3-2 Rheumatoid Arthritis & Gout Flashcards
(110 cards)
1
Q
What is Rheumatoid arthritis?
A
Chronic, system autoimmune disease of unknown etiology
2
Q
What characterizes rheumatoid arthritis? (2)
A
-inflammation and pain in the joints -progressive joint destruction (can also involve extra-articular sites)
3
Q
What are the mediators of rheumatoid arthritis? (6)
A
- T cells
- B cells
- TNF alpha
- IL-6
- IL-1
- Prostaglandin
4
Q
What are the treatment goals for Rheumatoid Arthritis? (2)
A
- Decrease ACUTE joint pain
- Prevent/control joint damage
5
Q
What are the classes of drugs to decrease acute joint pain? (3)
A
- NSAIDs
- Analgesics
- Glucocorticoids
*Symptomatic relief only!
6
Q
What are the classes of drugs to prevent/control joint damage? (2)
A
- Disease-Modifying anti-Rheumatic drugs (DMARDs)
- Biological Response Modifiers (BRMs)
7
Q
When would you normally use the drugs to reduce ACUTE joint pain?
A
Typically used to minimize symptomatics effects of RA while waiting for the clinical effects of the slow acting DMARDS and BRMs
8
Q
What are some examples of analgesics? (3)
A
- Acetominophen
- Capsacin
- Opioids
9
Q
What is an example of a Glucocorticoid?
A
Dexamethasone
10
Q
What are some examples of NSAIDS? (2)
A
- ibuprofen
- naproxen
11
Q
What are some DMARDs? (4)
A
- hydroxychloroquine
- sulfasalazine
- methotrexate
- leflunomide
12
Q
What are some classes of BRMs/Biologics? (5)
A
- anti-TNF drugs
- other anti-cytokine drugs
- drugs that inhibit T cells
- drugs that inhibits B cells
- Chemical inhibitors of cytokine signaling
13
Q
How long does it take for DMARDs to show efficacy?
A
weeks to months
*slow acting anti rheumatic drugs
14
Q
How long are DMARDs typically taken?
A
Long periods
such as, months to years
15
Q
What are some less commonly used DMARDs? (5)
A
- Azathioprine
- D-Penicillamine
- Gold Salts
- Cyclosporin
- Cyclophosphamide
16
Q
What is hydroxychloroquine?
A
Anti-malarial drug that is moderately effective for mild Rheumatic Arthritis
17
Q
What is the mechanism of Hydroxychloroquine?
A
Thought to involve
- inhibition of TLR signaling in dendritic/B cells
- inhibition of antigen presentation to T cells
*Low yield (unlikely to be a test question)
18
Q
How long does it take for hydroxychloroquine to take effect?
A
3 - 6 months
*Low yield (unlikely to be a test question)
19
Q
What is the side effect of Hydroxychloroquine?
A
- Occular Toxicity that can result in permanent visual loss RARE (1/40,000)
- Risk factors
- Length of treatment > 5 yrs
- Age > 60 yrs
- High dose
- Risk factors
Safe during pregnancy and lactation
Generally well tolerated
20
Q
What is a drug considered to be a Sulfasalazine?
A
Azulifidine
21
Q
How efficacious is sulfasalazine compared to methotrexate?
A
Similar efficacy
*Effective in up to 50% of patients
22
Q
How does Sulfasalazine become active?
A
Begins as a prodrug (5-aminosalicyclic acid) covalently linked to sulfapyridine
Cleaved to active components by bacteria in the gut THEN sulfapyridine is absorbed and is the active component in RA
23
Q
Mechanism of action of Sulfasalazine
A
thought to interfere with T and B cell immune responses
possibly inhibits activation of NF-kB
*low yield
24
Q
When will you see the effects of Sulfasalazine?
A
1 - 3 months
*Low yield
25
Side effects of Sulfasalazine (2)
1. Agranulocytosis within 2 weeks
2. fully reversible Hepatotoxity
More toxic than hydroxychloroquine
**_Safe during Pregnancy_**
26
How is it often prescribed?
