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Pediatric Rheumatology Board Exam > Drug Therapy 10% > Flashcards

Drug Therapy 10% Flashcards

1
Q

Which medications need to be biotransformed to their therapeutically active forms before they can exert their principle effects?

A 
Prednisone
Azathioprine
MMF
Cyclophosphamide
Leflunomide
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2
Q

What family of enzymes in the liver account for over 70% of drug metabolism in humans?

A

Cytochrome P450

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3
Q

What factors predict more durable response to intra-articular steroid injections in JIA?

A

In oligoarticular JIA
Younger patients
Shorter disease duration

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4
Q

How do glucocorticoids work?

A

They are synthetic analogs of endogenous cortisol and have both anti-inflammatory and immunosuppressive effects.

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5
Q

How do glucocorticoids cause immunosuppression?

A

Through reduction of circulating T lymphocytes
Affects T > B cells
Affects CD4+ T cells > CD8+ T cells

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6
Q

At what prednisone dose does growth suppression occur?

A

> = 3 mg/day

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7
Q

What is the most serious, life-threatening complication of chronic glucocorticoid use?

A

Acute adrenal insufficiency

At risk of vascular collapse, adrenal crisis, death

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8
Q

How does chronic glucocorticoid use cause osteoporosis?

A

Caused by osteoblast inhibition and apoptosis but also increased bone resorption by inhibition of gut absorption of Ca and increased urinary Ca excretion, potentially resulting in secondary hyperparathyroidism

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9
Q

Where is the most common location for avascular necrosis 2/2 glucocorticoid use?

A

Femoral head

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10
Q

What are hematologic side effects of glucocorticoids?

A

Transient lymphopenia and neutrophilia (neutrophil demargination)

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11
Q

What are some features that may help distinguish steroid-induced psychosis from psychosis 2/2 active lupus? (though still hard)

A

usually acute onset, occurs within 96 hours of initiation of steroids, and are related to high-dose steroids

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12
Q

What muscle fibers are affected by steroid-induced myopathy?

A

Atrophy of Type IIb myofibers

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13
Q

What are some features of steroid-induced myopathy?

A

Usually affect proximal muscles, is usually not painful, can have normal muscle enzymes, and EMG suggestive of myopathy

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14
Q

Methotrexate reduces the production of the following cytokines:

A

TNF, IFN-gamma, IL-1, IL-6, IL-8

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15
Q

How does methotrexate work?

A

Folic acid analog that is a competitive inhibitor of several enzymes in the folate pathway, including dihydrofolate reductase, TYMS, AICAR transformylase, adenosine deaminase resulting in adenosine accumulation and neutrophil adherence inhibition.

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16
Q

When is methotrexate use contraindicated?

A

Concurrent use with Bactrim increases risk of cytopenias due to synergistic effects on DHFR

Pregnancy
EtOH use
Renal or liver failure

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17
Q

How does methotrexate exert anti-inflammatory effect?

A

Adenosine accumulation may contribute to site-specific anti-inflammatory effects of methotrexate through inhibition of neutrophil adherence

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18
Q

Is methotrexate safe in pregnancy?

A

No. Teratogenic and fetogenic - increased risk of congenital anomalies and pregnancy loss with use during pregnancy.

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19
Q

Is breastfeeding okay in methotrexate?

A

No, methotrexate secreted in breast milk. Avoid breastfeeding.

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20
Q

What is azathioprine?

A

A purine analog that is metabolized to 6-mercaptopurine (6MP)

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21
Q

How does azathioprine exert immunosuppressive effect?

A

Immunosuppression primarily by inhibition of T cell growth during S phase of cell division

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22
Q

What are some relative contraindications to azathioprine?

A

In TPMT deficient patients

Concurrently with Bactrim

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23
Q

What idiosyncratic reaction can occur in TPMT deficient patients who receive azathioprine?

A

Arrest of granulocyte maturation

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24
Q

What is pharmacokinetics?

A

What the body does to the drug

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25
Q

What is pharmacodynamics?

A

What drug does to the body

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26
Q

What is bioavailability?

A

Expressed as a percentage and represents the amount of active drug that reaches the systemic circulation unaltered compared with when the drug is given IV

Affected by route given and dose

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27
Q

What is an example of pharmacogenetics/omics being used for precision medicine?

A

Checking TPMT enzyme activity or for TPMT gene variations prior to starting azathioprine

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28
Q

How do NSAIDs work?

A

Inhibit cyclooxygenase (COX) enzyme in the metabolism of arachidonic acid to prostaglandins, thromboxanes, and prostacyclins

Exception: indomethicin and diclofenac affect lipoxygenase pathway

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29
Q

How do NSAIDs work?

A

Inhibit cyclooxygenase (COX) enzyme in the metabolism of arachidonic acid to prostaglandins, thromboxanes, and prostacyclins

Exception: indomethicin and diclofenac affect lipoxygenase pathway

NSAIDs inhibit COX1 preferentially. NSAIDs more selective for COX 2 seem to have more favorable adverse effect profiles (celecoxib).

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30
Q

Where are NSAIDs absorbed?

A

Stomach and upper small intestine

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31
Q

How does concurrent NSAID use react with methotrexate?

