Systemic Lupus Erythematosus (2)

Question 1

Which patients does SLE occur most commonly?

Answer 1

Women of reproductive age (15-50 years old)
-higher in African descent

Note, while more rare, disease in men and children is more severe
Onset at a later age (over 50) also has a worse prognosis

Question 2

SLE general pathophysiology

Answer 2

SLE is an autoimmune disease caused by a vast array of autoantibodies - particularly antinuclear antibodies (ANA)
-generation of antibody can be genetic or environmentally related

Antibodies bind to self antigen and form complexes that deposit in cause an inflammatory response

This is a systemic condition, so every organ can be effected and it can present differently as a result, but the underlying cause for all of it is inflammation

Question 3

Autoantibodies of SLE

Answer 3

Antinuclear antibodies (ANAs) are the autoantibodies that form in SLE
They are grouped in 4 categories based on what they bind to…
1. antibodies to DNA
2. antibodies to histone (positively charged protein bound to DNA)
3. antibodies to non-histone protein bound to RNA
4. antibodies to nucleolar antigens

Other autoantibodies …
-bind to blood cells - RBCs, platelets, lymphocytes
-anti-phospholipid antibodies (present in 50% of patients with SLE)

Question 4

Antiphospholipid antibodies

Answer 4

These can be present in some healthy people without any problems
It becomes an Antiphospholipid Antibody Syndrome when thromboses occur
-arterial or venous thrombosis
-recurrent pregnancy loses

This can occur independently or in association to lupus (50% of patients with SLE have anti-phospholipid antibodies)

Question 5

SLE pathophysiology like which 2 hypersensitivity reaction types?

Answer 5

Mostly type 3 hypersensitivity reaction
-antibody-antigen complex deposits trigger compliment activation and inflammatory response

But also type 2 hypersensitivity reaction
-autoantibodies can bind to blood cells (RBCs, WBCs, platelets) and opsonize them for phagocytosis

Question 6

SLE clinical presentation

Answer 6

Autoantibody presence alone does not indicate diagnosis - they can be present for years without any symptoms

Different organ systems can be involved, so presentation varies

General symptoms:
fatigue, depression, anxiety, photosensitivity, joint pain, headache, weight loss, nausea/abdominal pain

Signs:
Rash, alopecia, fever, oral and nasal ulcers, arthritis, renal dysfunction, seizure, psychosis, pleuritis, pleural effusion, CV disease, pericarditis/myocarditis, heart murmur, hypertension, anemia, leukopenia, thrombocytopenia, lymphadenopathy, Raynaud’s phenomenon (vasoconstriction of extremities - no blood flow so white finger tips), vasculitis

Question 7

SLE diagnosis

Answer 7

Diagnosis is complicated since symptoms vary depending on which organ system is involved

Clinical criteria and score is used to diagnose
A score of 4 or higher with at least 1 clinical criteria and 1 immunologic criteria is needed for diagnosis OR biopsy proven lupus nephritis with positive ANA or anti-dsDNA for diagnosis
(kidney biopsy)

Question 8

Skin manifestations

Answer 8

Skin involvement is seen in 50-70% of patients

Acute cutaneous lupus erythematosus
-malar rash/butterfly rash on cheeks and nose
-is photosensitive
-waxes/wanes without scarring

Subacute cutaneous lupus erythematosus
-uglier rash (annular or papulosquamous)
-highly photosensitive
-usually heals without scarring
-sometimes accompanied with musculoskeletal pains
-can be caused by drug induced lupus

Chronic cutaneous lupus erythematosus
-worst skin condition
-associated with scarring and alopecia in those areas
-photosensitive
-associated with mouth ulcers, leukopenia, vasculitis, and chronic seizures
-more common in smokers and African Americans
(but patients with this have a lower incidence of other bad manifestations - arthritis, end-stage renal disease, and immunologic markers such as ANA, anti-dsDNA, and antiphospholipid antibodies)