In combination with other DMARDs (e.g. Hydroxychloroquine)
27
Indication for Methotrexate
Drug of choice for patients with patients with active moderate/severe disease (60% of RA patients)
-used at 10-1000X lower dose than that used in cancer treatment
28
Results of Methotrexate use (3)
1. decreases appearance of new bone erosions
2. improves the long term clinical outcome
3. up to 70% of patietns experience some response to the drug
29
How long does it take for Methotrexate to take effect?
4 - 6 weeks
\*low yield
30
Mechanism of Methotrexate
In Powerpoint FYI only
31
Side effects fo Methotrexate (4)
_Common SE_ - dose related hepatotoxicity (abstain from alcohol)
_Rare SE_
1. Pulmonary toxicity
2. Bone Marrow suppression
3. Increased risk of lymphoma
Generally well tolerated (\>50% of pts continue taken for over 3 years)
32
How is methotrexate excreted?
MTX is 80 - 90% renally excreted
\*adverse effects frequently observed in patients with renal impairment
33
What are the contraindications for Methotrexate? (3)
1. Pregnancy/breast feeding (used as abortifacient)
2. Not recommended for patients with pre-existing liver disease
3. Not recommended for patients with renal impairment
34
When would you use Leflunomide?
Alternative for those unable to take or non responsive to MTX
Low cost alternative to TNF inhibitors or those with preference for oral \<--(\*whistle\*)
As effective as either sulfasalazine or MTX
35
How long does it take for Leflunomide to take effect?
1 - 2 months
36
Mechanism of Action for Leflunomide(4)
"**U** **GL**a**D** Leflunomide is Low cost! "
1. Inhibits **U**ridine synthesis
2. Inhibits **G**1 cell cycle (arrest)
3. Inhibits **L**ymphocytes
4. Inhibits **D**ihydroororate Dehydrogenase
*Inhibitis [Dihydroororate Dehydrogenase] --\> DEC Uridine synthesis --\> [Inhibits G1 Cell cycle arrest]*
37
Side effects for Leflunomide (4)
1. Hypertension (especially with concurrent NSAIDs)
2. Diarrhea/nausea
3. rash (10 - 15% of patients)
4. Hepatotoxicity (10 - 13%)
1. more severe in presence of methotrexate requiring liver enzyme monitoring
38
Contraindications for Leflunomide (2)
1. Pregnancy/Breast feeding
2. Pre-existing liver diease
39
What are Biological Response Modifiers/Biologics?
Recombinant drugs that are specifically designed to inhibit either cytokines or cell types involved in the autoimmune response in RA
40
What are the pathways TNF alpha controls? (3)
1. Activated Endothelial cells --\> Leukocyte recruitment --\> Joint inflammation
2. Synoviocyte/Chondrocyte --\> Cartilage breakdown
3. Osteoclast Different --\> Bone resorption --\> Bone Erosion
It is synthesized by activated CD4+ T cells, macrophages and mast cells
41
What are some [TNF Alpha] drugs? (3)
"TNF-(**A**)**IE**"
1. **E**tanercept
2. **I**nfliximab
3. **A**dalimumab
42
Administration of anti-TNF alpha drugs (2)
1. given either subQ or IV
2. administered weekly/bi-weekly
## Footnote
*as effective as methotrexate*
43
How long does it take for [TNF alpha] drugs to take effect?
1 - 4 weeks
44
Clinical outcomes of anti-TNF alpha drugs (3)
1. decreased joint pain and swell
2. decreased formation of new bone erosions
3. decreased progression of structural joint damage
~30 - 60% of patients will exhibit a 20 - 50% improvement in their syptoms
45
Clinical use of Anti-TNF alpha drugs
Monotherapy
\*combination therapy with methotrexate [often added to patients not responding adequately to methotrexate monotherapy
46
Side effects of TNF alpha blockers? (5)
[**DICC**: **D**emyelination / **I**nfection / **C**HF / **C**A]
1. increased risk of opportunistic infx (bact. and fungal)
2. potential reactivation of latent TB and latent HBV)
3. Exacerbation of pre-existing CHF (Rare)
4. Developement of demyelinating diseases (e.g. multple sclerosis) (Rare)
5. Appearance of malignancies, especially lymphoma (Rare)
47
Contraindication for TNF alpha blockers
Should not be given to patients with either acute or chronic infx
\*treatment should be discontinued if a serious infx or sepsis develops
48
Name a T cell inhibitor.
