Gout RA OA Flashcards
1
Q
Type 2 collagen is good for what kind of stress?
A
Tensile strength
2
Q
What kind of cells line the synovial cavity?
What do these cells do?
A
cuboid cells; 1-4 layers thick
-produce synovial fluid; remove debris; regulate movement of solute, electrolytes, and proteins.
3
Q
NSAIDS
- What are two good drugs to use
- When do you use it?
- when should you not use.
- What do you need to consider in terms of side effects?
A
- Naproxen, Indomethecin,
- Use it within 24 hours
- Do not use within 24 hours
- becareful of GI side effects
4
Q
Name 3 good drug choices for acute gout attack
A
NSAIDs (not Aspirin), Steroids, and Colchicine
5
Q
Steroids
- What is it mostly for in a case of gout attack?
- What should you be careful to do?
A
- It can be used for symptomatic relief when NSAIDs are not tolerated.
- Make sure it’s not used for an extended periods.
6
Q
Colchicine
- mechanism of action
- when to use?
- effect on uric acid excretion
- administration method
- metabolism
- what does it interfere with? What are some implications due to this?
- side effects? severity?
- Contraindications
A
- Colchicine binds alpha/beta tubulin units and prevents polymerization. Therefore decreasing neutrophil recruitment and proliferation.
- Use in acute gout attacks or for prophylaxis.
- There is not effect on uric acid excretion itself
- oral admin
- Metabolized by CYP3A4
- it interferes with pglycoproteins…meaning it will interfere with other drugs that are eliminated via pglycoprotein channels.
- severe GI side effects (N/V/D/pain), because it affects rapidly overturning GI cells… and effect can be latent
- contraindications: hepatic and renal insufficiency… because this would increase concentration or prolong duration of colchicine
7
Q
What are reasons for prophylaxis of gout? (5)
A
- frequent attacks
- very severe attacks (disabling)
- renal disease
- urate nephropathy
- tophaceous gout
8
Q
What are some nonpharmacological ways to prevent gout?
A
- weight loss
- don’t drink alcohol
- stop taking drugs that impair uric acid excretion:
- -Asprin, thiazide diuretics, cyclosporin
9
Q
List 5 medications for prophylaxis of gout
-which one is also used for acute attacks?
A
- Febuxostat
- Allopurinol
- Probenecid
- Pegloticase
- (Colchicine)-MOSTLY used for acut attacks
10
Q
Allopurinol
- Mechanism of action
- Side effect of allopurinol (2 major; 4 minor)
- What worsens the likelihood of side effects?
- What can be done to alleviate one of the side effects?
- What are indications for allopurinol treatment?
A
Allopurinol is a analog of hypoxanthine. It is converted to oxipurinol by aldehyde oxidoreductase… and oxipurinol is an analog of xanthine. Therefore oxipurinol competes with xanthine in conversion to uric acid by xanthine oxidase.
- Hypersensitivity; and acute gout attack
- —-> also minor ones such as dizziness, diarrhea, HA, nausea.
- gout precipitating medications such as thiazide diuretics, ACE inhibitors and amoxicillin
- administering allopurinol with NSAIDs decreases the chance of acute gout attack via down reg of inflammation
- chronic gout/hyperurecemia (or chronic secondary conditions causing gout/hyperuricemia). Gout nephropathy, tophaceous depsitis, renal urate stones.
11
Q
What is allopurinol an analog of?
What is the active form of allopurinol? What converts allopurinol to this?
What is the half life of allopurinol?
What’s the half life of the activated product?
A
hypoxanthine.
- Oxipurinol. Aldehyde oxidoreductase.
- Allopurinol T1/2 is 1-2 hours; Oxipurinol T1/2 is 18-30 hours
12
Q
What should Allopurinol be given with? why?
A
Allopurinol should be given with NSAIDs to prevent acute gout attacks.
13
Q
Febuxostat
- mechanism (be specific)
- Side effects
A
Fubuxostat is a stabilizer of xanthine oxidase in both its reduced and oxidized forms. However, it is NOT a xanthine or hypoxanthine analog.
