Msk Pharm 2, Pathoma - Joint, Muscle

Front 1

T/F Steroids are disease-modifying drugs in RA

Back 1

T, even tho they used to not be thought of that way.

Front 2

What are daily, low-dose steroids used for?

Back 2

Daily anti-inflammatory therapy, sometimes as a substitute for NSAIDs, sometimes during a flare. Can't use them forever.

Front 3

How are steroids used as bridge therapy?

Back 3

They're started once a person has a dx of RA because the Disease Modifying drugs take awhile to start working. (3-6 months)

Front 4

Toxicities of steroids

Back 4

1) Osteoporosis
2) Avascular necrosis of bone
3) Weight gain, fluid retention
4) Glucose intolerance --> diabetes
5) Cataract formation
6) Elevated blood pressure and cholesterol
7) Immunosuppressive effect --> infections
8) Thin skin and easy bruising
9) Peptic ulcer risk (especially with NSAIDs)
10) Acne
11) CNS effects - insomnia, mood disturbance, memory loss
12) Pituitary effects: decrease ACTH -->adrenal atrophy

Front 5

How do exogenous corticosteroids cause adrenal atrophy?

Back 5

They decrease ACTH release due to negative feedback. No ACTH acting on the adrenals --> less production --> atrophy of adrenals.

Front 6

Consequences of adrenal atrophy

Back 6

1) Relative adrenal insufficiency - can't increase production for stressors like infection or surgery.

2) Glucocorticoids must be TAPERED, not immediately stopped.

Front 7

Sx of adrenal insufficiency

Back 7

Weight loss, fever, low blood pressure, diarrhea

Front 8

most common class of osteoporosis-causing drugs

Back 8

glucocorticoids

Front 9

How do glucocorticoids cause osteoporosis?

Back 9

a) Decr Ca absorption in GI tract
b) Incr Ca excretion in kidney
c) Apoptosis of osteoblasts
d) Increased activity of osteoclasts
e) Muscle atrophy leading to increase in falls, which is a greater fracture risk.

Front 10

What is given as treatment and/or dietary supplement when taking long-term glucocorticoids?

Back 10

All currently used treatments for osteoporosis.
Calcium + Vit D

Front 11

Disease-modifying anti-rheumatic drugs (DMARDs): onset of action

Back 11

slow; 6 weeks - 6 months

Front 12

Disease-modifying anti-rheumatic drugs (DMARDs): categories

Back 12

A) Antimalarials
B) Methotrexate (MTX)
C) Sulfasalazine
D) Others (no need to memorize)
E) Gold was previously used

Front 13

Most commonly used Antimalarial drug in RA, especially for mild disease or in combo therapy?

Back 13

hydroxychloroquine (Plaquenil)

Front 14

hydroxychloroquine : toxicity

Back 14

LOW toxicity, also low potency

Diarrhea

Retinal toxicity with long-term use

Anemia in patients with G6PD-deficiency.

Front 15

Methotrexate in RA: MOA

Back 15

Unclear, may be due to interfering with suppression of B cell function and lowering cytokine levels/activity.

Front 16

Most widely used DMARD

Back 16

Methotrexate

Front 17

MTX competitively inhibits which enzymes? Implications?

Back 17

dihydrofolate reductase.
Patients must be given supplement.

Front 18

Methotrexate: Toxicities

Back 18

a) Bone marrow suppression due to lack of folate (GIVE FOLATE)

b) Pneumonitis

c) Immunosuppressive --> Infections

d) Hepatotoxicity

e) TERATOGENIC!

f) Nuisance effects - stomatitis, hair loss, nausea, diarrhea, fatigue/malaise.

Front 19

Methotrexate Hepatotoxicity: worse in patients with what arthritis?

Back 19

Psoriatic arthritis

Front 20

Methotrexate: Who should not receive it?

Back 20

1) Liver disease, regular EtOH drinkers
2) Renal insufficiency
3) Women of child-bearing potential
4) Lung disease

Front 21

T/F MTX may worsen subcutaneous nodules

Back 21

T

Front 22

Sulfasalazine: what properties make it a treatment for RA?

Back 22

antibiotic and anti-inflammatory activities

Front 23

Sulfasalazine: potency for RA tx

Back 23

Intermediate

Front 24

Sulfasalazine: how is it usually used?

Back 24

In combo therapy (not as monotherapy).

Front 25

Sulfasalazine: dose-related toxicity

Back 25

a) GI intolerance
b) Hematologic - anemia or leukopenia - DO NOT continue drug.
c) Oligospermia

Front 26

Sulfasalazine: idiosyncratic toxicity

Back 26

A) Rash
B) pneumonitis
C) hepatitis
D) Agranulocytosis
E) Aplastic anemia

MUST STOP DRUG IF D) and E) OCCUR.

Front 27

GENERAL approach to treating RA

Back 27

Treat early with DMARDs.

Used steroids as bridge therapy until DMARDs kick in.

Use combo of several DMARD if disease is refractory or aggressive

Consider biologic therapy.