Aba**T**acept
49
What are T cell inhibitors?
Recombinant fusion protein of CTLA-4 and human IgG1
\*binds with high affinity to CD80/CD co-stimulatory molecules on APC
50
Mechanism of Action for T cell inihibitor
Inhibits T cell activation by blocking the delivery of CD 28 co-stimulatory signals that are essential for efficient T cell activation
51
Who are T cell inhibitors effective for?
Effective in patients non-responsive to TNF alpha inhibitors
~30 - 60% of patients will exhibit a 20 - 50% improvement in their symptoms
52
Side effect of T cell inhibitors
Increased risk of serious infx
\*screen for latent TB and HBV
53
Contraindication for T cell inihibitors
should not be given in combination with a TNF alpha blocker
54
Name one B cell inihibitor
Rituxima**B**
55
A: [B cell inhibitor] MOA
B: SE
A: Chimeric Ab that binds to [B-cell CD20]
B: Can **Deplete** Serum B-cells if given IV!!
*CD20 molecule expressed exclusively on B lymphcytes*
56
What role do B cells play in the etiology of RA? (2)
1. antigen presentation to T cells
2. formation of autoantibodies
Depletion reduces disease progression
57
What are the effects of B cell inhibitors? (2)
How long do they last?
1. Decrease signs/symptoms of disease
2. Reduces disease progression
Effects not seen for 3 months, although effects may last 6 months to 2 years
58
Who are B cell inhibitors effective in?
patients not responsive to TNF alpha inhibitors
59
Side effects of B cell inhibitors (3)
1. Increased infx
2. Reactivation of latent viruses
3. **Progressive multifocal leukoencephalopathy (PML)** -RARE fatal demyelinating disease associated with reactivation of JC virus
60
Name one anti-cytokine agent
Anakinra
61
What are anti-cytokine agents?
Recombinant version of an endogenous IL-1 receptor antagonist (IL-1RA)
62
How effective are anti-cytokine agents compared to anti-TNF agents?
Less effective
63
What is the half life of Anakinra?
short half life of 4 - 6 hours
\*must be given SubQ once/day
64
MOA of Anakinra
Competitively inhibits the pro-inflammatory effects of IL-1
65
Side effects of Anakinra (2)
1. Increased of neutropenia
2. Increased of serious infx
\*complications more frequent when given together with an anti-TNF alpha drug
66
Contraindication for Anakinra
Do not give to patient with acute/chronic infx
67
Name one cytokine Receptor (R) antagonist
Tocilizumab
68
What are cytokine R antagonists?
Chimeric humanized antibody directed against the ***IL-6 cytokine receptor***
69
How is Tocilizumab used clinically? (2)
1. Used in patients non-responsive to TNF inhibitors
2. combination Tx with MTX
70
Side effects of Tocilizumab (5)
"When I *Toc*k up...I want **CHIPC**"
1. **C**A (Malignancy)
2. **H**epatotoxic
3. **I**nfection (serious)
4. **P**ancytopenia
5. **C**holesterol INC
71
Contraindications for Tocilizumab (4)
1. Patients with acute/chronic infx
2. Should NOT be combined with other BRM drugs
3. Patients with pre-existing liver disease
4. Patients with low blood counts or on immunosuppressive therapy
72
Name one small molecule inhibitor of cytokine signaling
Tofacitinib
73
What are small molecule inhibitors of cytokine signaling?
Small molecule inhibitor that inhibits JAK tyrosine kinases involved in immune cell cytokine signaling
\*new class of anti-rheumatic drug
74
MOA of Tofacitinib
See Powerpoint for details
75
Side effects of Tofacitinib (4)
[**CHIP**: **C**holesterol / **H**epatotoxic / **I**nfection / **P**ancytopenia]
"*To Fat* only get 1 **CHIP**!"