Question 9

Musculoskeletal manifestations

Answer 9

Most patients have intermittent polyarthritis
-can be hard to distinguish from RA early on, sometimes people will meet criteria for both RA and SLE
-note with lupus there is no joint destruction like there is with RA

Joint pain can be mild or disabling

Question 10

Lupus nephritis

Answer 10

35% of patients present at time of diagnosis, 50-60% develop it by 10 years

More prevalent in men than women
And in African Americans and Hispanics

Renal biopsy is needed for staging … we treat stages III, IV, and V with medications
Note - stage 6 is most severe but is not treated with drugs because they won’t help at that point

Question 11

Central/peripheral nervous system manifestations

Answer 11

Cognitive dysfunction is common
Can be mild or complete psychosis
Headache, mood disorders

Seizures can occur (treated like regular seizure disorder on top of lupus treatment)

Cerebrovascular disease (ischemic stroke, TIA) … increased risk with presence of antiphospholipid antibodies (since they cause thromboses)

Movement disorders, cranial nerve neuropathies, aseptic meningitis

Question 12

What is the leading cause of death for patients with SLE?

Answer 12

Cardiovascular disease
-followed by renal disease and infections

Question 13

Cardiovascular manifestations

Answer 13

Pericarditis and myocarditis
Accelerated atherosclerosis

These occur due to chronic inflammation from the disease, but can also be due to side effects of drugs (high dose corticosteroids)

MI risk is increased with presence of antiphospholipid antibodies (because they increase risk of clots)

Question 14

Other SLE manifestations

Answer 14

Pulmonary
-pleuritis (with or without pleural effusion)

Hematologic
-anemia, leukopenia, thrombocytopenia

GI
-n/v/d
-autoimmune peritonitis and/or intestinal vasculitis
-increase in LFTs

Ocular
-conjunctivitis, retinal vasculitis/neuritis - blindness can develop quickly if not treated

Sjogren’s syndrome (inability to produce saliva/tears)

Question 15

Clinical course of SLE

Answer 15

High mortality rate - 3x greater than general population
-leading cause CV disease followed by renal disease and infections

Most people will continue living with active disease even on treatment, or have flares of active disease at least annually

35% of people live with low levels of disease while on treatment

Permanent complete remissions are rare

Fatigue and mylagias/arthralgias are present most of the time

Prognosis is better when limited to skin and musculoskeletal findings
Worst prognosis with renal or CNS involvement

Question 16

Drug induced lupus

Answer 16

To be considered drug induced lupus have to have:
Positive ANA + symptoms (plus taking a drug that is causing it)
(positive ANA alone does not meet diagnostic criteria)

Rarely involves kidneys or brain

Symptoms include: fever, malaise, arthritis or intense arthralgias/myalgias, serositis, and/or rash

Usually resolves over several weeks after discontinuing medication

If patient is taking offending agent, should test for ANA at the first hint of symptoms

Some offending agents: procainamide, disopyramide, propafenone, hydralazine, several angiotensin-converting enzyme inhibitors and beta blockers, propylthiouracil, chlorpromazine, lithium, carbamazepine, phenytoin, isoniazid, minocycline, nitrofurantoin, sulfasalazine, hydrochlorothiazide, lovastatin, simvastatin, TNF-alpha inhibitors

Question 17

NSAID and ASA for SLE

Answer 17

NSAIDs are recommended FIRST LINE for arthritis, MSK complaints, fever, and serositis
(these symptoms often do not go away with the chronic therapy options) - so chronic NSAID use is often needed
-consider side effects … especially renal and CV effects which occur with lupus alone too

Low dose aspirin can be used as prophylaxis for patients with antiphospholipid antibodies
-if they develop a clot, then you would just treat like you would any patient with thrombosis