Front 28

What is the Combination "Triple DMARD" therapy used for refractory disease or to rapidly induce remission?

Back 28

MTX + sulfasalazine + hydroxychloroquine

Front 29

Rituximab: MOA

Back 29

chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells. Rituximab destroys B cells, and is therefore used to treat diseases which are characterized by having too many B cells, overactive B cells or dysfunctional B cells. This includes many lymphomas, leukemias, transplant rejection and some autoimmune disorders.

Front 30

____ usually serves as the “building block” on which combo therapy is based

Back 30

MTX

Front 31

Infliximab: MOA

Back 31

monoclonal antibody against tumour necrosis factor alpha (TNFα). It is used to treat autoimmune diseases.

Front 32

Infliximab: Use in RA

Back 32

Works best in combo with MTX

Front 33

Adalumumab: MOA

Back 33

Human monoclonal Ig against TNF

Front 34

Adalumumab: Use in RA

Back 34

Can use alone or with MTX

Front 35

Etenercept: MOA and use in RA

Back 35

Soluble TNF-receptor fusion protein.

Can use alone or with MTX

Front 36

Three Anti-TNF Therapies

Back 36

Infliximab
Adalumumab
Etenercept

Front 37

Anti-TNF Therapies: side effect categories

Back 37

Immunosuppression
Autoimmune phenomena
Neoplasm

Front 38

What test must be done before Anti-TNF therapy initiated?

Back 38

PPD +/- CXR. It's because TNF is involved in TB containment.

Front 39

Anakinra: MOA

Back 39

interleukin-1 (IL-1) receptor antagonist.

Less potent than anti-TNF drugs.

Front 40

Abatacept: MOA

Back 40

fusion protein composed of the Fc region of the immunoglobulin IgG1, fused to the extracellular domain of CTLA-4, a molecule capable of binding B7. Abatacept is a selective costimulation modulator as it<b> inhibits the costimulation of T cells.</b>

Front 41

Effect of B cell depletion with Rituximab

Back 41

B cells are gone, BUT antibody levels remain normal for months.

Front 42

Tocilizumab : MOA

Back 42

humanized monoclonal antibody against the interleukin-6 receptor (IL-6R).

Front 43

Key to success in treating RA

Back 43

Early treatment with tight control

Front 44

What DMARD in Mild disease, risk averse?

Back 44

Hydroxychloroquine
Minocycline

Front 45

What DMARDs in Moderate to severe disease?

Back 45

Methotrexate
Sulfasalazine if contraindications to MTX
Leflunomide
Initial combination DMARD therapy

Front 46

purpose of articular cartilage

Back 46

allow movement between bones

Front 47

articular cartilage made of type ___ collagen

Back 47

2

Front 48

Degenerative joint disease: pathophys

Back 48

progressive degeneration of articular cartilage; wear and tear

Front 49

Degenerative joint disease: most commonly affected joints

Back 49

DIP, PIP
Hip, lower lumbar spine, knees

Front 50

Degenerative joint disease: evolution of pain throughout day

Back 50

joint stiffness in morning worsening over the course of day (with use)

Front 51

Eburnation: defn

Back 51

polishing of bone

Front 52

osteophytes: defn

Back 52

reactive bony outgrowths. classically in DIP and PIP joints of fingers.

Front 53

Rheumatoid arthritis: pathogenesis

Back 53

<b>inflammation of synovium (synovitis) --> leading to formation of pannus </b>(granulation tissues). Myofibroblasts in that granulation tissues can contract --> fusion of joint, dragging in different directions

Front 54

ankylosis:defn

Back 54

fusion of joint

Front 55

Rheumatoid arthritis: evolution of pain throughout day

Back 55

Worse in morning, gets better throughout day.

Front 56

DIP : defn

Back 56

distal interphalangeal joints

Front 57

PIP : defn

Back 57

proximal interphalangeal joints

Front 58

Classic joints NOT involved in RA

Back 58

DIP usually spared!

Front 59

Rheumatoid nodules: histology

Back 59

central necrosis surrounded by epithelial histiocytes

Front 60

IgM autoantibody against Fc portion of IgG

Back 60

Rheumatoid Factor - marker of tissue damage and disease activity.

Front 61

Complications of RA

Back 61

1) Anemia of chronic disease. (Chronic inflammation cuases production of acute phases reactants like Hepcidin, which blocks ability to use iron stored in macrophages.)

2) Secondary amyloidosis - SAA is acute phase reactant that gets converted to AA which gets deposited in tisuses.

Front 62

Pathophys of secondary amyloidosis in RA

Back 62

Inflammation causes activation of acute phase reactants. SAA (serum amyloid A) is acute phase reactant that gets converted to AA which gets deposited in tisuses.

Front 63

What other systems can be affected in ankylosing spondylitis?

Back 63

Eyes - uveitis
Aorta - aortitis

Front 64

"Can't see, can't pee, can't climb a tree" is a mnemonic for what?

Back 64

Reiter syndrome - Reactive arthritis.

