Exam 2 Flashcards
1
Q
Urate
A
Ionized form of uric acid
2
Q
Hyperuricemia
A
serum urate concentration >6.8mg/dL
3
Q
Gout
A
Monosodium urate (MSU) crystals in joints, bones, and soft tissue
4
Q
What do you think of when you think of gout?
A
Uric acid
5
Q
Causes of gout
A
Overproduction (10%)
Underexcretion (90%)
6
Q
Risk factors for gout
A
Male and postmenopausal females, age, obesity, alcoholism, dehydration, excess cell turnover, genetic conditions, hyperuricemia, hypothyroidism, medications, renal impairment, sex, trauma
Think about kidney dysfunction! Age and obesity can affect this.
7
Q
Causes of overproduction of uric acid
A
Dietary purine- meat, seafood, beer
Endogenous purine synthesis- malignancy, tumor lysis syndrome
Purine salvage- enzyme deficiency
Purine breakdown- glycogen storage disease
8
Q
Causes of underexcretion of uric acid
A
Urinary excretion- diuretics (thiazides, dose dependent), renal failure
Urinary reabsorption- alcohol, genetic defects
9
Q
Why might we limit purine in gout?
A
Purine is metabolized by xanthine oxidase and turned into uric acid.
10
Q
Acute gout
A
Uric acid crystal formation
Crystal deposits in joint
Phagocytosis of crystals leads to proinflammatory cytokine release.
Acute attacks will self-terminate but we often treat because of s/s
11
Q
What to think of when you think about osteoarthritis?
A
Cartilage
12
Q
Is OA inflammatory?
A
No
13
Q
OA pathophysiology
A
Cartilage repair problem
Can be because of- bone cyst, thickened joint capsule, synovial inflammation, cartilage fibrillation, meniscal degeneration, osteophyte formation, subchondral bone releases MMPs, bone marrow lesion, joint space narrowing.
14
Q
Risk factors of OA
A
Age, genetics, weight, environmental/repetitive use (sports, factory, construction, trauma), family history, previous joint injury, female
15
Q
What to think of when you think of RA
A
Broad spectrum very aggressive inflammation
16
Q
What is the cause of RA?
A
Unknown
Could be because of bacteria, genetics, smoking, other
Something causes abnormal IgG antibody development and the development of rheumatoid factor (an antibody) against the IgG antibodies.
RF forms a complex that leads to inflammation which can lead to cartilage damage.
The complement system is then activated which attracts leukocytes and stimulates inflammatory mediator release
17
Q
HLA-DR 4
A
If this is positive, you are more likely to have RA
It is a genetic receptor on cells that stimulate immune response
18
Q
Risk factors of RA
A
Age (30s-40s), female, genetics, obesity, tobacco use (linked to poor prognosis)
HLA-DR4 positive
19
Q
Can human convert urate to allantoin?
A
No, humans lack uricase
20
Q
Does gout need hyperuricemia?
A
No
21
Q
Hyperuricemia range in men and women
A
> 7 in men, >6 in women
22
Q
Does hyperuricemia= gout?
A
No
23
Q
Medications that increase uric acid levels
A
Cytotoxic agents, cyclosporine, diuretics (thiazides), levodopa, nicotinic acid, salicylates (<2g/day)
24
Q
Diagnosis of gout- EULAR 2018
A
1.) When possible, identify monosodium urate (MSU) crystals in the synovial fluid. This is painful and most patients will not allow.
- ) If not possible, clinical diagnosis based on clinical features and presence of hyperuricemia.
- MTP or ankle joint, previous gout, rapid onset, erythema, male gender, CV disease
3.) If diagnosis is uncertain, use imaging/ultrasound to look for crystal deposits
25
Diagnostic testing with gout
CBC, SCr, Serum uric acid
26
Acute gout attack symptom presentation
Affected joints- first metarsophalangeal joint, joints in fingers, wrist, or feet, monoarthritis in beginning
S/S- erythema, fever, intense pain, joint inflammation, swelling, warmth
27
Non pharm management of gout
Apply ice, dietary changes (avoid/minimize alcohol, purine rich foods, high fructose corn syrup), weight management (lose weight if needed)
28
Gout concurrent medication considerations
Conditional recommendation- change HCTZ to another antihypertensive agent, losartan preffered
Conditionally recommend against stopping low dose aspirin, changing cholesterol tx to fenofibrate
29
Acute gout treatment options
Colchicine, NSAIDs, glucocorticoids are 1st line
| IL-1 inhibitors rarely used
30
Colchicine
Low dose colchicine is preferred over high dose due to similar efficacy and lower risk of AE.
Gout
31
Contraindications of colchicine use
Hypersensitivity
Renal and hepatic impairment
Renal or hepatic impairment and taking either a P-glycoprotein inhibitor or a strong CYP3A4 inhibitor
32
Colchicine AE
GI, elevated hepatic enzymes, myopathy, neutropenia, thrombocytopenia
33
Onset of action for colchicine
12 hours
34
Colchicine prophylaxis dose
0.6 mg QD to BID
35
Colchicine acute flare management
1.2 mg x 1 followed by 0.6 mg one hour later. May repeat no earlier than 3 days
36
Colchicine dosing with strong CYP3A4 inhibitors
Clarithromycin, protease inhibitors, ketoconazole
| 0.6mg x 1 followed by 0.3 mg one hour later
37
Colchicine dosing with moderate CYP3A4 inhibitors
Diltiazem, fluconazole, grapefruit juice, verapamil
| 1.2 mg x 1- may repeat no earlier than 3 days later.