1. Pancytopenia (Lymphocytopenia, neutropenia, and anemia)
2. Increased risk of serious infx
3. Lipid abnormalities (increased cholesterol)
4. Increased Liver enzymes
76
Treatment Strategy for Rheumatoid Arthritis (by severity)
**_MILD dz:_** Hydroxychloroquine or Sulfasalazine or combination therapy
**_Moderate dz_**: Methotrexate (alternative - Leflunomide)
or Combination Therapy - DMARDs +/- TNF inhibitors
**_Severe dz:_** BRMs/Biologics
or Combination Therapy - DMARDs +/- TNF inhibitors (Resistance to TNF inh. --\> switch to other BRM
77
What is Gout?
Extremely painful form of arthritis
\*linked to a purine rich diet and excessive alcohol consumption
78
What is Gout associated with? (5)
1. Obesity
2. Hypertension
3. Hyperlipidemia
4. type - 2 diabetes
5. HYPERURICEMIA
79
What are the causes of Hyperuricemia in Gout? (2)
Hyperuricemia - high serum uric acid (\>7 mg/dL)
1. **overproduction** of uric acid (10% of patients)
2. **decreased excretion** of uric acid by the kidney (90% of patients)
80
Disease course of Gout
Asymptomatic hyperuricemia --\> Acute Gouty Attack --\> Intercritical phase --\> Multiple Acute Gouty Attacks --\> Chronic Gout
Intercritical phase - Hyperuricemia without symptoms (10% patients never experience 2nd attack)
81
A: Signs of an Acute Gouty Attack (2)
B: When does this resolve
1. Rapid onset of intense pain
2. swelling in a single joint
e.g. first metatarsophalangeal joint
B: typically resolves in 3 - 10 days
82
What characterizes Chronic Gout? (5)
1. Recurrent attacks
2. Increased Freq of attacks
3. Increased severity of attacks
4. Increased Joint Involvement
5. **Formation of TOPHI**
\*TOPHI - urate deposits around the joint that promote inflammation and joint destruction
83
In what ways can different drugs treat Gout? (4)
1. Relieve symptoms of acute gouty attack
2. Lower uric acid levels by promoting uric acid excretion
3. Lower uric acid levels by inhibiting uric acid synthesis
4. Directly degrade Uric acid
84
Name two drugs that relieve the symptoms of a Gouty Attack (2)
1. NSAIDs
2. Colchicine (traditional treatment)
85
A: Indications for NSAIDs (2)
B: What drug is **NOT** used for Gout Tx
1. Acute Gouty attack - Lowers pain and disability due to acute attack
2. Prophylactic treatment with other anti-GOUT drugs
\***Aspirin/Salicylates are NOT used** - both inhibit uric acid at low doses and can induce gout
86
MOA of Colchicine?
plant alkaloid that prevents tubulin polymerization into microtubules
87
Effects of Colchicine (2)
1. lowers leukocyte migration and phagocytosis
2. anti-inflammatory, but NO analgesic properties
88
When to use Colchicine?