Question 18

Corticosteroids for SLE

Answer 18

Topical - good for skin manifestations

Systemic
-rapid onset - good for flares
-the problem is long term use side effects, and for patients with lupus, it is sometimes not possible to get them off steroids quickly and it is a maintenance medication for many, so we see side effects - important to monitor for them
(osteoporosis, cataracts, glaucoma, hyperglycemia/diabetes, hypertension, dyslipidemia, thinning of the skin, weight gain, fat redistribution, sleep/mood disturbances, infection, psychological disturbances, osteonecrosis, and stroke)

Question 19

Hydroxychloroquine place in therapy for SLE

Answer 19

Should be given to all patients (including pregnant women)
-prevents flares and improves long term survival
-protects against bone mass loss
-protects against thrombosis
-prevents irreversible organ damage
-beneficial effect on lipids and fasting glucose
-decreases infections
-allows corticosteroid doses to be decreased

Question 20

Belimumab MOA

Answer 20

Fully human monoclonal antibody that binds to BLyS … a factor that simulated b cell activation
By, binding to BLyS, belimumab prevents BLyS from binding to the b cell - so the b cell will remain inactive and undergo apoptosis … less b cells = less autoantibodies produced

Question 21

Belimumab administration

Answer 21

Available IV or SQ
-note if switching from IV to SQ (which is more convienient for the patient)… need to consider when the last IV dose was, and when the next one should be - this is when SQ should be started

Question 22

Belimumab ADRs

Answer 22

Diarrhea/nausea
Hypersensitivity reactions
Infection
Psychiatrics disturbances
Infusion related reactions

Question 23

Belimumab monitoring

Answer 23

Hypersensitivity and/or infusion related reactions
Infections
Worsening depression, mood changes, suicidal thoughts

Question 24

Belimumab and pregnancy

Answer 24

Should be discontinued if pregnancy is confirmed

Question 25

Belimumab place in therapy for SLE

Answer 25

Approved to be used for SLE in addition to standard therapy (prednisone, NSAIDs, antimalarials, and/or immunosuppressive drugs [but not IV cyclophosphamide or other biologics])

Question 26

Rituximab place in therapy for SLE

Answer 26

Alternative for refractory lupus nephritis, severe hematological lupus, and some CNS manifestations of the disease (last line)

-efficacy is questionable - so reserved for last line

Question 27

TNF alpha inhibitor place in therapy for SLE

Answer 27

Infliximab
-some data for lupus nephritis

Etanercept
-long term treatment of refractory lupus arthritis

Question 28

Cyclophosphamide MOA

Answer 28

This is an alkylating agent used for chemotherapy - used for immunosuppression at lower doses

It is a prodrug, metabolized into 2 active metabolites in the liver…
1. Phosphoramide Mustard - causes cross linkage of DNA - this damage in DNA causes cell death
2. Acrolein - potent electrophile that reacts with nucleophiles on surface of cells that line the bladder, can cause hemorrhagic cystitis

Question 29

Cyclophosphamide can cause what? How can this be prevented?

Answer 29

Can cause hemorrhagic cystitis (inflammation of bladder lining) and bladder cancer (due to the acrolein active metabolite)
-note this is more common in smokers

This can be prevented with adequate hydration and Mesna (“sacrificial” nucleophile which neutralizes acrolein effect)

Question 30

Cyclophosphamide place in therapy

Answer 30

Used a lot in oncology, used off label for SLE
Served for patients that are very sick - have severe organ involvement in SLE - lupus nephritis, neuropsychiatric lupus, or severe systemic vasculitis

Question 31

Cyclophosphamide pregnancy considerations

Answer 31

CAN NOT BE USED IN PREGNANCY
-discontinue for 3-6 months before trying to get pregnant
-and 3 months for males before trying to conceive

Question 32

Cyclophosphamide monitoring

Answer 32

Hep B status
CBC with differential and platelets
BUN, UA
serum electrolytes
serum creatinine (active metabolites may persist in renal failure, dose adjustment may be needed)

Evaluate pregnancy status prior to use in females of reproductive potential.