A

Causes displacement from plasma protein binding sites, competition for renal secretion and impairment of renal function

Rarely clinically significant

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32
Q

Which NSAID is more effective in systemic JIA and spondyloarthropathies?

A

Indomethicin

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33
Q

Where are NSAIDs mainly metabolized?

A

Liver

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34
Q

What is a rare side effect of NSAID use in SLE?

A

Aseptic meningitis

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35
Q

What is a rare side effect of NSAID use in fair-skinned patients?

A

Pseudoporphyria

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36
Q

What is a rare side effect of aspirin use in children, often noted with use during viral infection (flu or chicken pox)?

A

Reye syndrome - encephalopathy and liver failure

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37
Q

Where are PO drugs primarily absorbed in the GI tract?

A

Small intestine

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38
Q

What are indications for hydroxychlorquine?

A

In general, for rheumatologic diseases with an arthritis or derm component

SLE
JDM
Systemic Sclerosis
APS
Cutaneous lupus
Lyme disease
Urticarial vasculitis
MCTD, UCTD
JIA?
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39
Q

What are contraindications for hydroxychlorquine?

A

QT prolongation - may occur in combination with other medications that prolong QT (e.g. azithromycin)

May exacerbate psoriasis and porphyria
Use with caution in patients < 7 yo because hard to get a good eye exam for retinal toxicity

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40
Q

How does hydroxychlorquine work?

A

Inhibits TLR 7/9
Inhibits neutrophil chemotaxis, NO production, phagocytosis
Antagonizes action of prostaglandins, interferes with IL-1 release by monocytes, interferes with production of TNF-a, IL-6, and IFN-g
Inhibits NK cell activity
Induces apoptosis
Has anti-platelet and anti-hyperlipidemic effects

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41
Q

Where is hydroxychlorquine absorbed and excreted?

A

Absorbed: intestine
Excreted: Mainly kidney, also liver

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42
Q

Chronic use of hydroxychlorquine > 5 years increases the risk of ___.

A

Retinal toxicity - demonstrated by drop out of letters from words when reading, photophobia, blurred distance vision, visual field defects, flashing lights

Advanced macular disease is characterized by central patchy area of depigmentation of macula surrounded by concentric ring of pigmentation - “bull’s eye lesion”

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43
Q

Can hydroxychlorquine be used in pregnancy?

Can hydroxychlorquine be used with breastfeeding?

A

Safe in pregnancy and while breastfeeding

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44
Q

When does risk of retinal toxicity increase in hydroxychlorquine use?

A

After 5-7 years of use or a cumulative dose of 1000 mg

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45
Q

What are indications for sulfasalazine?

A

IBD
JIA
Additive for AS (controversial)

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46
Q

What are contraindications for sulfasalazine?

A 
Sulfa allergy
In infants
Poor renal and liver function
G6PD
Prophylria
Relative contraindication in sJIA (in adults, a/w DIC)
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47
Q

In sulfasalazine use, concurrent use with which medication can increase risk of hepatotoxicity?

A

Methotrexate

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48
Q

Can sulfasalazine be used in pregnancy?

Can sulfasalazine be used when breastfeeding?

A

Safe in pregnancy

Sulfasalazine secreted in breast milk, use with caution

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49
Q

What are indications for colchicine?

A 
FMF
Recurrent aphthous stomatitis
Behcet disease
Cutaneous vasculitis
Gout

Not helpful in PFAPA

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50
Q

What are contraindications to colchicine?

A

Severe renal or hepatic disease

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51
Q

How does colchicine work?

A

Microtubule inhibitor

Works more on granulocytes than lymphocytes

Binding of its 2 rings to cellular microtubules inhibits the movement of intracellular granules and prevents secretion of various components to the cell exterior

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52
Q

What are side effects of colchicine?

A

GI discomfort, diarrhea - can divide dose BID and reduce lactose intake
Myelosuppresion
Azospermia at high doses
Myopathy - rare

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53
Q

What are some colchicine toxicities?

A

RARE

Proximal muscle weakness
Painful paresthesia
Elevated CK
Abnormal EMG
DIC
Multiorgan failure
Agranulocytosis
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54
Q

Which medication class can interact with colchicine?

A

CYP3A4 inhibitors

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55
Q

Is colchicine safe in pregnancy and with breastfeeding?

A

Safe in pregnancy

Safe with breastfeeding

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56
Q

What dietary item can interact with colchicine?

A

Grapefruit juice

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57
Q

Which TNFi is not effective in tx of uveitis?

A

Etanercept

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58
Q

What are common indications for TNFi?

A 
Polyarticular JIA
Psoriatic arthritis
Ankylosing spondylitis
Inflammatory bowel disease
TRAPS
Behcet
Takayasu arteritis
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59
Q

What is the treatment for latent TB infection? How long must one wait before starting a TNFi?

A

Isoniazid

May start treatment at least 1 month after initiation of isoniazid

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60
Q

What are contraindications to TNFi?

A

Severe infection
Sepsis
Demyelinating disease - personal or 1st deg FHx - obtain baseline brain MRI in patients who need TNFi but have +FHx
Hepatitis B infection - but can use if patient on antiviral tx for HBV
Heart failure

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61
Q

Do TNFi increase the risk of malignancy?

