urate crystals, resulting in decreased neutrophil activation
What cells are targeted in therapy of acute gouty arthritis?
neutrophils
What is a central mechanism involved in precipitating an acute gouty attack?
NEUTROPILS!!!!
What are other 2 types of cells play role in acute gouty arthritis?
synovial cells and macrophages
Depositions of what in pseudogout?
calcium pyrophosphate dihydrate crystals (in synovial fluid)
what is second line treatment for acute gouty arthritis?
colchicine
What 2 primarily involved joints in gout and pseudogout?
pseudo - knee (50proc)
gout - first metatarsophalangeal joint
What cells count is increased in synovial fluid in pseudogout and what cell predominance?
incr. WBC with neutrophils predominance
What is seen under polarized light in pseudogout?
rhomboid-shaped calcium pyrophosphate dihydrate crystals
Birefringent crystals in pseudogout?
Positively birefringent (IN GOUT NEGATIVE!)
Pseudogout crystals are blue when aligned …………
parallel
Pseudogout crystals are yellow when aligned ……….
perpendicular
Calcific tendonitis results from the deposition of …………..
calcium hydroxyapatite crystals in periarticular soft tissues (esp. tendons)
What is the most commonly affected structure in calcific tendonitis?
The rotator cuff tendons
What colour of gout crystals in parallel?
yellow
What colour of gout crystals when perpendicular?
blue
What immunity is involved in RA?
Both humoral and cell-mediated
What is humoral immunity in RA?
autoantibodies against citrullinated polypeptides (anti-CCP)
What T cells are activated in RA?
CD4 = Th1 and Th17
What cells play a role in early disease process in RA?
Th1 and Th17
What cells activation leads to progressive articular destruction?
macrophages
Activation of macrophages in RA leads to ……………..
development and progressive articular destruction
What cytokines release macrophages in RA?
IL-1 and TNF-alpha
What cytokines leads to progressive articular destruction in RA?
IL-1 and TNF-alpha
What enzymes contribute to cartilage destruction in RA?
proteases - collagenase, metalloproteinase
Why occurs bony erosions in RA?
due to effect of cytokines - TNF-alpha and IL-1 –> both activate osteoclasts –> bony erosions
Monoclonal antibodies that are used in RA are targeted to ………………
inhibits TNF-alpha and IL-1
What are rheumatoid antigens that activate …………..
citrullinated peptides, type II collagen; activates T lymphocytes
What leads to synovial hyperplasia?
activated T cells release cytokines –> synovial hyperplasia + recruitment of additional mononuclear cells
Why needed synovial angiogenesis in RA?
due to accelerated metabolic rate of inflamed synovial tissue
Accelerated metabolic rate of inflamed synovial tissue leads to ……………..
local hypoxia + increased hypoxia-inducible factor 1 + VEGF
What cells produce hypoxia-induced factor 1 and VEGF in RA?
Local macrophages and fibroblasts
Hypoxia-induced factor 1 and VEGF leads to ………..
synovial angiogenesis (neovascularization)
new blood vessels in RA due to neoangiogenesis provide ………….. and facilitate ……………
provide nutrients that facilitate expansion of inflammed synovium into a rheumatoid pannus
What is rheumatoid pannus?
Invasive mass in RA
Rheumatoid pannus consists of ……………
fibroblast-like synovial cells + granulation tissue + inflammattory cells
what can do rheumatoid pannus over the time?
it encroaches into the joint space and can destroy the articular cartilage and erode the underlying subchondrial bone.
What can lead to fusion of the bones across the affected joint (bony ankylosis)?
ossification of the panus
Ossification of the pannus can lead to …………………..
fusion of the bones across the affected joint (bony ankylosis).
What arthritis is in RA?
chronic, symetrical, polyarticular with swelling and stiffness
Late-stage RA is characterized by …………….
widespread joint deformities
Late stage RA deformities include ……………………….. (3)
ulnar deviation at the MCP joints, swan-neck deformities in the digits, and additional deformities (eg, volar subluxation of the carpus, radial drift) at the wrists.
eventually in RA joint space is replaced by ……………
rheumatoid pannus
What joints are primarily involved in RA?
Small joints of hands (MCP and PIP) and wrists
What are affected joints in RA?
PIP, MCP, wrist, elbow; knee, ankle metatarsophalangeal joints in feet
What joints are usually spared in RA?
lumbosacral and hips
What causes swelling, warmth and tenderness in RA?
overt synovitis
overt synovitis in RA leads to …………..
swelling, warmth and tenderness
X ray findings in RA?
joint space narrowing and marginal joint erosions
What 2 cytokines are likely protective against joint destruction in RA?
TGF-beta and IL-10
What T lymphocyte and interferon play a role in RA?