-dizziness, HA, nausea, diarrhea
14
Q
Allopurinol vs Febuxostat
- Which is more potent
- Which has less side effects? (which kind in which drug is worse?)
- Name advantages of Febuxostat (2)
A
- Febuxostat is more potent
- minor side effects such as nausea, diarrhea, HA, and dizziness are about the same in both
- cardiovascular side effects (antiplatelet trialists collaboration events) are worse in Febuxostat
- It is more potent and it is more effective in patients with renal disease (maybe because it’s more potent?)
15
Q
What is the natural urate removing enzyme that humans lack?
What does it convert urate to?
What is a synthetic analog of this enzyme used for gout therapy?
acute or prophylactic?
A
Uricase
converts uric acid to allantoin (inactive water soluble metabolite)
Pegloticase
prophylactic
16
Q
What is pegloticase? structurally
A
PEG=polyethylene glycol; covalently attached to recombinant uricase. molecule
17
Q
Pegloticase
- admin
- T1/2
- side effects
- therapeutic use
- advantage?
- Disadvantage
A
- IV admin (every 2 weeks)
- long t 1/2
- infusion site reaction, hypersensitivity to PEG, gout flare
- good for refractory chronic gout
- advantage is it has a very long T1/2… Therefore they can get infusions every other week.
- IV infusion rather than oral is a disadvantage.
18
Q
Probenecid
- effect on uric acid?
- Mechanism of action
- administration
- T1/2?
- what does it bind?
- side effects
- contraindications
- advantage?
- disadvantages
- Therapeutic uses? in which kind of patient population?
A
- It increases excretion of uric acid
- by blocking the organic anion transporters (OAT) and URAT1 channels in kidney tubules responsible for uric acid reabsorption.
- Oral administration
- T 1/2 dose dependent!!!
- It binds plasma proteins
- Side effects: GI discomfort.
- advantage is that it’s oral admin
- disadvantage is that it is ineffective in kidney disease patients since it affects kidneys.
- Do NOT use in pts with uric acid kidney stones
- Therapeutic use in chronic gout patients with underlying underexcretion (NOT overproduction or kidney insufficient pts)
19
Q
Drug interactions:
Allopurinol/Febuxostat (2)
Colchicine
Probenecid (5)
A
- Decrease metabolism of thereby increasing concentrations of Azathioprine and Mercaptopurine
- decreased metabolism of and transportation of colchicine (Amprenavir, Ritonavir, AmiodaroneClarithromycin, Cyclosporine, Erythromycin); increased metabolism of colchicine (Clarithromycin, Rafampin)
- decreased renal excretion of thereby increased concentration of Clofibrate, Methotrexate, Palatrexate, Penicillin, Salicylate,
20
Q
Rheumatoid arthritis
- what percent of the population is affected?
- Immunological involvement? What type of cells are involved? (very general)
- What genetic factors contribute to RA?
- Other contributions to RA.
- Pathogenesis? What does it resemble?
A
- 1%
- T cells (mostly) and B cells
- HLA-DR4 is often involved. It’s an over expression of shared epitopes
- Environment (smoking) and hormonal (female >male)
- invasion of immune cells in the synovium along with FIBROBLASTS (formation of pannus and granulation tissue) leads to scarring, (Synovitis) inflammation, and deformation (fibromyoblasts). joint is destryed. It resembles a benign, but locally invasive, tumor.
21
Q
- What is chronic Rheumatoid arthritis called?
- What cells are involved? (4)
- What do these cells form in the joints?
- what cells and molecule are involved in the acute phase?
- What is the morphology of cells in RA? cell number? gross structure?
- What is the characterizing feature of RA? what does it do overtime? (3)
- –what is different from osteoarthritis?
- histological appearance (2)
A
-Called chronic papillary synovitis
-CD4+ T cells, plasma cells, macrophages, and giant cells
-these cells form lymphoid follicles
-Neutrophil invasion and fibrin in the acute phase
-Hyperplastic cells with papillary protrusion grossly that covers the articular surface.