A

Risk of malignancy in patients with JIA is ill-defined

Information from manufacturers document 48 cases of malignancy in children on TNFi. Half were lymphoma. Others were leukemia, melanoma, and solid organ cancer. 11 died from T cell lymphoma. 88% of the cases were in patients on other immunosuppression such as AZA, 6-MP, or MTX.

Another study reported that children with JIA have an increased rate of malignancy in general c/w children without JIA. Treatment for JIA including TNFi and/or MTX did not appear to be significantly associated.

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62
Q

Describe Enbrel’s mechanism of action.

A

Fully human, dimeric fusion protein made up of the extracellular ligand-binding portion of the TNF-receptor linked to the Fc portion of human IgG1.

Can also. bind to TNF-beta, though relevance in JIA is unknown

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63
Q

Describe Humira’s mechanism of action.

A

Recombinant human IgG1 mAb against TNF

Binds to soluble TNF but also membrane-bound TNF, leading to both antibody-dependent and complement dependent cytotoxicity

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64
Q

Describe Remicade’s mechanism of action.

A

Chimeric mAb consisting of a mouse Fab’ fragment Ab and the constant region of human IgG1 against TNF

Binds to soluble TNF but also membrane-bound TNF, leading to both antibody-dependent and complement dependent cytotoxicity

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65
Q

Describe Simponi’s mechanism of action.

A

Recombinant human mAb to TNF

Like Remicade except the heavy and light variable regions are human instead of mouse

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66
Q

Describe certolizumab/Cimzia’s mechanism of action.

A

Pegylated (e.g. conjugated with polyethylene glycol) humanized Fab’ fragment of a mAb to TNF

Certozilumab is a monovalent Fab Ab fragment (missing Fc portion of Ab)with high affinity for TNF, which distinguishes from other TNFi , which are full-length bivalent IgG mAb
Does not induce complement activation, antibody-dependent cellular cytotoxicity, or apoptosis

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67
Q

When do acute infusion reactions occur with Remicade infusions?

A

Within 24 hours, usually between 10 min and 4 hours
Most Remicade infusion reactions are acute

Decrease risk by using MTX in combination

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68
Q

When do delayed infusion reactions occur with Remicade infusions?

A

Within 1-14 days after start of treatment, usually between 5-7 days

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69
Q

What cytopenias can occur with TNFi?

A

Neutropenia, usually mild

Pancytopenia and aplastic anemia are rare

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70
Q

Before using TNFi, what FHx should you obtain and what rare adverse effect should you counsel the patient about?

A

Risk of development of demyelinating syndrome, particularly multiple sclerosis

Obtain FHx of 1st degree relative with demyelinating disorder.

Optic neuritis and Guillain Barre syndrome have been reported.

If TNFi is necessary, consider baseline brain MRI in a patient with +FHx

71
Q

What are possible autoimmune adverse effects of TNFi?

A

Development of auto-antibodies, particularly lupus-associated Ab.

Lupus, APS, LCV, new psoriasis, Crohn disease, CHF with no previous risk factors in adults on TNFi

72
Q

What are rare possible pulmonary adverse effects of TNFi?

A

Granulomatous disease - sarcoidosis-like disease

Pulmonary fibrosis/ILD, usually in patients with RA on methotrexate + TNFi combo therapy

73
Q

What correlates with occurrence of infusion reactions with Remicade and accelerates clearance of the drug?

A

Human anti-chimeric antibodies

74
Q

Which TNFi may be preferred when needed during pregnancy?

A

Certolizumab/Cimzia has minimal placental transfer, suggesting no in utero fetal exposure

75
Q

What are indication for leflunomide?

A

JIA

Arthritis in other connective tissue diseases

76
Q

What are contraindications to leflunomide?

A

Pregnancy

Breast feeding

77
Q

How does leflunomide work?

A

Leflunomide turns into active plasma metabolite A77-1726

Inhibits de novo PYRMIDINE synthesis by inhibiting enzyme dihydroortate dehydrogenase

Results in translocation of p53 from cytoplasm to nucleus and initiates cellular arrest in the G1 phase of cell cycle

Inhibits leukocyte endothelial adhesion
Decreases serum metalloproteinase activity similar to MTX
Affects cytokine production
In vitro, inhibits production of prostaglandin E2, matrix metalloproteinase 1 and IL-6
Modulates various tyrosine kinases and growth factor receptors

78
Q

What lab monitoring is recommended for leflunomide?

A

CBC with diff, LFTs, creatinine (+/- urine HCG) baseline and in 2-4 weeks with dose adjustments then every 3 months while on maintenance doses

79
Q

What are side effects of leflunomide?

A

Usually mild and dose-dependent

GI: abdominal pain, dyspepsia, diarrhea, etc
Allergic rash
Reversible alopecia
Mild weight loss
Elevation of LFTs-reversible
No increased risk of infection reported 
Teratogenic
80
Q

A patient on leflunomide would like to get pregnant. How long should the patient be off of leflunomide before they can safely conceive?