Th1 and INF-gama
histopathologic findings of subcutaneous RA nodules include ……….
necrotic center surrounded by palisading macrophages and lymphocytes
Cutaneous manifestation of RA? (2)
subcutaneous nodules and leg ulcers
histology of RA?
Synovial hyperplasia
What cervical pathology seen in advanced RA?
antlantoaxial subluctation (displacement of C1 and C2 vertebrae)
Atlantoaxial subluxation (ie, displacement of C1 on C2 vertebrae) is caused by ……………………
ligamentous deterioration in the cervical spine
What can lead to dislocation and spinal cord injury in RA atlantoaxial subluxation?
significant neck extension (eg during intubation)
What is the most common form of arthritis?
osteoarthritis
What joints affects osteoarthritis?
knee, lumbar spine, hips and distal joints of hand
In osteoarthritis pain typically ……………………………… and is relieved by …………….
Pain typically worsens with activity and is relieved by rest
What accelerates the progression of osteoarthritis?
age, joint trauma, excessive mechanical stress (eg obesity, joint deformities) + repetitive stress
Osteoarthritis is characterized by …………. (2)
progressive fibrillation + erosion of articular cartilage
Fibrillation in osteoarthritis include (3)
fissuring, fracturing, flaking
What is a major contributor to cartilage destruction in osteoarthritis?
increased intraarticular metalloproteinase activity
How strongly manifest synovitis in osteorthritis?
symptoms such redness or warmth is less prominent than in classic inflammatory arthritis disorders
What proinflammatory mediators have been linked to osteoarthritis? (3)
IL-6, macrophage chemotactic protein-1
What is the level of effusion in osteoarthritis?
if it occurs, then effusions are small
what 2 changes include the periarticular area in osteoarthritis? why they occur?
osteophyte formation and subchondrial sclerosis;
due to excessive bone remodeling
RA vs OA periarticular changes?
RA - periarticular bone erosions;
OA - osteophyte formation and subchondral sclerosis
clinical manifestation of osteoarthritis?
chronic knee pain + crepitus
If there is arthritis in thoracic spine - what 2 probable pathologies maybe it is?
osteoarthritis or spondyloarthritis
musculoskeletal manifestation in hereditary hemochromatosis? (2)
Arthritis
Chondrocalcinosis
What joints are affected in hereditary hemochromatosis?
2nd and 3rd MCP joints
HH-associated arthritis is thought to be caused by ………………..
iron deposition
Where are iron depositions in HH-assoc arthritis?
Iron deposition in the articular cartilage and synovium.
Iron deposition in the articular cartilage and synovium leads to ………………….. (2)
free radical damage and crystal deposition
HH-assoc arthritis resembles …………….
osteoarthritis
X ray of HH-assoc arthritis
characteristic deformities (hook like osteophytes) and chondrocalcinosis (depositions of calcium pyrophosphate dihydrate in the articular cartilage)
what is relation of erosion in gouty arthritis and cartilage?
Bony erosion are commonly near the articular surface
What induces patho of ankylosing spondylitis?
Altered gut biome/defective mucosal barrier
What cytokines increased in ankylosing spondylitis? (3)
IL-17, TNF-alpha, prostaglandins
What genes increase risk for ankylosing spondylitis?
HLA-B27
Exercise increase or reduce pain in ankylosing spondylitis?
Relieved with exercise but not with rest. Rest at night therefore induces nocturnal pain
Age of onset of ankylosing spondylitis?
<40 y/o
Where is pain in ankylosing spondylitis?
chronic inflammatory back and buttock pain
X ray in ankylosing spondylitis? 2 main
sacroiliitis, bridging syndesmophytes
What relieves pain in ankylosing spondylitis?
activity and warm shower
What are inflammations in fingers and tendons in ankylosing spondylitis?
dactylitis and enthesis
Changes in ankylosing spondylitis in chest region?
Decreased chest expansion
inflammatory markers in ankylosing spondylitis?
CRP and ESR
What means seronegative spondyloarthropathies?
absence of serum rheumatoid factor
AS vs RA?
AS - simultaneous erosion of bone and new bone formation.
RA – only erosions are seen.
Changes in gut microbiome/intestinal mucosal barrier leads to …………………..
enhanced IL-17-mediated inflammatory response.
IL-17–mediates inflammatory response via ……………. and …………….
Innate lymphoid cells and T helper cells (eg, Th1, Th17)
IL-17 stimulates production of additional inflammatory factors …………… (2)
primarily TNF-alpha and prostaglandins
Cytokines in ankyl. spond. activates ………… and leads to ……………….
Cause activation of osteoclast precursor cells –> bony erosions
Bony erosions occurs primarily in ……………..
It results in ……………. and increases risk for ……………..
Vertebral bodies –> results in destruction of the microarchitecture, increasing the risk for secondary osteoporosis and compression fractures.
When starts bone formation (reparation) in ankyl. spond?