-The defining characteristic is formation of pannus over the joint. Leading to 1. destruction of the cartilage, 2. destruction of underlying bone, and 3. ankylosis of the joint space due to fibrosis and ossification (myofibroblasts)
-it’s different from OA because it does not have prominent osteophytes ( new bone formatioN)
-Grossly its got papillary protrusions, but it also has lymphocytes
-
22
Q
Rheumatoid nodules
- location (1 common; 6 uncommon)
- how common is this?
- clinical presentation
- microscopic findings
- cause of nodules?
A
- pressure points on BUE are most common; less common are visceral locations–lungs, spleen, pericardium, myocardium, heart valves, aorta
- It is 25% of patients with severe RA
- fibrinoid necrosis at the center of nodule with surrounding epithelioid histiocytes then plasma cells and lymphocytes
- the nodules are due to vasculitis and then necrosis caused by rheumatoid factor.
23
Q
What type of necrosis is found at the center of a rheumatoid nodule? What surrounds it?
-What is this pattern called?
A
Fibrinoid necrosis. surrounded by epithelioid histiocytes and then lymphocytes + plasma cells
-palisaded inflammation
24
Q
History features of RA
- duration of morning stiffness.
- Does the stiffness improve or worsen?
- onset speed?
- symmetrical or asymmetrical?
- physical symptoms/difficulty with what activities
- Which joints are involved?
- what are some common physical finding (4)
A
- morning stiffness lasting for more than 1 hour for more than 6 weeks.
- The stiffness improves with activity
- gradual onset
- symmetrical sx
- pain with activities requiring turning motion of the fingers. Also metatarsal pain with walking on hard floors.
- PIP and MCP. DIP is usually spared.
- Radial deviation of the radiocarpal joint; Ulnar deviation at the MCP joint; Swan neck deformity (due to tightness of intrinsic muscles); and Boutinere’s deformity (extensor muscles fall down to act as flexors)
25
RA risk factors: (6)
- Genetics: HLA-DR4 and HLA-DR1 (first degree relatives have a 1.5x chance of developing disease
- Gender: females have 2.5x more than males
- Infection
- Stress
- Smoking
- Ethnicity (Rural africans (0.1%); Chippewa and Pima Indians (5%)
26
Which cytokinds are active players in RA?
Inflammatory: IL1 and TNFalpha, MCSF, IL17
27
What is Rheumatoid Factor?
It's an autoIgM against the Fc portion of IgG.
28
What can you test for to diagnose RA? (2)
When is one seen over another?
Which is more sensitive?
Which is more specific? (what does this mean?)
what do these markers correlate with?
You can test for rheumatoid factor (RF) and anticyclic citrullinated Peptide (CCP)
-The CCP sometimes may be present in early RA or in RF negative RA.
-Both are equally sensitive.
-CCP is more specific...as about 25% of RF false positives may occur with Hepatitis C pts
-The markers correlate with disease activity.
-
29
RA leads to destruction of bone. Where does this first start?
Erosion first starts in regions NOT covered by the cartilage...where the synovium is attached.
30
What is swan neck deformity?
What is Boutinere's deformity?
What are these associated with?
- swan neck is due to tight intrinsic hand muscles
- boutinere's is due to extensor muscles falling down to act as flexors.
- These are both associated with rheumatoid arthritis.
31
Classification of RA (7 characteristics)
| Diagnostic criteria
dx criteria: 4/7 of the characteristics AND >6 weeks
1. morning stiffness >1 hour
2. symmetric arthritis
3. at least 3 joints are swollen
4. wrist, PIP, and MCP involvement
5. Rheumatoid nodules
6. RF +
7. X-ray typical for RA.
32
RA is a systemic disease... what are other disease-sx associated with RA? (6)
1. Sjorgren's in about 20%. Sicca sx
2. CVD. (the risk for CVD in RA is about the same as DM)
3. Pulmonary
4. GI-USUALLY due to chronic NSAID use. not intrinsic to RA
5. Neuro- neuropathy, carpal tunnel
6. other autoimmune disese
33
RA. body parts affected? (7)
1. joints/bones/cartilage (including spine)
2. eyes
3. lungs
4. heart
5. mouth
6. skin
7. blood/vessels
34
RA: Lung involvements (4)
| -treatments (3 drugs)
- Rheumatoid Pleuritis (with effusion that is high in neutrophils (exudate) and low in glucose)
- Interstitial fibrosis
- nodules
- Caplan's syndrome-AKA rheumatoid pneumoconiosis
- Treatments: leflunomide; methotrexate, antiTNF
35
Rheumatoid vasculitis
- clinical presentations
- "classic sign"
- fibrinoid necrosis
- extremities are affected
- classic sign is nail fold infarcts
36
Cardiovascular disease in RA
- prevalence
- the risk factor for CVD in RA is similar to what other disease?
