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PT 2 > Block 8 - L7 > Flashcards

Block 8 - L7 Flashcards

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1
Q

What are the 2 treatment goals of RA?

A
  1. Decrease acute joint pain

2. Prevent or control joint damage

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2
Q

What drugs are used to decrease acute joint pain in RA?

A
  1. NSAIDs
  2. Analgesics
  3. Glucocorticoids
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3
Q

What drugs are used to prevent or control joint damage in RA?

A
  1. Disease-modifying anti-Rheumatic Drugs (DMARDs)

2. Biological response modifiers (BRMs)

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4
Q

What is the goal of NSAIDs, analgesics, and glucocorticoids in the treatment of acute joint pain iN RA?

A

Symptomatic pain relief while waiting for the clinical effects of the slow acting DMARDs and BRMs

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5
Q

List the 4 DMARDs.

A
  1. Hydroxychloroquine
  2. Sulfasalazine
  3. Methotrexate
  4. Leflunomide
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6
Q

List the types of BRMs (biologics).

A
  1. Anti-TNF drugs (entanercept, adlimumab, infliximab)
  2. Other anti-cytokine drugs (ankinra/tocilizumab)
  3. Drugs that inhibit T cells (abatacept)
  4. Drugs that inhibit B cells (rituximab)

Chemical inhibitors of cytokine signaling (tofacitinib)

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7
Q

What are the general features of DMARDs?

A
  1. Reduce and/or prevent joint damage
  2. Slow-acting (weeks to months to show efficacy, taken for long periods)
  3. Inhibit the overactive immune system
  4. Should be considered soon after onset of the disease
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8
Q

What is hydroxychloroquine?

A

Anti-malarial drug that is moderately effective for mild RA

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9
Q

What is the MOA of hydroxychloroquine?

A

Unclear; thought to involve inhibition of TLR signaling in dendritic/B cells, inhibition of Ag presentation to T cells

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10
Q

What is the time to effect of hydroxychloroquine?

A

3-6 months

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11
Q

Discuss the AE of hydroxychloroquine.

A

Generally well-tolerated, safe during pregnancy and lactation

Rare/serious: occular toxicity that can result in permanent visual loss

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12
Q

What are risk factors for developing occular toxicity due to hydroxychloroquine?

A

Length of treatment (>5 years), >60 y/o, high dose

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13
Q

What is sulfasalazine?

A

Drug that decreases signs and symptoms of disease and slows joint destruction

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14
Q

How does sulfasalzine compare to hydroxychloroquine and methotrexate?

A

More toxic than hydroxy

Similar efficacy to methotrexate

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15
Q

What is the MOA of sulfasalazine?

A

Prodrug (5-aminosalicylic acid covalently linked to sulfapyridine) is cleaved to its active components by bacteria in the gut. Sulfapyridine (active component) is absorbed. MOA is unclear, but thought to interfere with T and B cell immune responses (possible inhibition of NF-kappa-B activation)

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16
Q

What is the time to effect of sulfasalazine?

A

1-3 months

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17
Q

Discuss the AE of sulfasalazine.

A

Safe during pregnancy

Agranulocytosis within 2 weeks (very rare, fully reversible) and hepatotoxicity

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18
Q

What is the drug of choice for patients with active moderate/severe RA (~60% of patients)?

A

Methotrexate

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19
Q

Discuss the effects of methotrexate.

A

Decreases the appearance of new bone erosions and improves the long-term clinical outcome.

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20
Q

What is the time to effect of methotrexate?

A

4-6 weeks

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21
Q

What is the MOA of methotrexate in RA (aka - low dose methotrexate)?

A

Indirectly increases the production of adenosine, which exhibits known immunosuppressive properties (different MOA than in cancer)

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22
Q

What are the AE of methotrexate?

A

Common: dose-related hepatotoxicity (abstain from alcohol intake)

Rare: pulmonary toxicity, bone marrow suppression, increased risk of lymphoma (requires clinical monitoring)

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23
Q

What are the contraindications of methotrexate?

A

Pregnancy/breast feeding (abortifacient)
Pre-existing liver disease
Renal impairment (80-90% renal excretion)

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24
Q

Discuss the efficacy of Leflunomide and why it is prescribed.