A

At least 10 weeks but can take up to 2 years for leflunomide to leave the body

Leflunomide is teratogenic and should not be used while breast feeding.

81
Q

What are indications for cyclophosphamide?

A

SLE (LN class IV and some III, CNS lupus, life threatening organ involvement
JDM, Systemic Sclerosis, PAN,
Renal complications of HSP
ANCA related vasculitis

82
Q

What is cyclophosphamide?

A

Alkylating agent
Nitrogen mustard derivative
Inactive until metabolized in liver by CYP enzymes
Active metabolite is phosphoramide mustard
Destroys purine ring and prevents cell replication

83
Q

How does cyclophosphamide cause its immunosuppressive effects?

A

Affects mononuclear cells and cellular immunity
Causes B cell > T cell lymphopenia
Oral dosing is more cell-mediated immunity
High dose IV affects B cell immunity
Lowers IgG and IgM

84
Q

What are short-term toxicities a/w cyclophosphamide?

A

Short term toxicity: cytopenias, infections, anorexia, nausea and vomiting, and alopecia
Alopecia dose related usually reversible
Leukopenia and thrombocytopenia most common

85
Q

What bladder toxicity is caused by cyclophosphamide?

A

Hemorrhagic cystitis, fibrosis
Transitional cell carcinoma

Due to inactive metabolite ACROLEIN

Prevent bladder toxicity with pre-hydration, post-hydration, mesna, NSB, emptying bladder q2hr even overnight

86
Q

What are the risks of malignancy with cyclophosphamide use?

A

Bladder cancer in GPA
Skin cancer
4x increased risk of myeloproliferative disorders in RA

87
Q

How does cyclophosphamide affect fertility?

A

Increased risk of infertility that is dose-dependent

Decrease risk with use of leuprolide (luteinizing hormone releasing hormon)

88
Q

A teenage female with active lupus on Cytoxan has amenorrhea. What could be the cause of her amenorrhea?

A

Underlying disease activity

Less likely adverse effect of cyclophosphamide

89
Q

Can you use Cytoxan while pregnant and breastfeeding?

A

No
Teratogenic
Crosses placenta

90
Q

What are the indications for use of cyclosporine?

A

1) Solid organ transplants
2) Psoriasis
3) Steroid resistant nephrotic syndrome

Calcineurin inhibitors used in these rheumatic diseases:

1) MAS
2) JIA
3) JDM
4) Uveitis
5) Lupus nephritis (WHO III, IV, V)
6) Behçet (eye)
7) Efficacy in RA –thought to act as a DMARD – indicated for severe active RA not responded to methotrexate

91
Q

What are the contraindications to cyclosporine?

A

1) Breast feeding
2) Uncontrolled HTN
3) Abnormal renal function
4) Hypersensitivity ( contains castor oil)
5) Known malignancy
6) Uncontrolled Infection

92
Q

How does cyclosporine work?

A

Calcineurin inhibitor

1) Combines with receptor cyclophilin – becomes active –complex binds to calcineurin and inhibits IL-2 and T-cell activation
2) Inhibits IL-3, Il-4, INF y, IL- 15
3) Antiangiogenic
4) Enhances production of transforming growth factor B1 protein

93
Q

How do inhibitors and inducers of cytochrome P450 affect cyclosporine?

A

Cyclosporine is CYP P450 3A4/5 substrates
Thus any drug that inhibits or enhances may interact

Inhibitors of P-450 3A - increase Cyclosporine
(antidepressant, cimetidine, macrolide, diltiazem, azole antifungal e.g. fluconazole)

Inducers P-450 decrease Cyclosporine levels
(anticonvulsants, rifampin, dexamethasone) decrease Cyclosporine levels

94
Q

Can you use cyclosporine/calcineurin inhibitors while pregnant or breast feeding?

A

Category C medication: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Breast feeding - contraindicated

95
Q

What are the indications for mycophenolate?

A 
Lupus
Proliferative lupus nephritis
Inflammatory myopathies - 2nd line
Systemic vasculitides - 2nd line
Noninfectious uveitis - 2nd line
Inflammatory arthropathies(?)
96
Q

What are absolute contraindications to mycophenolate?

A 
Severe bone marrow suppression
Pregnancy
Breastfeeding
Hypersensitivity to mycophenolate
Hypersensitivity to polysorbate 80 (TWEEN) (intravenous)
97
Q

What are the relative contraindications to mycophenolate?

A
  • Cardiac transplantation patients, switched from calcineurin inhibitor (CNI) therapy to sirolimus; due to increased incidence of acute rejection reported compared with patients maintained on CNI therapy
  • Concomitant use with azathioprine
  • Active or serious digestive system diseases (increased risk of perforation)
  • Hereditary deficiency of HGPRT (Lesch-Nyhan)
  • History of malignancy or prior chemotherapy
98
Q

How does mycophenolate mofetil work?

A

Mycophenolic Acid (MPA) non-competitively binds to inosine monophosphate dehydrogenase, which is required for synthesis of guanine nucleotide, a pathway on which T and B lymphocytes are primarily dependent.

MMF is selective for T and B lymphocytes.