- 3.43 years/100 years of RA patient vs. 0.59/100 years of non RA
- inflammation mediated athrosclerosis that is similar to DM
37
What are the therapeutic goals of RA treatment?
- reduce inflammation
- reduce pain
- slow down joint damage
- improve functionality
38
What are two general categories of drugs used to treat RA?
What are they and what are advantages/limitations of each?
1. NSAIDS
- adv: alleviates pain and inflammation
- disadv: does not slow down disease; need large doses for long durations, and side effects associated with NSAID use
2. DMARDS-disease modifying antirheumatic
- adv: These are biological response modifiers that will decrease sx and decrease disease progression.
- disadv: perhaps more expensive
39
Name 4 main DMARDs and their main action
| Name 3 other DMARDS and their main action
- Entanercept, Adalizumab, Tocilizumab, Tofacitinib
| - Anakrinra, Abatacept, Rituximab
40
Etanercept (AKA?)
- structure of the drug
- mechanism (be specific)
- admin?
- onset post admin?
- T 1/2
- Side effects (3)
- therapeutic indication? (4)
AKA Enbrel
- Structure: IgG Fc protion attached to receptors for TNFalpha...therefore will bind soluble TNFalpha and reducing inflammation
- IV administration or SubQ admin
- onset about 1-2 weeks post injection
- SE: injection site reaction; increased risk for infections (MUST screen for TB before admin); and lymphoma in children/adolescents
- indicated in early onset RA, mod-severe RA, juvenile RA, and mod to severe plaque psoriasis
41
Adalimumab (AKA?)
- drug structure?
- mechanism? (be specific)
- admin? interval?
- adverse effects (3)
- Therapeutic uses
- optional combinations?
- Humira
- all human IgG against both soluble and transmembrane TNFalpha therefore preventing it binding to R and reducing inflammation
- SubQ; every 2 weeks
- SE: injection site reaction; infections, and lymphoma
- uses: active juvenile RA, and active adult RA
- Adalimumab can be used alone or with methotrexate or other DMARDs
42
- name 3 drugs that act on TNFalpha. What's the difference?
| - Which one(s) is/are better?
Etanercept binds membrane bound TNFalpha
Adalimumab and Infliximab bind TNF alpha in both soluble and membrane bound forms.
-Adalimumab and Infliximab are better
43
Tocilizumab (AKA?)
- structure
- mechanism (specific)
- admin; frequency?
- adverse effects: (3)
- Therapeutic use
- Structure: humanized ab against IL6R, therefore stopping signals.
- IV every 4 weeks; and subQ every 2 week
- Injection site reaction; Infection; changes in lipid profile (increased cholesterol, triglycerides, LDL and HDL.
- mod-severe RA not responding to TNFalpha therapy
44
What DMARDs drug is first line for RA? What is secondline?
Adalimumab/Infliximab are first, then etanercept, then Tocilizumab
45
Tofacitinib
- mechanism; what does it bind? (be specific)
- what's the result of Tofacitinib? (4)
- admin?
- metabolism
- adverse side effects (2)
- Therapeutic use
-It is an inhibitor of the JAK receptor's transmission to STAT.
(JAKs receive information from cytokines and growthfactors)
-result is there are no CD16/56+ NK cells, IgG, A, M, C-reactive proteins. However there will be an INCREASES in B cell.
-oral admin only
-metabolized by CYP3A4 and CYP2C19 minorly
-SE: Infection; Increased lipids (cholesterol, triglycerides, LDL, and HDL) *oral only therefore no injectionsite rxn
-Use in patients who either don't have enough response or cannot tolerate Methotrexate.