A

As effective as sulfasalazine or methotrexate; alternative for those unable to take or non-responsive to MTX; low cost alternative to TNF inhibitors

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25
What is the time to effect of leflunomide?
1-2 months
26
What is the MOA of Leflunomide?
Inhibits the enzyme dihydroorotate dehydrogenase; this enzyme is responsible for synthesis of uridine (RNA building block). This causes G1 cell cycle arrest, inhibiting both T cell proliferation and the production of autoantibodies by B cells
27
What are the AE of leflunomide?
Hypertension (especially with NSAIDs) Diarrhea, nausea, rash Hepatotoxicity (requires monitoring)
28
What are the contraindications of Leflunomide?
Pregnancy/breast feeding, pre-existing liver disease
29
Which biologic inhibits IL-1?
Anakinra
30
Which biologics inhibit TNF-alpha?
Etanercept Adlimumab Infliximab
31
Which biologic inhibits IL-6?
Tocilizumab
32
Which biologic inhibits T-cells?
Abatacept
33
Which biologic inhibits immune cytokine signaling?
Tofacitinib
34
Which biologic inhibits B-cells?
Rituximab
35
Discuss the critical role of TNF-alpha in the pathogenesis of RA.
It is synthesized by activated CD4+ T cells, macrophages, and mast cells. 1. Activates endothelial cells, which recruit leukocytes -> joint inflammation 2. Impairs activity of synoviocytes and chondrocytes -> cartilage breakdown 3. Activates osteoclast differentiation -> bone resorption and bone erosion
36
What is the MOA of anti-TNF-alpha drugs?
Bind soluble TNF-alpha and prevent it from binding to its receptor; prevents biological response
37
Discuss the efficacy and administration of anti-TNF-alpha drugs.
As effective as methotrexate Administered weekly/bi-weekly Subcutaneous or IV
38
What is the time to effect of anti-TNF-alpha drugs?
1-4 weeks
39
What are the effects of anti-TNF-alpha drugs?
Decreased joint pain, swelling, formation of new erosions, progression of structural joint damage
40
What are the AE of anti-TNF-alpha drugs?
1. Increased risk of opportunistic infections (fungal and bacterial) 2. Potential reactivation of latent TB and latent HBV (screen for both!) 3. Rare - exacerbation of pre-existing CHF, development of demyelinating disease (MS), appearance of malignancies (lymphoma)
41
What are the contraindications of anti-TNF-alpha drugs?
Patients with acute or chronic infection
42
What is the MOA of Abatacept?
Inhibits T-cell activation by blocking the delivery of CD28 co-stimulatory signals that are essential for efficient T cell activation (recombinant fusion protein of CTLA-4 and human IgG1 that binds with high affinity to CD80/CD86 molecules on APC)
43
What are the effects of Abatacept?
Slows damage to bone and cartilage, relives symptoms and signs of RA
44
What are the AE of Abatacept?
Increased risk of serious infection (screen for latent TB and HBV), do not give with TNF-alpha blocker
45
What is the MOA of Rituximab?
Chimeric Ab that binds to CD20 on B cells, leading to depletion of B cells from blood
46
Discuss the time to effect of Rituximab.
Effects not seen for 3 months, but they effects may last 6 months to 2 years following a single infusion
47
What are the AE of Rituximab?
1. Increased infections 2. Reactivation of latent viruses 3. Progressive multifocal leukoencaphlopathy (PML) - rare but fatal demyelinating disease associated with reactivation of JC virus
48
What is the MOA of Anakinra?
Competitively inhibits the pro-inflammatory effects of IL-1 as an IL-1 receptor antagonist
49
What are the AE of Anakinra?
1. Increased risk of neutropenia | 2. Increased risk of serious infections
50
What is the MOA of Tocilizumab?
IL-6 receptor antagonist
51
When is Tocilizumab indicated?
Patients who are non-responsive to TNF inhibitors or in combination therapy with MTX
52
What are the AE of Tocilizumab?
1. Increased risk of BM suppression (lymphocytopenia, neutropenia, anemia) 2. Increased risk of serious infections 3. Hepatotoxicity 4. Increased cholesterol 5. Increased risk of malignancy
53
What are the contra-indications of Tocilizumab?
1. Patients with acute/chronic infections 2. Patients taking other BRMs 3. Patients with pre-existing liver disease 4. Patients with low blood counts or on immunosuppressive therapy
54
What is the MOA of Tofacitinib?
Inhibits JAk tyrosine kinases involved in immune cell cytokine signaling
55
What are the AE of Tofacitinib?
1. Lymphocytopenia, neutropenia, anemia 2. Increased risk of serious infections 3. Increased cholesterol 4. Increased liver enzymes
56
When treating mild RA, what is the overall strategy?
1. Symptomatic relief | 2. Hydroxychloroquine or sulfasalazine or combination therapy
57
When treating moderate RA, what is the overall strategy?
1. Symptomatic relief | 2. Methotrexate (alternative - Leflunomide), can do combination therapy (DMARDs +/- TNF inhibitors)
58
When treating severe RA, what is the overall strategy?
1. Symptomatic relief 2. BRMs/biologics, can do combination therapy If resistance to TNF inhibitors, switch to other biologics
59
What is gout and what is it associated with?
Extremely painful form of arthritis Linked to a purine-rich diet, excessive alcohol consumption, obesity, HTN, hyperlipidemia, DM2 Associated with hyperuricemia