38
Colchicine with P-glycoprotein inhibitors dosing
Cyclosporine, ranolazine- 0.6mg x 1- do not use earlier than 3 days later
39
Colchicine in CrCl <30 or severe hepatic impairment
May repeat no earlier than 2 weeks
40
Does colchicine help improve CV outcomes?
Yes
41
NSAID BBW
CV risk, GI risk
42
NSAID precautions
Alcoholism, anemia, anticoagulant therapy, aspirin sensitive asthma, breastfeeding, heart disease, hepatic disease, kidney disease, peptic ulcer disease, pregnancy >20 weeks, steroid therapy
43
NSAIDs for gout
Celecoxib: 800mg x 1 followed by 400mg on day 1; then 400mg BID for 1 week
Ibuprofin: 400-800 mg TID-QID
Indomethacin 50 mg TID
Meloxicam 7.5-15 mg QD
Naproxen 750 mg x 1 and then 250 mg q 8 h until attack subsides
44
Contraindications to corticosteroids
Hypersensitivity
Serious infection
Systemic fungal infection
45
Prednisone AE
Glucose intolerance, insomnia, increased appetite, agitation, BP elevation, predisposition in infections
46
Prednisone DDI
```
NSAIDs- increase risk of ulceration
Variable effects on warfarin
Cyclosporine
Live vaccines
Immunosuppressants
```
47
Corticosteroid dosing for gout
Prednisone- 30-60 mg QD x 3-5 days, then taper by decreasing 5 mg/day
IM triamcinolone- 60 mg x 1 followed by prednisone
Intra-articular- triamcinolone 10-40 mg (large joints) or 5-20 mg (small joints) in combo with 1 of the acute treatment agents
48
IL-1 inhibitors for gout
Anakinra- 100 mg SC QD for 3 days
| Canakinumab- 150 mg SC QD
49
Who should receive urate lowering therapy?
Strongly recommend if >1 tophus, evidence of radiographic damage attributable to gout, > 2 gout attacks per year
Conditionally recommend if previously experienced >1 flare but have infrequent flares (<2 per year) or experiencing first flare and CKD stage >3, serum uric acid >9
50
ACP
Gout guideline
| Treat to avoid symptoms with no uric acid level monitoring
51
ACR
Gout guideline
| Serum urate concentration <6 mg/dL
52
Tophaceous gout
Tophi= urate deposits
| Complications- deformity, joint destruction, nerve compression, pain
53
Kidney impact of gout
Uric acid kidney stones
Acute uric acid nephropathy
Chronic uric acid nephropathy
54
What urate lowering therapy is recommended?
Allopurinol is preferred as first line
| Allopurinol or febuxostat stronglt recommended over probenecid for patients with moderate to severe CKD
55
Gout anti-inflammatory prophylaxis
Strongly recommend initiation of concurrent anti-inflammatory prophylaxis (colchicine, NSAID, prednisone) x 3-6 months over no anti inflammatory prophylaxis
56
Urate lowering therapy (ULT) options
Xanthine oxidase inhibitors (XOI)= allopurinol and febuxostat
Uricosurics- probenecid, Lesinuraf + XOI
57
AE of XOI
```
N/V
Bone marrow suppression (allopurinol)
Acute arthritis attack
Arthralgia
Cardiac adverse events (febuxostat)
Skin rash
```
58
Allopurinol and didanosine DDI
Pancreatitis risk
59
Can you use febuxostat in hepatic impairment?
Unknown, has not been studied
60
Febuxostat DDI
Azathioprine, mercaptopurine
61
Allopurinol hypersensitivity syndrome risk
Female, 60 years or older, initiation dose >100 mg /day, kidney disease, CV disease, use of allopurinol for asymptomatic hyperuricemia, HLA-B *5701 allele
62
XOI DDI
Azathioprine, mercaptopurine- metabolized by xanthine oxidase
ACEI, thiazides- may predispose patients to hypersensitivity rxn w/ allopurinol
Capecitabine
Pegloticase
63
Allopurinol dosing
Start at <100mg/day. If CKD stage 3 or 4, start at 50/day
100-300mg daily or every other day (max 800mg/day)
Titrate q 2-5 weeks prn
64
Febuxostat BBW
Risk of CV death
65
Febuxostat dosing
Begin at 40 mg daily
| May increase to 80 mg daily after 2 weeks
66
Probenecid (uricosuric) contraindications
```
Hypersensitivity to drug or sulfonamides
Aspirin
Bone marrow suppression
Children <2 years old
Renal impairment
H/O renal uric acid stones
Uric acid overproducers
```
67
Probenecid AE
Bone marrow suppression, GI, precipitation of acute arthritis attack, stone formation
68
Probenecid DDI
Increases concentrations of ketorolac and methotrexate
69
Probenecid dosing
250 mg BID x 1-2 weeks; then, 500 mg BID
| Give plenty of fluids
70
Lesinurad
Add-on uricosuric to XOI
| For patients not reaching target serum uric acid levels with XOI
71
Lesinurad contraindications
Severe hepatic impairment
CrCl <45
ESRD, kidney transplant, dialysis
Secondary hyperuricemia
72
Lesinurad DDI
CYP2C9 substrate, weak CYP3A4 inducer, hormonal contraceptive, increases nisoldipine, valproic acid
73
Lesinurad AE
HA, increased creatinine levels, GERD, possible increased risk of CV events
74
Lesinurad dosing
200 mg PO QAM with food and water
75
Pegloticase
Use if XOI treatment and uricosurics have failed to achieve optimum serum uric acid target.