Inosine monophosphate dehydrogenase comes in 2 forms, IMPDH1 and IMPDH2, 1 on most all cells, and 2 on activated T cells. MPA inhibits stronger at IMPDH2 so preferentially works on T cells.

99
Q

Where is mycophenolate mofetil converted to active form, mycophenolic acid?

A

Hydrolyzed in liver by carboxylesterases

100
Q

What are GI side effects from mycophenolate?

A

Abdominal pain, diarrhea - mitigate by reducing dose or dividing into 3-4 doses/day

Rarely esophagitis, gastritis, GI tract hemorrhage

101
Q

What are hematologic side effects from mycophenolate?

A

Leukopenia
Anemia
Thrombocytopenia
Pancytopenia

Holding medication (if WBC < 3.5, plt < 100) usually results in count recovery within 1 week

Check CBC every 4-12 weeks

102
Q

How does metronidazole and ciprofloxacin affect mycophenolate concentrations?

A

Metronidazole and ciprofloxacin DECREASES mycophenolate concentration

103
Q

How does cyclosporine and tacrolimus affect mycophenolate concentrations?

A

Cyclosporine > tacrolimus DECREASES mycophenolate concentration

104
Q

What decreases absorption of mycophenolate?

A

Use of antacids containing aluminum or magnesium

105
Q

What is an adverse effect of concomitant use of mycophenolate and alemtuzumab, tacrolimus, and azathioprine?

A

Pure red blood cell aplasia

106
Q

What are the recommendations for use of mycophenolate during pregnancy or with breastfeeding?

A

Teratogenic: first trimester miscarriage, structural congenital anomalies
Crosses placenta

No data re: use with breast feeding

Recommended to switch to AZATHIOPRINE during pregnancy

107
Q

What are some rheumatologic indications for IVIG?

A

Kawasaki disease - 1st line
JDM - 2nd line

Adjunctive in:
Lupus
Catastrophic Antiphospholipid Syndrome
ANCA-associated vasculitis
Systemic vasculitides
Systemic JIA?
Poly JIA?
APS?
108
Q

What is a contraindication to IVIG?

A

IgA deficiency - increased risk of anaphylaxis

May give preparation without IgA

109
Q

What is the proposed mechanism of action for IVIG in JDM?

A

Fc portion of IVIG binds complement components C3b and C4b, reducing MAC complex formation and inhibiting complement-mediated damage in the intramuscular endocapillary region

110
Q

What is the proposed mechanism of action for IVIG in Kawasaki disease?

A

Anti-cytokine (IL-1, IL-6) Ab from IVIG interact directly to neutralize IL-1 and IL-6

111
Q

What is the proposed mechanism of action for IVIG in lupus?

A

Similar idiotype/anti-idiotype interactions may occur on the surface of T cells, B cells, and monocytes via IVIG Ab to cell-surface receptors, reducing activation of inflammatory cascades and down-regulation of pro-inflammatory cytokines (IL-1, TNFa).

112
Q

What are 5 major adverse effects of IVIG?

A 
Anaphylactoid reactions
Thromboembolic events
Renal complications: osmotic nephrosis and acute renal failure
Hemolysis
Aseptic meningitis
113
Q

How can one mitigate adverse effects of IVIG?

A

Minimize side effects by slowing infusion rate or changing preparation (e.g. Gammagard vs Gammunex) and premedication with hydrocortisone

114
Q

When can a patient be vaccinated with live vaccines after IVIG is given for Kawasaki disease at a dose of 2 gram/kg?

A

11 months after IVIG

115
Q

When can a patient be vaccinated with live vaccines after IVIG is given for ITP at a dose of 400 mg/kg?

A

8 months after IVIG

116
Q

What is the mechanism of action of Tylenol?

A

Inhibits cyclooxygenase (COX) pathways in CNS > PNS to reduce prostaglandin production

Does not bind directly to COX-1 or COX-2
Exact mechanism unclear
CNS > peripheral effects

117
Q

What is duloxetine?

How does it work in adult fibromyalgia?

A

Selective Serotonin and Norepinephrine Reuptake Inhibitor

Increases activity of descending noradrenergic anti-nociceptive pathways in brain and spinal cord, resulting an analgesia

Milnacipran is another SNRI mentioned in Petty 7th ed

118
Q 
What class of drug are gabapentin and pregabalin in?
How does it work in adult fibromyalgia?
A

Antiepileptic drugs, gabapentinoids

Blocks neuronal release of excitatory neurotransmitters with anxiolytic and analgesic effect with ability to improve slow-wave sleep

Alpha2-delta CCBs that function by binding to the alpha2-delta subunit of voltage-gated calcium channels in the central nervous system

One study reported pregabalin not effective in juvenile fibromyalgia

119
Q

What is the most common toxicity in Tylenol?

A

Liver toxicity

120
Q

What are common adverse effects of SSRIs/SNRIs?

A

Both: Increase the risk of bleeding, suicidal ideations

SNRIs: somnolence, nausea, decreased appetite

121
Q

What are common adverse effects of TCAs?

A

Prolonged QTc, arrhythmia

Obtain EKG prior to med start or with dose change

122
Q

What are common adverse effects of gabapentin, pregabalin?