Refers to arthritis, conjunctivitis, urethritis

Front 65

Infectious arthritis: two most common bacteria

Back 65

N. gonorrheae
S. aureus

Front 66

Infectious arthritis: symptoms

Back 66

involvement of single joint, usually knee.

systemic infection symptoms.

Front 67

Breakdown of _______ leads to uric acid

Back 67

purines (adenine and guanine)

Front 68

xanthine is converted to __________ by xanthine oxidase

Back 68

uric acid.

Front 69

Salvage pathway gets ___ and ____ before they become uric acid

Back 69

hypoxanthine and guanine

Front 70

HGPRT: defn

Back 70

hypoxanthine guanine phospho ribo transferase (HGPRT). Decreases amount of xanthine --> decrease uric acid.

Front 71

Lesch - Nyhan syndrome: pathophys

Back 71

Deficiency of hypoxanthine guanine phospho ribo transferase (HGPRT), an enzyme that salvages breakdown products of purine catabolism.

Without it, excess xanthine --> uric acid builds up.

Front 72

How does renal insufficiency cause gout?

Back 72

Kidney excretes uric acid. If it can't do this --> hyperuricemia.

Front 73

Why does meat consumption trigger gout?

Back 73

Bringing in lots of protein

Front 74

Two big triggers for acute gout

Back 74

Meat eating

Alcohol

Front 75

What is seen on microscopic exam for gout?

Back 75

needle shaped crystals with negative birefringence on polarized light.

Front 76

Negative birefringence: defn

Back 76

When crystals lay flat, they're yellow
lay LOW --> YELLOW

Front 77

Pseudogout is due to deposition of ________

Back 77

Calcium pyrophosphate

Front 78

What is seen on microscopic exam for pseudogout?

Back 78

Rhomboid shaped crystals with weak positive birefringence on polarized light.

Front 79

dermatomyositis is associated with __________.

Back 79

gastric carcinoma.

Front 80

dermatomyositis : symptoms

Back 80

1) bilateral proximal muscle weakness (can't comb hair or climb stairs.)

2) Rash of upper eyelids - heliotrope.

3) Malar rash - NOT lupus.

4) Red papules on elbows, knuckles, knees.

Front 81

dermatomyositis : lab findings

Back 81

1) Increased creatinine kinase due to muscle breakdown.

2) Positive ANA and anti-Jc-1 Ig. (NOT LUPUS)

3) Perimysial inflam with perifasciular atrophy of muscle.

Front 82

perimysium: defn

Back 82

around, outside of muscle.

Front 83

polymyositis: pathophys

Back 83

endomysial inflam (contrast with dermatomyositis)

Front 84

polymyositis: how is it different from dermatomyositis?

Back 84

NO SKIN involvement

Involves endomysial inflam, NOT perimysial.

Front 85

polymyositis: how is it similar to dermatomyositis?

Back 85

Proximal muscle weakness presentation.

Front 86

X-linked muscular dystrophy involves replacement of skeletal muscle by _________

Back 86

adipose tissue

Front 87

X-linked muscular dystrophy (Duchennes) is due to deletions of _________

Back 87

dystrophin

Front 88

Why do spontaneous mutations often happen in dystrophin?

Back 88

It's the largest gene in human.

Front 89

dystrophin: normal function

Back 89

linker molecule with ECM to muscle cytoskeleton.

Front 90

X-linked muscular dystrophy (Duchennes) : symptoms

Back 90

proximal muscle weakness around age 1 --> following distal muscle weakness.

Front 91

How is Duchenne's different from Becker muscular dystrophy?

Back 91

Duchennes: DELETION of dystrophin (DDD)

Becker: mutated dystrophin. Clinically milder disease.

Front 92

myasthenia gravis: pathophys

Back 92

competitive antibody against postsynaptive AChRs. Gets worse with activity due to less ACh being released.

Front 93

myasthenia gravis: symptoms

Back 93

muscle weakness worsening with use.

Often involves eyes --> double vision and ptosis.

Front 94

myasthenia gravis: associations with what other diseases?

Back 94

thymoma; thymic hyperplasia.

Front 95

Eaton Lambert syndrome: pathophys

Back 95

Ig against pre-synaptic Calcium channels. When open, Calcium channels result in release of ACh --> can't release ACh.

Front 96

myasthenia gravis: tx

Back 96

AChE inhibitors

Front 97

Eaton Lambert syndrome: associations with what other diseases?

Back 97

paraneoplastic syndrome related to small cell carcinoma

Front 98

most common benign soft tissue tumor

Back 98

lipoma

Front 99

most common malignant soft tissue tumor

Back 99

liposarcoma

Front 100

Rhabdomyoma

Back 100

benign tumor of skeletal muscle

Front 101

Most common malignant soft tissue tumor in children

Back 101

Rhabdomyosarcoma

Front 102

Rhabdomyosarcoma: characteristic cell

Back 102

rhabdomyoblast

Front 103

rhabdomyoblast are positive for ____.

Back 103

desmin

Front 104

Rhabdomyosarcoma: most common site

Back 104

head and neck; vagina in young girl (embryonal sarcoides)