MOA: recombinant uricase enzyme. Increases conversion of uric acid to allantoin.
76
Pegloticase BBW
Only in specialized treatment facilities
77
Pegloticase contraindication
G6PD deficiency
| Caution in HF
78
Types of arthritis
Gouty arthritis
Osteoarthritis
Rheumatoid arthritis
79
Inflammatory mediators in RA
IL-6, TNFa, prostaglandins
80
Drug therapy for RA
Mild- NSAIDs
| Moderate to severe= DMARDs
81
DMARDs
Disease modifying AntiRheumatic Drug
Slow down progression of disease= disease-modifying
Not a reduction of symptoms alone
82
DMARDs include
Etanercept, Infliximab, Adalimumab, Anakinra
83
Immune signaling in arthritis
IL-1 signaling, JAKSTAT signaling, TNF alpha signaling
84
Entanercept
Recombinant form of soluble human TNF receptor linked to IgG1
MOA- soluble protein binds to TNF-alpha inhibiting its action at endogenous receptor.
Long acting injection
85
Entanercept AE
significant immunosuppression, can result in neuronal demyelination (rare), increased risk of lymphoma, hepatitis B reactivation
86
Infliximab and Adalimumab
Same MOA as entanercept
Different version of humanized antibodies that bind to TNF alpha
AE- immunosuppression
87
Certolizumab
Humanized Fab' fragment- PEG linked
PEG fragment increases plasma 1/2 life
Neutralizes membrane-associated and soluble human TNF alpha
88
Golimumab
Neutralizes membrane associated and soluble human TNF-a
subq injection once monthly
Used for RA WITH methotrexate
89
Anti-metabolites
Act to halt cell growth or division
| Most interfere with the cellular machinery required for these processes
90
Methotrexate
Suppresses the proliferation of immune cells.
Inhibits dihydrofolate reductase (DHFR)
Inhibits neutrophils and T cells and results in B cell reduction
91
Methotrexate ADME
A- readily absorbed in GI tract
D- slow, CNS
M- minimal metabolism
E- renal
92
Leflunomide
```
Pyrimidine synthesis inhibitor
Inhibits dihydroorotate dehydrogenase
Used for RA
AE- liver damage, immunosuppression
BBW- pregnancy
```
93
Colchicine MOA
antimitotic effects, arrests cells in G1 phase
94
Probenecid moa
Organic anion transporter (OAT) inhibitor. inhibits the reuptake of uric acid from urine to blood.
95
Probenecid ADME
A- complete orally
D= plasma protein bound
M- dose dependent, 5-8 h
E- kidney
96
5 steroid classes
```
Progestogens
Glucocorticoids
Mineralcorticoids
Androgens
Estrogens
```
97
Progestogens
Pregnancy maintenance
98
Glucocorticoids
Gluconeogenesis and glycogen formation, inflammatory response inhibition.
99
Mineralcorticoids
Salt and water balance, modulate BP and volume
100
What are steroids derived from?
Cholesterol
101
Steroid MOA
Bind to cytosolic intracellular receptors which enter the nucleus.
Hormone receptor heterodimer acts as a transcription factor and alters gene expression.
102
physiologic corticosteroid regulation
```
Exogenous glucocorticoids (prednisone) inhibit the release of corticotropin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH)
Leads to symptoms of addisons disease (primary adrenal insufficiency)
```
103
Hydrocortisone
Exogenous cortisol acts to alter immune system function and inhibit inflammation.
MOA- regulation of glucocorticoid receptor and gene transcription
104
Excessive corticosteroid AE
Cushings disease
105
Corticosteroids dose tapering
All corticosteroids require gradual dose reductions
Can have rebound effect (steroid withdrawal syndrome)
Tapering can take months or years
106
Corticosteroid therapy length
Lowest doses should be utilized
Short term therapy- tapered over 1-2 weeks
Long term therapy= months to years
107
Osteoarthritis definition
OA affects primarily the weight-bearing joints, causing pain, limitation of motion, deformity, progressive disability and decreased quality of life. It is characterized by increased cartilage destruction and subsequent proliferation of adjacent bone.
108
How is joint distribution different for OA compared to gout?
OA- hip, hand, knee, spine, feet
| Gout- big toe, 1 joint space, peripheral
109
Primary/idiopathic OA vs secondary OA
Primary/idiopathic- generalized or localized. Has about a 30% genetic component.
Secondary- Congenital factor, inflammatory arthritis, metabolic r endocrine disorder, trauma
110
Compare and contract the risk factor for gout and OA
Both- age, trauma, overweight, FH
Gout- males
OA- females, recreational activity
111
Gout diagnosis
History, physical exam, lab parameters (ESR and RF negative), Radiographic findings (joint space narrowing, osteophytes, subchondral sclerosis)
112
Presentation of OA
Symptoms limited to involved joints (weight bearing joints, 1 or fewer)
Joint pain most common symptom. Pain on motion and relieved by rest.