Monitor for signs/symptoms of hemorrhagic cystitis or other urinary/renal toxicity, pulmonary, cardiac, and/or hepatic toxicity

Question 33

Azathioprine MOA

Answer 33

prodrug of mercaptopurine
acts as an antimetabolites - purine analog
Interferes with purine nucleic acid metabolism, destroying lymphoid cells

Question 34

Azathioprine DDI consideration

Answer 34

xanthine oxidase is an enzyme that metabolizes purines … AZA is a purine analog, so it is metabolized by xanthine oxidase

So, xanthine oxidase inhibitors will increase the levels of AZA…
dose reduction is needed with allopurinol use
(should be avoided with febuxostat)

Question 35

AZA adrs

Answer 35

Bone marrow suppression
Skin rashes
Fever
N/v/d
hepatic dysfunction

Question 36

What genetic testing should be done before AZA use

Answer 36

Test for the presence of TPMT 3A allele

AZA is converted by TPMT to a non toxic form
Patients who have TPMT 3A allele have low levels of TPMT… so they will have increased toxicity with AZA … require dose reduction
(otherwise high risk for GI adverse effects and myelosuppression)

Question 37

AZA pregnancy consideration

Answer 37

Category D risk, but may be continued in pregnancy if there are no other choices (risk v benefit decision)

Question 38

Mycophenolate mofetil (MMF) MOA

Answer 38

Prodrug metabolized to mycophenolic acid (MPA) which inhibits de novo guanine triphosphate (GTP) synthesis

Nucleic acids are needed for lymphocyte proliferation - so this inhibits both b and t cell activity

Question 39

mycophenolate mofetil (MMF) ADRs

Answer 39

Blood pressure changes - can increase or decrease
Hyperglycemia
Hypercholesteremic
CNS effects
Rash
Liver toxicity
GI
Infection
Increased SCr

Question 40

MMF monitoring

Answer 40

CBC
renal and liver function
Infection signs

Question 41

MMF pregnancy considerations

Answer 41

Avoid if safer options are available
(but risk vs benefit decision - may be continued if no other options)

Question 42

MMF place in therapy

Answer 42

Most studied for lupus nephritis

●may also be useful for arthritis, cutaneous lupus, and hematologic and cardiorespiratory involvement, and can be steroid sparing

Question 43

Methotrexate place in therapy

Answer 43

Can be used for arthritis and skin disease associated with SLE
-can be steroid sparing

Question 44

Intravenous Immune Globulin (IVIG)

Answer 44

Polyclonal antibody - pool of nonspecific human immunoglobulin from healthy human donors

They do not bind to a specific antigen - so they bind to many antigens and have an overall neutralizing effect on the immune system
-if it is hyperactive - it suppresses if
-if there is immunodeficiency - it boosts it

The mechanism is complicated, but in general it normalizes the patient’s immune networks

Question 45

3 last line therapy options for SLE

Answer 45

IVIG

Calcineurin inhibitors (systemic forms last line, some topical forms can be used earlier in therapy)

Plasmapheresis- like dialysis for the immune part of blood, filtering out components that are causing inflammation and giving blood back to patient

Question 46

What is the backbone treatment for lupus that is used for all manifestations?

Answer 46

Hydroxychloroquine

Question 47

Non pharm therapy

Answer 47

Protection from the sun
-clothing
-SPF sunscreen applied every 2 hours

Manage stress

Smoking cessation

Exercise

Weight control

Counseling and support groups

Keeping warm if Raynaud’s phenomenon occurs (vasoconstriction due to coldness, results in lack of blood flow to the finger tips - can be treated with vasodilating DHP CCB -pines)

Question 48

What are the only 4 FDA approved drugs for lupus

Answer 48

Aspirin
Hydroxychloroquine
Prednisone
Belimumab

So a lot of preferred therapies are actually off label use

Question 49

Cutaneous lupus drug therapy

Answer 49

Hydroxychloroquine

Topical corticosteroid
-low potency should be used on face, mid potency on trunk and extremities, high potency on thick skin areas (scalp, soles, palms)