60
Define hyperuricemia; why does it happen in gout?
Serum uric acid >7 mg/dL Overproduction of uric acid (10%) or decreased excretion by the kidney (90%)
61
How is acute gout treated?
With drugs that relieve the symptoms of the acute gouty attack (NSAIDs, colchicine, corticosteroids)
62
How is chronic gout treated?
1. Drugs that lower uric acid levels by promoting uric acid excretion (uricosuric agents) 2. Durgs that lower uric acid levels by inhibiting uric acid synthesis (allopurinol, febuxostat) 3. Drugs that directly degrade uric acid (pegloticase)
63
Discuss the use of NSAIDs in relieving the symptoms of an acute gouty attack.
Decreases pain and disability due to an acute attack; may be used as prophylactic treatment with other anti-gout drugs
64
What NSAIDs are not used to treated an acute gouty attack and why?
Aspirin and salicylates; both inhibit uric acid excretion at low doses and can INDUCE gout
65
Discuss the use of cochicine in relieving the symptoms of an acute gouty attack.
Plant alkaloid that prevents tubulin polymerization into microtubules; leads to decreased leukocyte migration and phagocytosis Anti-inflammatory, but not analgesic; effective when given during the first 24-48 hours Narrow therapeutic window (N/V, diarrhea)
66
Discuss the use of corticosteroids in relieving the symptoms of an acute gouty attack.
Oral or intra-articular injections inhibit inflammation; used in patient unable to take NSAIDs or cochicine
67
List the two uricosuric agents used in the treatment of chronic gout.
Probenecid | Lesinurad
68
What is the MOA of probenecid?
Weak organic acid inhibits anion transports in the proximal renal tubules involved in the reabsorption of uric acid; by blocking URAT1 (transporter), uric acid reabsorption is decreased, urine excretion is increased
69
When is probenecid indicated?
In patients that underexcrete uric acid (90% of patients); however, should not be given until 2-3 weeks after the initial attack, as it can initiate or prolong symptoms of an acute gouty attack
70
What are the contraindications of probenecid?
Patients that overproduce uric acid (increases risk of kidney stones) Patients with kidney stones or renal insufficiency
71
What are the DDI of probencid?
Can lead to decreased clinical efficacy of drugs that are normally reabsorbed in the kidney by URAT1
72
What is the indication of allopruinal and febuxostat?
Chronic gout to block overproduction of uric acid Useful in patients with high levels of endogenous uric acid synthesis, recurrent kidney stones, renal impairment, and grossly elevated uric acid levels (presence of tophi)
73
What is the MOA of allopurinal and febuxostat?
Inhibition of xanthine oxidase (catalyzes the final two steps in purine degradation)
74
What are the AE of allopurinal and febuxostat?
1. Induction of acute gouty attack (without NSAID prophylaxi) 2. Rash, leukopenia, thrombocytopenia, fever 3. Allopurinol hypersensitivity syndrome
75
What are the symptoms of allopurinol hypersensitivity syndrome? Note - does not happen with Febuxostat
Erythematous rash, fever, hepatitis, eosinophilia, cute renal failure
76
Who is at risk for developing allopurinol hypersensitivity syndrome?
Patients taking excessive doses of drug in the presence of renal failure and/or use of diuretics; associated with HLA-B*5801 allele
77
What are the DDI of allopurinol?
6-mercaptopurine and azathiorpine These drugs are purine synthesis inhibitors and are used in immunosuppression and in treatment of leukemia and lymphoma; allopurinol blocks xanthine oxidase, which normally inactivates 6-mercaptopurine. Leads to increased toxicity
78
How is chronic gout managed?
1. Hyperuricemia by itself does not indicate treatment 2. Treatment for patients with multiple gouty attacks, those susceptible to future attacks (renal insufficiency), patients with very high levels of uric acid (>12 mg/dL) 3. Lifelong treatment required to be effective
79
What is the treatment goal in management of chronic gout?
Reduce serum uric acid levels to <6 mg/dL
80
If the 24 hour urinary uric acid excretion is <700 mg/dL, which drug is indicated and why?
Probenecid (undersecretion problem)
81
If the 24 hour urinary uric acid excretion is >700 mg/dL, which drug is indicated and why?
Allopurinol (overproduction problem)
82
What are allopurinol/febuxostat specifically indicated for?
Patients with a history of uric acid kidney stones, with renal insufficiency, and with tophi
83
What is used to treat drug-resistance chronic gout?
Pegloticase
84
What is the MOA of Pegloticase?
Causes enzymatic conversion of uric acid to soluble metabolites (allanation)
85
When is pegloticase indicated?
Advanced, actively symptomatic gout uncontrolled with other uric acid lowering drugs (presence of frequent flares, tophi, contraindications of other gout drugs) Administration by IV infusion every 2 weeks, requires NSAID/cochicine prophylaxis, effective in moths vs. years with oral agents
86
What are the AE of pegloticase?
Generally well-tolerated, generation of anti-drug Ab limits treatment

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