Joint- tenderness, instability, deformity
Osteophyte formation
Morning joint stiffness
113
OA Physical exam
Decreased range of motion
| Typically joints do NOT have erythema, heat, large effusions, extreme tenderness to palpation
114
OA in hands
```
Heberdons Node (at distal interphalangeal joint)
Bouchards Node- at proximal interphalangeal joint
```
115
WOMAC pain severity
Used for RA
Hip and knee
24 items, 5 point likert scale
Stiffness, pain, effect on daily activities/physical function
116
Non pharm recommendations for hand OA
Exercise, self-efficacy and management programs, 1st CMC orthosis
117
Non pharm for knee OA
Exercise, self efficacy and management, weight loss, Tai Chi, Cane, TF Knee brace
118
Non pharm for hip OA
Exercise, self-efficacy and management programs, weight loss, tai chi, cane
119
Pharmacologic recommendations for hand OA
Oral NSAIDs only think strongly recommended
| Can use other agents- topical NSAIDs, I-A steroids, APAP, tramadol, duloxetine, chondroitin
120
Pharmacologic recommendations for knee OA
Oral NSAIDs, topical NSAIDs, I-A steroids
121
Hip pharmacologic recommendations for OA
Oral NSAIDs, imaging guidance
122
Oral NSAIDs for OA
Celecoxib- 100 mg BID or 200 mg QD
Ibuprofen 400-800 mg TID-QID
Naproxen 250-500mg BID
123
Diclofenac gel for OA
Smaller joints (hand, knee)- dose 2 or 4 grams or no more than 2 joints QID (max 32 grams/day)
124
Diclofenac gel administration
Wash hands before/after application
Do not wash hand for 1 hour after application to hand
Do not shower for 1 hour after application
Do not apply to open wounds
Do not use occlusion or heat on application site. Do not cover with clothes for 10 minutes after application.
Minimize sun exposure after application
125
Intra-articular steroids in OA
May be a placebo effect
Intra-articular triamcinolone 5-40 mg q 3 months, depending on formulation
Onset of pain relief- 1-2 days lasts for 1 month
Dose q 3 months
126
APAP in OA
1 gram QID
| Not as effective as NSAIDs
127
Tramadol in OA
Used in moderate-severe pain before stronger opioids
IR- 24-50 mg q 6 h prn
ER- 100mg/day
May cause seizures
128
Duloxetine in OA
30 mg QD for 1 week and then, increase to 60 mg QD
| AE- N, dry mouth, falls, fatigue, drowsiness
129
Chondroitin in OA
Modest efficacy
800-2000 mg/ day (QD or divided doses)
SE- GI
130
Topical capsaicin in OA
Apply a thin layer of cream TID-QID
Delayed onset
Burning, stinging possible
131
What should you NOT use in OA?
Biphosphonates, glucosamine, hydroxychloroquine, methotrexate, TNF inhibitors, IL-1 ra
132
Multifactorial care in OA
Depression, fall risk minimization, occupational maintenance, recreational activity maintenance, sleep, stress management
133
RA guideline
American college of rheumatology
134
RA definition
RA is a common, chronic, progressive autoimmune condition that primary affects the joint and synovium but can also have detrimental effects on organ systems throughout the body
135
What has a protective effect on RA?
Omega-3 rich diet (>3 g/day)
| Testosterone
136
Clinical presentation of RA
```
Hands, wrists, ankles, feet (multiple joint involvement)
Symmetry (very important!)
Warmth and swelling
Joint stiffness in morning > 30 minutes
Decreased function
Symptoms for 6+ weeks
```
137
Labs for RA
```
Rheumatoid factor +
Anti-cyclic citrullinated antibodies
Erythrocyte sedimentation rate +
C-Reactive protein +
Synovial fluid analysis- WBC, but no bacteria
```
138
Clinical involvement- X rays RA
```
Joint space narrowing
Joint subluxation
Joint deviation
Bony erosions
Periarticular osteopenia
```
139
Clinical presentation of RA- extra articular involvement
```
Generalized fatigue and weakness
Rheumatoid nodules
Interstitial lung disease
Vasculitis
Sjorgens syndroms
Pericarditis
Felty syndrome
Coronary artery disease
Ocular manifestations
```
140
Diagnosis of RA
Earlier diagnosis of patients with RA allows for earlier treatment to prevent joint damage
There is a scoring system that assigns points based on the number and types of joints involved. A score of 6 or m ore is diagnostic of RA
141
How often should treatment of RA be reevaluated?
At least every 3 months
142
Treatment of RA
csDMARDs- hydroxychloroquine, sulfasalazine, methotrexate, leflunomide
bDMARDs- TNF inhibitors, IL-6 inhibitors
tsDMARDs- JAK inhibitors
143
Synthetic DMARDS
csDMARDs- methotrexate, leflunomide, sulfasalazine, hydroxychloroquine
Targeted synthetic DMARDs- baricitinib, tofacitinib, upadacitinib
144
Biologic DMARDs
TNFi- adalimumab, certolizumab, etanercept, golimumab, infliximab
IL-6Ri- sarilumab, tocilizumab
Costimulation-I- abatacept
Anti-B cell- rituximab
145
Biosimilar DMARDs
For adalimumab, etanercept, infliximab, rituximab
146
Are biosimilars considered equivalent to FDA approved bDMARDs?