- effective when given during the first 24 - 48 hours of the attack
- can also be used in prophylaxis with other anti-GOUT drugs
**\*very narrow therapeutic window** - limited by side effects (especially at high doses/ 80% of patients develop NVD)
89
Name one Uricosuric agent
Probenecid
Uricosuric agent - drug that enhances uric acid excretion
\*Lesinurad newly approved Dec 2015
90
MOA of Probenecid
weak organic acid inhibits anion transporters in the proximal renal tubules involved in the reabsorption of Uric Acid
91
Outcomes of Probenecid usage
INC Uric Acid **Excretion**
92
A: Indication for Probenecid
B: When is it given
patients that **under excrete** uric acid (90% of patients)
\***should not** be given until 2 -3 weeks after initial attack. Drug can initiate and/or prolong the symptoms of an acute gouty attack (by affecting uric acid homeostasis)
Prophylactic NSAID Tx should be provided to dec. risk of attack
93
Contraindications for Probenecid (2)
1. Patients that overproduce Uric acid (inc. risk of kidney stones)
2. Patients with kidney stones and/or renal insufficiency
94
Drug Interactions for Probenecid
Many drugs that are normally reabsorbed in the kidney by URAT1
\***Dec. Clinical efficacy**
Examples of drugs using URAT1 - Indomethacin, naproxen, lorazepam, cephalosporins, methotrexate, captopril, AZT, and ganiciclovir
95
Name two drugs that decrease uric acid synthesis (2)
1. Allopurinol
2. Febuxostat
96
Indication for Allopurinol/Februxostat
Which patients are they particularly useful for? (3)
Used in the treatment of chronic gout to block overproduction of uric acid
1. _high level of endogenous_ uric acid synthesis
2. recurrent kidney stones
3. renal imairment
97
MOA for Allopurinol/Februxostat
Inhibitors of Xanthine Oxidase, an enzyme that catalyzes the final two steps in purine degradation
98
Side effects of Allopurinol/Februxostat (5)
**FLAG** and **R**ash!
1. **F**ever
2. **L**eukopenia and Thrombocytopenia
3. [**A**llopurinol Hypersensitivity Syndrome]
4. **G**outy attack-Acute if NSAID px is not given
5. **R**ash
The last 3 can occur in 3 - 5 % of patients
99
Symptoms of Allopurinol hypersensitivity syndrome (RARE)(5)
Potentially life threatening reaction (25% mortality)
1. erythematous rash
2. fever
3. hepatitis
4. eosinophilia
5. acute renal failure
100
When is the allopurinol hypersensitivity syndrome most likely to hapen?
most likely to occur in patients taking **excessive doses** of drug in the presense of **pre-existing renal failure** and/or **diuretics**
**\***dosage reduction required in renal impairment
101
What is the characteristic genetics of the allopurinol hypersensitivity syndrome?
HLA-B\*5801 allele
* more common in Korean, Han Chinese, Thai ancestry
102
Important drug Interaction with allopurinol/Febuxostat
What drug(s)?
What is the drug(s) used for?
6-mercaptopurine and azathioprine (prodrug)
* purine synthesis inhibitors
* used in immunosuppression and in treatment of leukemia/lymphoma
* metabolized by _Xanthine Oxidase_ (allopurinol blocks this) to inactive metabolite
The blockage of Xanthine oxidase decreases conversion of 6-mercaptopurine into Inactive metabolite leading to Toxicity
103
A: Which chronic gout patients are indicated for treatment? (3)
B: Tx goal
1. Patients with multiple gouty attacks
2. Those that are more susceptible to future attacks (e.g. renal insuffciency)
3. Patients with very high levels of uric acid (\>12 mg/dL)
B: reduce serum uric acid levels to \<6 mg/dL
104
Criteria to categorize patient as over-producer or an under-secretor of uric acid
* Under**excretion** (Probenecid) = 24 hour urinary uric acid excretion \<**700** mg/dL [90% of patients]
* Overproducer (Allopurinol vs. Febuxostat) = 24 hour urinary uric acid excretion \>**700** mg/dL [10% of patients]
105
How long is effective therapy for Chronic Gout?
LIFELONG
106
Name one drug used to treat drug resistant Chronic Gout
Pegloticase
107
MOA of Pegloticase
Porcine uricase linked to PEG (polyethylene glycol)
Enzymatic conversion of Uric Acid to soluble metabolite
\**Humans lack* Uricase enzyme
108
Indication for Pegloticase
Advanced, actively symptomatic gout which is uncontrolled with other uric acid lowering drugs
* presence of frequent flares
* presence of TOPHI
* contraindications to other GOUT drugs
109
Clinical use of Pegloticase
A: Dosage Timing
B: Caveot
A: administration by IV infusion every 2 weeks
B: requires NSAID/Colchicine prophylaxis
*effective in months vs. years with oral agents?*
110
Side effects of Pegloticase (0)
Generally well tolerated
GENERATION OF ANTI-DRUG ANTIBODIES LIMITS TREATMENT