A

Dizziness, nausea, and fatigue

Discontinue gradually because sudden discontinuation may precipitate seizures in susceptible individuals

123
Q

What class of drug can interact with TCAs?

A

Plasma concentration of TCAs can increase with diminished CYP P450 activity (e.g. genetic variation, concomitant medications that decrease enzyme activity)

124
Q

What is anakinra?

A

Human recombinant form of IL-1Ra antagonist (a competitive antagonist)

IL1-Ra is a naturally occurring, acute phase anti-inflammatory protein

125
Q

What are the indications for anakinra?

A 
Systemic JIA - 1st line
MAS
Adult Still's disease
NOMID (> 4 years old) - FDA approved
Cryopyrin associated periodic syndrome
DIRA
RA (severe > 18 yo with 1 failed DMARD)
Poly JIA (not studied in < 2 years old)
126
Q

What is rilonacept?

A

Fully human dimeric fusion protein that incorporates the extracellular domains of both IL-1 receptor components required for IL-1 signaling (IL-1 receptor type 1 and IL-1 receptor accessory protein), linked to the Fc portion of human IgG1

Think of it like the top portion is like Enbrel attached to the Fc portion of human IgG1

127
Q

What is canakinumab?

A

fully human IgG1k mAb specifically targeting IL-1b

128
Q

What are the indications for canakinumab?

A

Cryopyrin associated periodic syndrome
Systemic JIA
NOMID

129
Q

What is the role of IL-1 in rheumatoid arthritis?

A

Stimulates synoviocytes and chondrocytes to produce prostaglandins and matrix metalloproteinases leading to cartilage destruction and bony erosions

IL-1 increases RANKL expression leading to osteoclast differentiation and increased bone resorption

130
Q

What are adverse effects of IL-1 therapy?

A

Injection site reactions - most common, occur within the first 4 weeks. Canakinumab has milder injection site reactions
Infections - not opportunistic, no increased risk of TB
Neutropenia, especially if combined with TNF
Anemia, thrombocytopenia

Anti-rilonacept Ab noted in 42% of patients in a study but did not effect efficacy or safety

Canakinumab had 7 episodes of MAS and 2 deaths in 1 study. Majority of MAS triggered by infection but also occurred in patients with well-controlled disease.

131
Q

What medications/vaccines should not be used together with anakinra?

A

TNFi - though combo used to treat HIDS
Tacrolimus
Live vaccines

Caution with leflunomide due to hematologic side effects. Must monitor CBC monthly.

May increase toxic effects of canakinumab
Ok to use in combo with methotrexate!

132
Q

What medications/vaccines should not be used together with rilonacept and canakinumab?

A

TNFi

Live vaccines

133
Q

How do pro-inflammatory cytokines affect hepatic CYP460 enzymes? Why is that important in canakinumab use?

A

The expression of hepatic CYP450 enzymes may be suppressed by pro-inflammatory cytokines, such as IL-1b.

Thus, CYP450 expression may be normalized when potent cytokine inhibitory therapy, such as canakinumab, is introduced. As a result, patients taking other products metabolized by the CYP450 system, particularly those products with a narrow therapeutic index, should be monitored closely.

134
Q

What is tocilizumab?

A

humanized mAb to the soluble IL-6 receptor that is produced by grafting the complementarity-determining region of mouse anti human IL-6 receptor antibody to human IgG1

135
Q

What are the indications for tocilizumab?

A

Systemic JIA - especially if prominent arthritis component

Polyarticular JIA

136
Q

What are adverse effects of tocilizumab?

A 
Infections - most common
Transaminitis
Neutropenia and thrombocytopenia
LDL cholesterol elevation, serum lipid abnormalities
Hypersensitivity reactions

Should be used with caution in patients with intestinal ulceration or diverticulitis, peritonitis, gastrointestinal perforation, fistulae, intra abdominal abscesses

137
Q

What are drug interactions a/w tocilizumab?

A

No live vaccines

Can be used with methotrexate or other non-biologic DMARDs

138
Q

What is abatacept?

A

Fully human, soluble fusion protein of the extracellular domain of cytotoxic T lymphocyte antigen-4 (CTLA-4) and the Fc component of IgG1

139
Q

What are indications for abatacept?

A

pJIA (approved for >/=2yo pt’s)
RA
PsA
Off label use in JDM, SLE/MTCD, localized scleroderma, uveitis

140
Q

What are contraindications to abatacept?

A

Active infections: bacterial infection, varicella, measles. Hep B reactivation if not on antiviral therapy.
Caution with concurrent use of other biologics

141
Q

What is the mechanism of action of abatacept?

A

Inhibits T cell activation

CTLA-4 binds CD80/86 (also called B7) preventing CD28 on T cells from binding it which is the 2nd signal required to activate the T cell after the TCR binds to MHC.

142
Q

What are adverse effects of abatacept?

A

Injection site reactions

IV formulation has maltose, which can falsely elevate blood glucose

143
Q

What are drug interactions a/w abatacept?

A

No live vaccines or within 3 months of stopping abatacept
Concurrent use with other biologics
+/- with methotrexate

144
Q

Can abatacept be used during pregnancy or with breastfeeding?