Yes
147
Serious infection
an infection requiring IV abx or hospitalization
148
Triple therapy in RA
Hydroxychloroquine, sulfasalazine, and either methotrexate or leflunomide
149
Treat to target in RA
Refers to the systematic approach involving frequent monitoring of disease activity using validated instruments and modification of treatment to minimize disease activity with the goal of reaching a predefined target (low disease activity or remission)
150
Recommendations referring to bDMARDS exclude what
rituximab unless pts have had an inadequate response to TNF inhibitors of have a history of lymphoproliferative disorder
151
Disease Activity Score (DAS28)
Scale 0-9.4
Remission <2.6
Low disease activity: 2.6-3.2
High disease activity >5.1
RA assessment tool
152
DMARD-Naive patients with moderate to high disease activity tx- RA
Methotrexate strongly recommended over hydroxychloroquine or sulfasalazine, bDMARD, or tsDMARD monotherapy
Methotrexate plus a non TNF inhibitor bDMARD or ts DMARD
153
Should you initiate csDMARD with or without long or short term glucocorticoids for DMARD naive patients?
Without
154
Recommendations for csDMARD treated, but MTX naive patients with moderate to high RA disease activity
Methotrexate monotherapy is recommended over combination of MTX plus a bDMARD or tsDMARD
155
DMARD naive patients with low disease activity recommendations
Hydroxychloroquine recommended over other csDMARDS
Sulfasalazine recommended over MTX
MTX recommended over leflunomide
156
MTX initiation recommendations
Titrate to a weekly dose of at least 15 mg within 4-6 hours
157
Target for RA?
Remission
158
What tx approach is recommended in RA?
Treat to target approach
159
Nonpharm for RA
Assistive devices, heat, mental health resources, occupational therapy, patient education, physical activity, physical therapy, weight loss, rest (limited)
160
RA ACR suggested baseline evaluation
CBC, creatinine, CRP, ESR< LFTs, BMP, stool guaiac, synovial fluid, urinalysis
Radiography, ultrasonography, or magnetic resonance imaging of affected joint
161
Live vaccines
```
Adenovirus
BCG
Measles, mumps
Oral polio
Oral typhoid
Rubella
Smallpox
Varicella
Yellow fever
```
162
How long do you have to avoid live vaccines after steroids?
Live vaccines should be avoided for at least 1 month after completing high dose systemic steroid therapy (pred >20mg/day for > 14 days)
163
Methotrexate BBW
```
Pregnancy and breastfeeding (avoid pregnancy for 6 months after last dose, m/f)
Ascites
Bone marrow suppression
Diarrhea
Exfoliative dermatitis
Hepatic disease
Infection
Intraeuterine fetal death
Lymphoma
Pleural effusion
Pulmonary disease
Radiation therapy
Renal impairment
Requires an experienced clinician
Stomatitis
Tumor lysis syndrome
```
164
Methotrexate monitoring
AST, ALT, Alk phos- hepatotoxicity
CBC- bone marrow suppression
SCr- kidney function
165
Methotrexate contraindications
Pregnancy/ breastfeeding
Alcoholism
Bone marrow suppression/immunodeficiency
Hepatic disease
166
Methotrexate AE
GI (N/D), alopecia, hematologic, pulmonary, hepatic, stomatitis, folic acid deficiency
167
MTX DDI
```
NSAIDs- increase MTX concentrations
Trimethoprim/Bactrim- increase BMS
leflunomide- increased hepatotoxicity
Highly protein bound drugs- increase MTX conc
Probenecid- increase MTX conc
High dose ASA- increase MTX conc
PPIs- decrease renal elimination
```
168
Methotrexate dose
7.5-15 mg/ week
7.5 mg/week to start
Add folic acid 1 mg daily
Max 25 mg/week
169
Methotrexate monitoring
Watch for mouth ulcers, SOB, new onset cough, N/D, s/s of immunosuppression, pregnancy
Need labs before therapy
170
Leflunomide contraindications
Liver disease (BBW)
Pregnancy/breastfeeding (BBW)
Men wanting to father children
171
Washout protocol for leflunomide
Cholestyramine 8g TID x 11 days
| Level must be <0.002mcg/mL (if not, repeat)
172
Leflunomide AE
```
GI (D)
Hepatotoxicity
Alopecia
HTN
Bone marrow toxicity
Peripheral neuropathy
Skin rash
```
173
Leflunomide DDI
Moderate CYP2C9 inhibitor
- hepatotoxins
- Live vaccines
- Rosuvastatin, possible other statin
- Uricosurics
174
Leflunomide dose
10mg QD x 3 days followed by 20 mg QD or 10-20 mg QD without LD
175
Monitoring of leflunomide
Diarrhea, weight loss, N/V, pregnancy
| Same labs as MTX
176
Hydroxychloroquine contraindications
Hypersensitivity, visual changes due to 4-aminoquinoloines, pre-existing ocular disease, G6PD deficiency
177
Hydroxychloroquine DDI
CYP2D6 inhibitor, decreased by antacids
QT prolonging drugs
Increases cyclosporine
178
Hydroxychloroquine dose
200 mg BID or 400 mg QD with food
| Do not exceed 5mg/kg/day or 400 mg daily
179
Hydroxychloroquine monitoring
Visual changes, eye exams
180
Sulfasalazine dose
500 mg QD-BID titrated to 1000 mg BID
181
Sulfasalazine monitoring
watch for immunosuppression, photosensitivity, rash, GI
CBC
Consider G6PD evaluation at baseline
Caution use in hepatic or renal impairment
182
What to do prior to giving biological DMARDs
Prior to starting therapy, give tuberculin skin test, hepatitis B screen, assess infection risk
Drug interactions- live vaccines, other biologics
183
Is there added efficacy to being on 2 biologics?