Once the inflammation subsides
Excessive bone formation especially occurs in …..(what areas)…………….. in ankyl.spond.
in areas where fat metaplasia fills previously eroded sites.
bone formation occurs primarily at the ……………
It manifests as …………
periosteum-cartilage junction and manifests as bridging syndesmophytes in the vertebral column
bridging syndesmophytes in the vertebral column leads to ……………. (manifestation)
Spinal rigidity, postural alterations and increased risk of fracture.
in what bones are seen bridging syndesmophytes?
in vertebral column
Where occurs ankylosis?
bony fusion of the apophyseal and sacroiliac joint).
What is ankylosis?
bony fusion
Skeletal manifestations of AS occur primarily at sites of ……….. likely due to …………
mechanical stress, such as the entheses, likely due to the migration of activated immune cells to these areas
What 3 medications in ankyl. spondyl?
Nsaids –> prostaglandins
anti-TNFalpha
anti-IL-17
What 2 cytokines inhibits IL-17?
IL-2 and INF-gamma
IL-4 may play protective role in ankyl.spondyl how?
Limit IL-17 production by Th1 and Th17
What are antiinflammatory in ankyl spond?
IL-10 and TGF-beta
If patient is suspected with ankyl. spond. What method to diagnose?
undergo xray of spine and pelvis
What shows pelvis xray in akyl.spond?
inflammatory arthritis of the sacroiliac joints (ie, sacroiliitis), visible as joint erosions with subchondral sclerosis.
Sacroiliitis on xray in ankyl spond is visible as ………..
joint erosions with subchondral sclerosis.
What shows xray in ankylosis (bony fusion)?
heterotropic ossification affecting the margins of the vertebral bodies, which are visible as bridging syndesmophytes
How is called continuous syndesmophytes formation in akyl spondyl?
bamboo spine
do serologic tests are used in ankyl spondyl?
no need, because it is seronegative spondyloarthropathy
What are conditions related to HLA class II?
RA, DM1, celiac disease
RA is assoc with what HLA class?
II
ankyl spondylo. What class of HLA?
I
what 2 joints are affected in anky spondyl??
sacroiliac and apophyseal joints –> leads to restricted spinal mobility
what 3 extraskeletal systems are affected in ankyl spondyl?
respiratory, cardiovascular, eyes
Respiratory involvement in ankyl spondyl?
thoracic spine and enthesopathies –> involved costovertebral and costosternal junctions –> limit chest wall expansion –> hypoventilation
The most common cardiovascular complication of AS is …………..
ascending aortitis, which can lead to dilation of the aortic ring and aortic insufficiency.
eye involvement in ankyl spoondyl?
Anterior uveitis –> pain, blurred vision, photophobia, and conjunctival erythema.
How manifest anterior uveitis in ankyl spondyl?
pain, blurred vision, photophobia, and conjunctival erythema.
What is normal respiratory variable in ankyl spondyl despite limited chest wall?
peak respiratory flow
Reactive arthritis classic triad?
urethritis + conjuctivitis + asymetric mono/oligoarthritis
age of reactive arthritis?
20-40
What induces reactive arthritis?
genitourinary or enteric infection –> autoimmune reaction initiated by the infecting pathogen
m/o genitourinary in reactive arthritis?
chlamydia ttrachomatis
m/os enteritis in reactive arthritis?
salmonella, shigella, yersinia, campylobacter, clostridium difficile
What is musculoskeletal manifestation of reactive arthritis?
asymetric mono/oligoarthritis, enthesitis, dactylitis
What extraarticular systems involved in reactive arthritis?
ocular, genital, dermal, oral ulcers
Dermal manifestation in reactive arthritis? (2)
gkeratoderma belnnorrhagicum (yperkeratotic vesicles on the palms and soles) and circinate balanitis (serpiginous annular dermatitis of the glans penis)
Genital manifestation in reactive arthritis? (3)
urethritis, cervicitis, prostatitis
Ocular manifestation in reactive arthritis? (2)
conjuctivitis, anterior uveitis
What musculoskeletal manifestation occurs in 20proc of reactive arthritis?
Axial involvement, including sacroiliitis, may occur in about 20% of cases.
treatment of reactive arthritis?
Symptoms usually resolve within a few months and would not be chronic
dactilits assoc with ….. (3) manifestations
ankyl spondyl, reactive artrhritis, enthesitis
enthesitis assoc with ….. (3) manifestations
ankyl spondyl, reactive artrhritis, psoriasis/psor. arthritis
where manifest enthesitis?
areas of mechanical stress - insertion of tendons, ligaments, joint capsules on bones
3 common clinical syndromes in enthesitis?
Achilles tendinitis, plantar fasciitis, and dactylitis (“sausage digits”).
Where is pain in achilles tenditinis?
posterior heel pain
Where is pain in plantar tenditinis?
plantar heel pain