Alternative therapy: topical calcineurin inhibitors

If refractory disease can add: oral corticosteroids, methotrexate, mycophenolate mofetil, azathioprine, immunomodulatory drugs (dapsone, thalidomide, or lenalidomide), biologics (rituximab or belimumab), or oral retinoids

Question 50

Joint pain drug therapy

Answer 50

If intermittent joint pain: NSAIDs

If severe or persistent: prednisone (10 mg or less daily) + hydroxychloroquine

If inadequate response: methotrexate + hydroxychloroquine

Question 51

Lupus nephritis drug therapy

Answer 51

Hydroxychloroquine

ACE inhibitor or ARB
-keep blood pressure low (important for kidney protection) and overall have protective kidney function

If LDL > 100 mg/dL … statin

If severe, we do aggressive therapies
Leading up to last line: cyclophosphamide

Question 52

Neuropsychiatric lupus drug therapy

Answer 52

therapy
Treatment is specific to symptomatic presentation

If seizures - anticonvulsants
If depression - antidepressants

Question 53

Which drug is associated with ovarian failure and infertility?

Answer 53

Cyclophosphamide
-can consider harvesting eggs before starting

Question 54

Contraception considerations

Answer 54

Estrogen containing oral hormonal contraceptives increase the risk of thrombosis
-not contraindicated but risk vs benefit decision

Progestin only contraceptives cause acne, hirsutism, bleeding, and have risk of osteoporosis with long term use

Intrauterine devices are a good choice for patients with lupus

Question 55

Dealing with pregnancy and lupus

Answer 55

The timing of pregnancy is important - ideally it should be after the patient has inactive disease for 6 months, and after being off a teratogenic medication for 3 months (methotrexate, leflunomide, mycophenolate, cyclophosphamide, and thalidomide)

It is considered a high risk pregnancy
If a patient has lupus and is pregnant they should receive low dose aspirin to prevent preeclampsia

Use of hydroxychloroquine should be continued
Supplements are important - calcium, vitamin D, folic acid
NSAIDs should be avoided

Question 56

Antiphospholipid syndrome management in pregnancy

Answer 56

LMWH, switch to heparin 4 weeks before due date
-warfarin is teratogenic
-heparin has a shorter half life and is reversible - better to use to decrease bleeding risk in labor which is why we switch to it

(note low dose aspirin should be taken for prophylaxis, this is if thrombosis occurs)

Question 57

Neonatal lupus

Answer 57

Baby can get antibodies from mom and present with lupus manifestations, but this usually resolves

Question 58

Which antihypertensives can be used in pregnancy (4)

Answer 58

Labetalol
Hydralazine
Methyldopa
Nifedipine

(these are old drugs so they have the most data)

Question 59

Which drug should be used for lupus flares in pregnancy and why?

Answer 59

Azathioprine
-it is safe because the fetal liver cannot metabolize it into its active form

Other option - calcineurin inhibitors (not as safe)
If corticosteroids are needed should use lowest dose for lowest duration

Question 60

Antiphospholipid syndrome drug therapy

Answer 60

Thromboprophylaxis is needed for patients in high risk situations (hospitalization, surgery, prolonged immobilization, after childbirth)
-LMWH

Primary prevention: hydroxychloroquine + low dose aspirin (81 mg)

Secondary prevention: warfarin
-may require combination therapy
-INR goal 2-3, may be above 3 if arterial thrombosis
-no role for DOACs here

Question 61

Immunizations and lupus

Answer 61

There is an increased risk of infections because of the disease and because of immunosuppressive therapy

Vaccines should be administered when disease is stable and prior to starting immunosuppressants

There is some evidence for flaring after vaccine administration- but this is not a contraindication to receiving vaccines - patients should be monitored

Immunosuppressed patients have impaired response to vaccines - check titers and revaccinate if needed

Live vaccines are contraindicated with biologic use (and should be cautioned with other high dose immunosuppressants)