No, just an increased risk of infection
184
TNF inhibitors
```
Etanercept
Infliximab
Adalimumab
Certolizumab
Golimumab
```
185
Which TNFi are available IV?
Infliximab- IV only
| Golimumab- IV and SC
186
Which TNFi increase risk of upper respiratory tract infections?
Certolizumab, golimumab
187
AE of infliximab
infusion-related reactions, HA, abdominal pain, antibody formatin
188
AE of certolizumab
Upper respiratory tract infection, rash, UTI
189
TNFi BBW
Infection, malignancy risk
| Certolizumab- children
190
TNFi absolute contraindications
Sepsis
| Murine protein hypersensitivity (infliximab)
191
Is infliximab always used with MTX?
yes
192
TNFi precautions
HF, demyelinating disorders, risk for pancytopenia, lupus-like reaction, immunosuppression, hepatotoxicity, COPD
193
TNFi DDI
Contraindicated- other TNF inhibitors, live vaccines, rilonacept
Avoid other biologic therapies
194
TNFi monitoring
```
S/S infection
S/S of CHF or demyelinating disease
Tuberculin skin test
CBC
LFTs
```
195
Abatacept, what is it? warnings?
Non-TNFi (only use if pt has failed TNFi)
Warnings- anaphylaxis, COPD, infection, malignancy risk
contraindications- hypersensitivity to abatacept or maltose
196
Abatacept AE
HA, upper respiratory infection, nausea, drug infusion reaction, serious infection
197
How is abatacept given?
IV or SC
198
IL-6 inhibitors BBW and contraindications
BBW- infection (check tuberculosis prior to starting)
| Contraindications- not recommended for initiation, need to dose modify or dc if abnormal LFTs, ANC, or platelet count
199
IL-6 monitoring
ANC, LFTs, platelet count, lipids, neutrophils
200
IL-6 AE
Infection, BP changes, increased ALT, lipid changes, lower intestinal perforation, malignancy
201
IL-6 DDi
```
Live vaccines
other biologics
drugs metabolized by CYP3A4
Simvastatin
Cyclosporine
```
202
IL-6 inihbitor agents
Tocilizumab- SC and IV
| Sarilumab- SC
203
JAK inhibitors BBW
Infection, new primary malignancy, thromboembolism, mortality
204
Jak inhibitors warnings
Do not start if lymphocyte <500 or if ANC <1000 or hemoglobin <9
GI perforation
Renal disease
205
JAK inhibitor AE
Infection, thrombosis, lipids, LFTs elevation, neutropenia, anemia
206
JAK inhibitor agents
Baricitinib, tofacitinib, upadacitinib
207
JAK Inhibitors renal and hepatic dose changes?
Need dose changes for both.
| Upadacitinib does not have dose changes in renal disease
208
JAK inhibitors drug interactions
Baricitinib- OAT3 inhibitors (probenecid)
Strong CYP3A4 inhibitors or inducers
Do not use bDMARDs, live vaccines, azathioprine, or cyclosporine
209
When to use corticosteroids in RA
```
Bridging therapy (before DMARDs are effective)
Continuous low dose therapy
Bursts for acute flares
```
210
Corticosteroids for RA dose
Normal: prednisone 5-30mg QD
| Immunosuppressive dose- pred 2 mg/kg/day or >20 mg /day for >14 days
211
AE of corticosteroids
Hypothalamic pituitary adrenal suppression, cushings disease, osteoporosis, myopathies, glaucoma, cataracts, gastritis, HTN, hirsutism, electrolyte changes, glucose intolerance, skin atrophy, infection risk
212
Biosimilar
Biological product that is highly similar to the reference product.
Must be same dosage form, route of administration, and strength
Must be demonstrates as safe and effective as reference
213
Pregnancy and RA tx
Shorter acting NSAIDs (NOT COX-2) in 1st and 2nd trimester
Prednisone at lowest effective dose
Hydroxychloroquine
Sulfasalazine- with folic acid supplement
Certolizumab
214
Lactation and Ra tx
Entanercept, hydroxychloroquine, ibuprofen, prednisone, sulfasalazine (only full term)
215
Migraine characteristics
Age of onset: 15-35 yo
Gender prevalence: 3:1 women to men
Common migraine: without aura
Classic migraine: with aura
216
S/S of migraine
HA duration of 4-72 hours
Pain with two of the following: intense, pulsatile, unilateral, exacerbated by activity
Accompanied by one of the following: N/V, photo/phonophobia, osmophobia
217
Migraine POUND
```
Pulsatile
One day duration (4-72 h)
Unilateral
N/V
Disabling intensity
```
218
Phases of migraine attack
Prodromal- hours to days prior to migraine. Triggers.