--->use alone, incombo with methotrexate, or in combo with another DMARD
46
Pathogenesis overview of RA on the molecular level.
self antigen presented by dendritic APC to T cells--> T cells recruit macrophages, CD8 T cells, and activate B cells. macrophages and CD8 lead to production of TNFalpha, IL1, and IL6...etc and B cells produce autoab.
47
Abatacept
| -mechanism for RA
-CTLA4 receptor attached to ab... thereby inactivating T cells; no T cell costimulation, and T cell will die
48
Methotrexate
| -mechanism for RA
-inhibits dihidrofolate reductase... therefore no pyrimidine synthesis... and no thymine synthesized. Decreases inflammatory cells
49
Leflunomide
| -mechanism for RA
-also blocks dihydrofolate reductase. thereby blocking thymine synthesis. Decreases inflammatory cells.
50
Anakrinra
| -mechanism for RA
Anti IL 1 thereby decreasing inflammation
51
Glucocorticoids
| -mechanism for RA
Inhibits T cell activation and IL2 production via Glucocorticoid receptor... thereby decreasing inflammation
52
Rituximab
| -mechanism
-anti CD20 B cells
53
Osteoarthritis
- definition
- what is the characteristic trait?
progressive joint disorder caused by GRADUAL LOSS of cartilage. Wear and tear based... but not entirely.
-Can see bony spurs.
54
History characteristics
- symmetry v asymmetry?
- morning stiffness?
- progression or alleviation during day?
- joints involved?
- exam findings? 2 positive; 3 negatives
- asymmetric
- morning stiffness <30 minutes
- gets worse during the day
- knees, hips, shoulders, PIP, and DIP
- positives: crepitus, locking
- negatives: no erythema, edema, or fever
55
risk factors for OA? (6)
- Age (increase)
- gender: female
- trauma
- obesity
- genetic predisposition
- race/ethnicity
56
OA
what does the histology show?
what does the joint look like grossly? (4)
What are some clinical findings? (1)
-cracked and fibrillation of cartilage matrix.
-decreased chondrocyte proliferation and matrix formation
-roughened=damaged catrilage
-shiny=no cartilage (eburnation=polished bone)
Subchondral sclerosis-dense bone under damaged region to withstand added force.
subchonral cyst--due to bone breakage then infiltration with synovial fluid
-Osteophytes/ increased joint size
57
what does the wall of the subchonral cyst look like?
wall is fibrous
58
What are clinical findings specific to the hands?
| What about the hips?
Hands: Heberden nodes (DIP), and Bouchard nodes (PIP)
Hips: osteophytes all over joint surface, but typically large flat osteophyte on medial surface to fovea
59
What is the cause of osteoarthritis?
imbalance of cytokines and growth factors leading to matrix loss.
-age alone is not enough, but wear and tear helps. other risk factors work in conjunction to age
60
Secondary causes of osteoarthritis (6 major categories)
1. trauma
2. bone disease
- septic joint, RA, Paget's, avascular necrosis
3. crystals (gout/CPPD)
4. congenital
- congenital hip displacement, bone dysplasia, hemachondromatosis
5. Metabolic
- ochronosis (deposition of homogenisate in soft tissue), acromegaly, hypothyroidism, Wilson's diease
6. Neuropathic arthropathy
61
Joints most affected by OA? (6)
wrist at radiocarpal, DIP, PIP, hips, knees, MTP
62
clinical findings of osteoarthritis (5 general; 2 hands; 1 feet; 2 legs)
- firmness/enlargement of joints
- crepitus
- deformity/instability
- decreased ROM
- weakness of muscle acting on joint
- Heberden's and Bouchard's nodes
- Hallux valgus
- Genu varus (bowed knees)
- Genu Valgus (locked knees)
63
Diagnosing osteoarthritis (2) and 1 in general
- image joint, and analyze joint fluid to r/o septic joint
| - blood work could be done to help determine treatment... not for dx.
64
Osteoarthritis...what do you see upon x-ray? (4)
- narrowing of joint space
- osteophytes
- subchondral cyst and subchondral sclerosis