A

EULAR recommends against use in pregnancy unless no other medication to control symptoms.

Little known about breastfeeding, so probably should avoid.

145
Q

What is rituximab?

A

Chimeric mouse-human monoclonal ab that binds to the B cell CD20 receptor

146
Q

What is the mechanism of action of rituxmab?

A

Removes the CD20+ B cells from circulation by ab-dependent and complement dependent cellular cytotoxicity and by induction of apoptosis of B cells.

Although the antibody-producing plasma cells are not removed, B cells that may act as antigen-presenting cells, produce cytokines, and infiltrate tissues are removed for a prolonged period.

Memory B cells which are also ab producing may also be removed.

147
Q

What are contraindications to rituximab?

A

JC virus infection
Active infection such as hepatitis, opportunistic infections
Anaphylaxis

148
Q

What are contraindications to rituximab?

A

JC virus infection
Active infection such as hepatitis (Hep B), opportunistic infections
Anaphylaxis

149
Q

What pre-medications are used with rituximab?

A

Tylenol
Benadryl
Steroids (e.g. Solu-Medrol)

150
Q

What monitoring labs are recommended for rituximab?

A 
JC virus?
Hepatitis B
B cell subsets (flow cytometry) before start and 1 month after
IgGAM q3mo
Liver enzymes q3mo
151
Q

What severe, irreversible complication is associated with rituximab?

A

Progressive multifocal leukoencephalopathy due to reactivation of JC virus

152
Q

What is belimumab?

A

human IgG1 neutralizing monoclonal antibody against B-lymphocyte stimulating factor (BLyS) aka BAFF (B cell Activating Factor)

153
Q

What is the mechanism of action of belimumab?

A

Belimumab binds with high affinity to BLyS (BAFF) and inhibits its binding to its 3 receptors therefore inhibiting BLyS induced proliferation of B cells and decreased survival of autoreactive B cells.

154
Q

What are indications for belimumab?

A

Lupus - especially with skin, MSK, and hematologic sx
Lupus nephritis

Approved for patients aged 5 and older in SLE receiving standard therapy and for adults with lupus nephritis receiving standard therapy.

155
Q

What are contraindications to belimumab?

A

Anaphylaxis
ACR does not recommend use with cyclophosphamide and bDMARDs

Hold for bacterial or fungal infection, varicella or measles
Would also maybe not use if patient has significant depression or recent SI, past attempts

156
Q

What is the most common serious adverse effect of belimumab?

A

Serious infections

157
Q

What are common adverse effects of belimumab?

A 
Depression
Nausea
Diarrhea
Pyrexia
Nasopharyngitis
Bronchitis
Insomnia
Pain in extremities
Migraine
Pharyngitis
158
Q

A patient is treated with IVIG. Within an hour, the child has developed hypotension, wheezing and generalized hives. You think that she may have developed anaphylaxis. Deficiency of which antibody can result in such a clinical picture?

A

IgA deficiency

This occurs in 1 in 500-1000 patients. Serious anaphylactoid reactions occur soon after the administration of IVIG. Most preparations of IgG have traces of IgA. Anaphylaxis associated with sensitization to IgA in patients with IgA deficiency can be prevented by using IgA-depleted immune globulin. IgA-deficient patients with severe recurrent viral or bacterial respiratory tract infections or with isolated IgA who may develop severe anaphylactic reactions after an IVIG infusion should receive the first infusion in the hospital under medical supervision.

159
Q

What medication can cause a peripheral neuropathy in glove and stocking distribution?

A

Thalidomide

With strict precautions on the use of thalidomide in women of childbearing potential, peripheral neuropathy is now the major dose-limiting toxicity. Most commonly, patients will present with pain and paresthesias, typically in a glove-and-stocking distribution. This complication has been reported in anywhere from 1% - 70% of patients and may occur independent of dose/duration of therapy. Treatment includes discontinuation of drug; however, symptoms may be irreversible.

Could consider use in recurrent aphthous stomatitis

160
Q

A patient on methotrexate and Huimra was exposed to Varicella. What should you do?

A

Give Varicella Zoster immunoglobulin (VZIg) within 72 hours after exposure

161
Q

A patient on methotrexate and Humira was exposed to Varicella. They develop chickenpox. What should you do?

A

Stop biologic or DMARD
Continue glucocorticoid
Treat with PO or IV acyclovir depending on severity and spread

162
Q

A patient on methotrexate and Huimra was exposed to Varicella. They develop chickenpox. What should you do?

A

Stop biologic or DMARD
Continue glucocorticoid
Treat with PO or IV acyclovir depending on severity and spread

163
Q

A patient presents with a hyperpigmented patch of thickened skin with erythematous borders after MMR vaccine. What rheum dx are on the differential?

A

Localized scleroderma

Especially eosinophilic fasciitis

164
Q

For a lupus patient on cytoxan with low IgG but no recurrent or current infection, what should you do?

A

Measure IgG antibody titers to diphtheria, tetanus, and pneumococcal antigens

In patients without infection, it is beneficial to assess the immune response to protein and polysaccharide antigenic stimuli (vaccine challenge) prior to supplemental immune globulin therapy.