Aura- sensory, motor, or focal neurological changes. Lasts less than 1 hour.
HA- lasts 4-72 hours
Postdromal- lethargy, irritability
219
Theories of migraine moa
Vascular theory- reduced cerebral blood flow followed by extracranial vasodilation
Neural- cortical-spreading depression. Brain stem could send pain signals to cortex
Integrated neurovascular theory- neurogenic inflammation and the trigeminal nerve
220
Vasoconstriction of cranial vessels in migraine
Vasodilation may be a causative factor in migraines.
| Ergots and sumatriptan are both vasoconstrictors.
221
Pathophysiology of migraine
Central migraine "generator" in cortex or brainstem. Possible due to defect in calcium channels mediating 5-HT and/or glutamate.
Peripheral pain mechanisms in meninges are initiated leading to neurogenic inflammation.
Nociceptive afferents carry pain signals to cortex.
222
Inhibition of neurogenic inflammation in migraines
The trigeminal nerve innervates the blood vessels on the dura and transmits pain signals. Stimulation of the trigeminal ganglion releases proinflammatory neuropeptides which produce vasodilation and activate pain signals.
Many drugs inhibit neurogenic inflammation
223
Trigeminal system and migraine
5-HT1B- causes vasoconstriction
5HT1D- inhibits substance P
5HT1F- Involved with pain signals
224
Neurogenic inflammation involves
Brainstem trigger
Trigeminal activation
Release of vasoactive peptides
Vascular distention/inflammation/protein extravasation
Pain impulses via trigeminal nerve to trigeminal nucleus to cortex
225
Drugs to treat migraines
APAP, NSAIDs, dopamine antagonists, opioids, serotonergic agents
226
Symptomatic relief for mild to moderate migraine
APAP + caffeine
Metoclopramide
Midrin
227
Abortive-type therapy: migraine specific drugs
Ergots
| Triptans
228
Is tolerability an issue with triptans?
No
229
What is the only selective 5HT1F agonist?
Lasmiditan
230
Prophylactic tx for migraines
Tricyclic antidepressants, beta blockers, anti-epileptics, CCBs, serotonin antagonists, botox
231
MIDAS
Migraine disability assessment test
232
Acute antimigraine agents
Nonspecific- OTC analgesics, NSAIDs, sympathomimetic agents, antiemetics
Specific agents- triptans, ergot alkaloids, ditans, gepants
233
What meds are not recommended for migraines
Opioids
| Butalbital containing agents
234
Stratification according to severity of migraine
Mild
Moderate-severe
Extremely severe
235
Mild migraine analgesic approach
NSAIDs
Excedrin (APAP, ASA, Caffeine)
Isometheptene compounds
Metoclopramide to reduce N
236
Moderate-severe analgesic approach migraines
```
Triptan tailored to individual needs +/- NSAID
Ditan
Gepants
Ergotamine derivatives
Metoclopramide to reduce N
```
237
Extremely severe analgesic approach migraines
```
DHE IV or SQ sumatriptan
Ketorolac
Dexamethasone
Magnesium sulfate
Other additions- metoclopramide, dopamine antagonists, opioids
ER visit
```
238
Prostaglandin inhibitors in migraine
Effective in mild-moderate migraine.
Reduce the neurogenic inflammation in trigeminal vascular system.
Ibuprofen, naproxen, Excedrin Migraine
239
Sympathomimetics/combinations in migraines
APAP/ASA/Caffeine
Isometheptane/dichloralphenazone/APAP
Psuedophedrine
240
Non selective acute migraine 5HT1 agonists
ergotamine
| Dihydroergotamine
241
Group I Triptans
Sumatriptan, Zolmitriptan, Rizatriptan, Almotriptan, Eletriptan
Faster onset, higher potency, higher recurrence
242
Group II Triptans
Naratriptan, Frovatriptan
| Slower onset, lower potency, lower recurrence
243
Which triptans have the longest Tmax?
Naratriptan and frovatriptan (2-3 hours)
244
Longer 1/2 life of triptans=
Less recurrence
245
Which triptans have the longest 1/2 lifes?
Naratriptan, Frovatriptan
Eletriptan is in the middle
Lowest recurrence
246
Which triptan has the poorest oral bioavailabilty?
Sumatriptan
247
What triptan has the nest oral bioavailability?
Naratriptan, Almotriptan
248
Triptans with non oral preparations
Sumatriptan- nasal spray, SQ, supp
| Zolmitriptan- nasal spray
249
Which triptans have the longest OOA
Naratriptan and Frovatriptan
250
Which triptans have the fastest OOA?
Sumatriptan injection and spray
| Oral triptans are around 30 min
251
Contraindications of eletriptan
Contraindicated within 72 hours of potent 3A4 inhibitor (erythromycin, azoles)
252
DDI of naratriptan
Oral contraceptives- decrease cl of N
| Cigarettes- Increase cl of N
253
DDI of Rizatriptan
Propranolol increases AUC of R
254
DDI of Zolmitriptan
Propranolol, oral contraceptives, cimetidine- increase AUC of Z
Z increases AUC of APAP
255
Which triptan has no DDI?
