drug hypersensitivity, allergies, immune-mediated toxicities

Question 1

Describe the laboratory clinical presentations of SLE

Answer 1

full blood count: low RBC (hemolytic anemia), WBC, lymphocytes and platelets

immunologic: positive for Anti-nuclear antibody, Anti-Smith antibody, Anti-dsDNA antibody, Anti-Ribonucleoprotein antibody, low complement (C3, C4, CH50)

Question 2

Describe the clinical presentations of SLE and the complications involved

Answer 2

Facial rash (butterfly pattern)

Arthritis (joint swelling, tenderness and pain in the wrists, hands, ankles)

Lupus nephritis (leading to renal failure)

Cardiovascular disease (pericarditis, myocarditis, accelerated atherosclerosis)

Neuropsychiatric lupus (stroke, cerebrovascular disease, anxiety, seizures, cognitive dysfunction, confusion, peripheral neuropathy, psychosis etc.)

Question 3

Name the four drugs approved by FDA for use in treatment of SLE

Answer 3

Hydroxychloroquine (all patients, incl. pregnant women should be on hydroxyhloroquine), prednisolone, aspirin, belimumab

Question 4

Name the S/E of systemic glucocorticoids

Answer 4

osteoporosis (patient should receive osteoporosis preventive therapy), cataract, glaucoma, hypertension, hyperlipidemia, hyperglycemia/diabetes, fat maldistribution, weight gain, thinning of skin, sleep/mood disturbances

Question 5

Name the S/E of topical glucocorticoids

Answer 5

skin atrophy, spider veins, dermatitis

Question 6

Name the S/E of hydroxychloroquine

Answer 6

retinal toxicity (>10% in patients who use it for over 20 years; risk increases with doses of >5mg/kg/day, more than 5 years of therapy, renal or macular disease or concurrent tamoxifen use), gastric intolerance, rash, skin hyperpigmentation

Question 7

Name the S/E of belimumab

Answer 7

infusion reactions, hypersensitivity, nausea, diarrhea, fever, nasopharyngitis, bronchitis, pain in extremities, insomnia, depression, migraine

Question 8

Name the S/E of cyclophosphamide (IV/PO)(immunosuppressant; induction therapy)

Answer 8

hemorrhagic cystitis (greater risk with oral as compared to IV, decrease with hydration and mesna), bladder malignancy, infertility, myelosuppression, opportunistic infections

Question 9

Name the S/E of mycophenolate mofetil (immunosuppressant; induction and maintenance therapy)

Answer 9

N/V/D (gastrointestinal effects may limit use and compliance, less symptoms with enteric coated form), myelosuppresion, hepatotoxicity

Question 10

Name the S/E of azathioprine (immunosuppressant; alternative to mycophenolate for maintenance therapy)

Answer 10

hepatotoxicity, myelosuppression

(test thiopurine methyltransferase - TPMT before starting as toxicity is greatly enhanced if deficient)

Question 11

Name the S/E of methotrexate

Answer 11

hepatotoxicity, pulmonary toxicity, hematologic toxicity, stomatitis (inflammation of the oral mucosa, presenting with ulcers)

Question 12

Name the S/E of rituximab

Answer 12

infusion reactions, infections, neutropenia, mucocutaneous reactions, fever, fatigue, progressive multifocal leukoencephalopathy

Question 13

Which of the drugs used for SLE are safe in pregnancy?

Answer 13

Hydrochloroquine (not more than 5mg/kg/day calculated using actual body weight) & Azathioprine

the rest: cyclophosphamide decreases fertility, and is teratogenic esp. in the 1st trimester, mycophenolate mofetil/methotrexate are teratogenic, steroids can cause gestational diabetes, pre-eclampsia, hyperglycemia, hypertension and should be minimized in pregnancy

Question 14

Name the drugs with the highest risk of developing SLE

Answer 14

Procainamide, hydralazine, quinidine

Question 15

Name the anti-phospholipid antibodies found in those with anti-phospholipid syndrome (APS) in SLE patients (found in 40% of SLE patients)

Answer 15

APA: lupus anticoagulant, anti-cardiolipin, anti-beta2 glycoprotein 1

Question 16

What is the general treatment for anti-phospholipid antibody positive patients?

Answer 16

non-pregnant:
primary thromboprophylaxis: aspirin
secondary thromboprophylaxis: warfarin

pregnant:
primary thromboprophylaxis: aspirin
secondary thromboprophylaxis: parental anticoagulants, e.g. heparin (warfarin is CI in pregnancy)
note: hydroxychloroquine has some protective effects as it suppresses some clotting factors

Question 17

Describe the monitoring regime for SLE:

Answer 17

monitor for adverse drug reactions, development of co-morbidities, measures of disease activity (SLEDAI, BILAG), regular labs every 1-3 months with active disease, every 6-12 months if stable

labs: urinalysis (assess renal function), anti-dsDNA antibodies, complement C3 and C4 levels, c-reactive protein, full blood count, liver function test

• ANA, anti-Sm, anti-RNP do not need to be repeated with each visit, as the levels do not fluctuate with disease activity

Question 18

What is are the common combinations for maintenance immunosuppression therapy for organ transplantation?

Answer 18

most common: calcineurin inhibitor (cyclosporin/tacrolimus) + mycophenolate + corticosteroids

other options: calcineurin inhibitor (cyclosporin/tacrolimus) + mTOR inhibitors (sirolimus/everolimus) -> however, the increased risk for nephrotoxicity limits its use

*calcineurin inhibitor is nephrotoxic, and toxicity worsens when it is combined with a mTOR inhibitor

Question 19

What are the common drugs used for induction immunosuppression therapy for organ transplantation?

Answer 19

lymphocyte depleting agents to cause cell lysis: antithymocyte globulin (ATG) and alemtuzumab (off-label)

immunomodulator to prevent activation and proliferation of T cells: Basiliximab

Question 20

What are the common drugs used for maintenance immunosuppression therapy for organ transplantation? (by pharmacological class)

Answer 20

calcineurin inhibitors: *cyclosporin, *tacrolimus
S/E: nephrotoxicity (worse when combined with mTOR inhibitor), hypertension, hyperlipidemia, hyperglycemia

antimetabolites: *mycophenolate, azathioprine
S/E: bone marrow suppression, hepatotoxicity

mTOR inhibitors: *sirolimus, *everolimus

biologics: adalimumab, belatacept

corticosteroids

Question 21

Describe the HPA axis suppression by long term use of corticosteroids

Answer 21

HPA axis: Hypothalamus-pituitary-adrenal axis (cortisol production pathway/control)

hypothalamus produces CRH (corticotropin releasing hormone), which stimulates the anterior pituitary to produce ACTH (adrenocorticotropic hormone), which stimulates the adrenal cortex to secrete cortisol

The introduction of exogenous glucocorticoids stimulates negative feedback loops which decrease the production of CRH and ACTH, thus leading to HPA Axis suppression. When exogenous glucocorticoids are stopped, the HPA axis is unable to recover its function quickly, leading to adrenal insufficiency.

Question 22

Who are at greater risk for adrenal insufficiency?

Answer 22

Patients who are on corticosteroids with a dose greater than 5mg of prednisolone once daily equivalent, for more than 3 weeks. But all patients taking long term steroids should have a tapered withdrawal and a degree of suspicion of adrenal insufficiency should be maintained in all patients who are taking or have taken corticosteroids