Lupus nephritis with nephrotic-range proteinuria, can have hypogammaglobulinemia. cyclophosphamide and rituximab can cause hypogammaglobulinemia.
Patients with low immunoglobulin levels and repeated infections need immune globulin supplementation regardless of their ability to mount a response to vaccine stimulus.

165
Q

What is a rare side effect of anakinra that you would see in a patient’s labs?

A

Thrombocytopenia and neutropenia are rare but reported adverse effects of anakinra.

New cytopenias in a patient with systemic juvenile idiopathic arthritis being treated with anakinra may be related to concurrent viral illness, macrophage activation syndrome in the context of flaring disease, or possible medication adverse effects and must be interpreted in the context of clinical presentation.

166
Q

What interaction can happen with Mycophenolate and oral contraceptive pills?

Why is this important?

A

Mycophenolate may decrease the concentration and reduce the effectiveness of oral contraceptive pills.

Given the known teratogenic risks associated with mycophenolate, recommendations advise the use of a secondary barrier method of contraception in addition to hormonal contraception.

Routine pregnancy screening is recommended prior to starting mycophenolate, 8 to 10 days after initiation, and during all regular follow-up visits.

Embryo-fetal toxicity associated with mycophenolate includes:

  • increased risk of first trimester pregnancy loss
  • congenital malformations including
  • -external ear abnormalities,
  • -cleft lip and palate,
  • -anomalies of the distal limbs, heart, esophagus, kidney, and nervous system.

The combination of ear, eye, and lip/palate abnormalities has been identified as mycophenolate embryopathy.

167
Q

The combination of ear, eye, and lip/palate abnormalities in a fetus/baby can be due to which rheumatic medicine?

A

Mycophenolate

The combination of ear, eye, and lip/palate abnormalities has been identified as mycophenolate embryopathy.

Embryo-fetal toxicity associated with mycophenolate includes:

  • increased risk of first trimester pregnancy loss
  • congenital malformations including
  • -external ear abnormalities,
  • -cleft lip and palate,
  • -anomalies of the distal limbs, heart, esophagus, kidney, and nervous system.
168
Q

What pathway leads to the development of drug induced lupus with TNF inhibitors?

A

activation of pro-inflammatory genes by transcription factor NF-κB via Jak-STAT1 signaling

Inhibition of tumor necrosis factor, including via administration of biologic medications, may lead to the overexpression of interferon and subsequent development of drug-induced lupus.

169
Q

What are the neurological side effects of cyclosporine?

A

tremors, paresthesias, headaches,

Clinical signs of cyclosporine toxicity include the following:

Tremors in 7% to 55% of patients
Hypertension in 8% to 53% of patients; its risk increases with increasing dose or duration of use.
Nephrotoxicity with elevated creatinine levels, hyperkalemia, or hematuria; requires monitoring.
Adverse gastrointestinal effects (eg, emesis, gastritis, ulcers, and gingival hyperplasia)
Other adverse effects including hypertrichosis, paresthesias, headaches, and increased risk of infection

170
Q

What medicines/med classes have serotonergic properties and if combined can lead to serotonin syndrome?

A 
SSRIs
SNRIs
tricyclic antidepressants
cyclobenzaprine 
St. Johns Wort
Tramadol

Of note, tramadol is an opioid analgesic with serotonergic properties

171
Q

What medications should not be given in conjunction with tramadol?

A

Serotonin meds, increases risk of serotonin syndrome

tramadol is an opioid analgesic with serotonergic properties

SSRIs
SNRIs
tricyclic antidepressants
cyclobenzaprine 
St. Johns Wort
172
Q

What lab abnormality is a clue that you are dealing with adrenal insufficiency?

A

Hyponatremia, low Na

Adrenal insufficiency can present with anorexia, nausea, emesis, weight loss, fatigue, myalgias, arthralgias, weakness, headache, abdominal pain, lethargy, postural hypotension, fever, skin desquamation, tachycardia, emotional lability, and even delirium.

As noted, patients with central adrenal insufficiency (including those secondary to glucocorticoid withdrawal) should not manifest with mineralocorticoid deficiency. As such, electrolyte abnormalities and true “adrenal crisis” with hypotensive shock is less common. However, in isolated cases, normokalemic, dilutional hyponatremia (because of the role of cortisol on free water excretion) and hypotension may be seen because of glucocorticoid deficiency alone.

Adrenal function recovers within 6 months for most patients after prolonged glucocorticoid exposure; however, a few studies have demonstrated adrenal suppression for up to 2 years after completion of treatment.

173
Q

Toxicity to the bladder from cytoxan is due to what metabolite?

A

acrolein

Bladder toxicity is caused by contact between the acrolein metabolite and the bladder mucosa.

In the longer term, bladder exposure to acrolein can result in transitional cell carcinoma.

174
Q

Toxicity to what cells is the cause of cytoxan’s risk of ovarian failure?

A

granulosa cells

Toxicity toward the granulosa cells leads to death of growing ovarian follicles and ultimately depletion of the follicular reserve

Increased age at time of administration is associated with increased risk for ovarian failure; administration at earlier ages, particularly before menarche, appears to lower the risk.

Pediatric Rheumatology Board Exam (21 decks)

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