Frovatriptan
256
Advantages of zolmitriptan
Melt for N or convenience
257
Triptan symptoms
```
Tingling sensation involving the head or any other part of the body
Numbness
Strange feeling
Sensation of warmth, heat, burning, cold
Pressure sensations
Anxiety
Agitation
```
258
Safety of triptans
RIsk of CV events low, but do not use in severe Cv disease
259
Contraindications of triptan therapy
```
Uncontrolled HTN
Ischemic disease
Prinz-Metal angina
Cardiac arrhythmias
Multiple risk factors for atherosclerotic vascular disease
Primary vasculopathies
Basilar and hemiplegic migraine
```
260
What do you modify triptan therapy for?
```
Recurrence
Partial response
Nonresponse
Inconsistency
Tachyphylaxis
```
261
Recurrence
Occurs with all triptans
The overall average recurrence rate is 30%
2nd dose of same triptan useful for treating recurrence in most patients.
Naratriptan and frovatriptan have least recurrence
Triptan + COX2 or NSAID may also reduce recurrence rate
262
What to do if you have a partial response to triptan?
Second dose of same triptan
263
what to do if you have nonresponse to triptan
Try another triptan
264
Which triptan has the worst inconsistency?
Sumatriptan due to poor bioavailability
265
Which triptans have the best consistency rates?
Zolmitriptan, rizatriptan, eletriptan
266
What to do if you have tachyphylaxis on triptan
(falling off response after repeated use)
| Switch to a diff triptan
267
Dihydroergotamine (DHE) for migraines
Efficacy compared to triptans
Not orally available- IV, IM/SQ/ Nasal
Do not use in CV issues
Pregnancy category X
268
Lasmiditan
5-HT1F agonist
Little or no CV issues
Recommended not to drive for 8 hours
Scheduled V controlled
269
Ubrogepant
Acute migraine w or w/o aura
| Contraindicated with potent 3A4 inhibitor
270
Rimegepant
Acute migraine w or w/o aura
ODT, do not repeat w/in 24 hours
Avoid with strong inhibitors or inducers of 3A4
271
When are the use of gepants, ditans, or neuromodulatory devices appropriate?
Licensed clinician
>18 yo
ICHD-3 migraine diagnosis
Either of the following:
Contraindication or inability to tolerate triptan
Inadequate response to two or more oral triptans
272
Prophylactic antimigraine agents
Antiepileptic drucs, Beta blockers, CGRP i, antidepressants, gepant, triptan, NSAID
273
Goals of preventative therapy
Reduce attack frequency, severity, duration, disability
274
Indications for prophylaxis (migraines)
Attacks significantly interfere with pts daily routines
Frequent attacks
Contraindication to , failure, or overuse of acute tx (>10/month tx)
AE
Patient preference
275
Migraine prophylaxis success
50% reduction in frequency of days w/ HA or migraine
Significant decrease in attack duration and severity
Improved response to acute tx
Reduction in migraine related disability
QOL increased
Allow 2 months to take effect
276
Migraine prophylaxis anticonvulsants
Divalproex
- use especially for pts with bipolar or seizures
- Topiramate
277
Migraine prophylaxis beta blockers
Metoprolol, timolol, propranolol
| Takes 1-2 weeks to see effect
278
Migraine prophylaxis antidepressants
No Level A recommendation
| Amitriptyline, venlafaxine
279
Migraine prophylaxis NSAIDs
Fenoprofen, Ibu, ketorolac, naproxen, celecoxib
280
CGRP inhibitors
New migraine tx
expensive
erenumab, fremanezum, galcanezumab, eptinezumab
281
Indications for treatment with monoclonal antibodies to CGRP
Licensed medical provider
>18 yo
Specific criteria based on HA, lack of response to other tx, functional assessments
282
Natural/herbal for migraine prevention
Butterbur extract (Petasites hybridus 75 mg BID)
283
Prophylaxis of mestrual migraines
NSAID 3-5 days prior and throughout menstruation
| Naproxen 550mg BID
284
Characteristics of lupus
Female, aged 15-45
More common in non-caucasians
All cause mortality rates 2.6 fold
First degree relatives with FH of SLE have 6 fold higher risk of developing SLE and 4 times higher risk of developing other autoimmune disease
285
Current treatment landscape of lupus nephritis
Induction treatment- glucocoticoids + NIH IV, Euro-lupus IV, mycophenolate
Maintenance treatment- Mycohenolate, Azathioprine
286
Mycophenolate (MMF) MOA
Inactive prodrug that is hydrolyzed to active MPA. MPA inhibits lymphocyte proliferation and lymphocyte migration; anti-fibrotic activity
287
Mycophenolate AE
GI (D most common), leukopenia, anemia, hepatotoxicity, infections; lymphoproliferative malignancies
Caution in pregnancy and lactation
288
Mycophenolate follow up
CBC, LFTs weekly with dose changes and then CBC every 1-3 months
289
Myfortic
Some patients will tolerate Myfortic when they have experienced severe GI AE from MMF
290
Cyclophosphamide (CYC)
Inactive prodrug that is activated by hepatic cyp450 enzymes.
Causes bone marrow suppression and infection, hemorrhagic cystitis, bladder cancer
Caution in pregnancy and lactation
