Systemic Lupus Erythematosus (2) Flashcards
Which patients does SLE occur most commonly?
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
SLE general pathophysiology
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
Autoantibodies of SLE
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)
Antiphospholipid antibodies
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)
SLE pathophysiology like which 2 hypersensitivity reaction types?
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
SLE clinical presentation
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
SLE diagnosis
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)
Skin manifestations
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)
Musculoskeletal manifestations
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
Lupus nephritis
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
Central/peripheral nervous system manifestations
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
What is the leading cause of death for patients with SLE?
Cardiovascular disease
-followed by renal disease and infections
Cardiovascular manifestations
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)
Other SLE manifestations
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)
Clinical course of SLE
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
Drug induced lupus
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
NSAID and ASA for SLE
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
Corticosteroids for SLE
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)
Hydroxychloroquine place in therapy for SLE
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
Belimumab MOA
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
Belimumab administration
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
Belimumab ADRs
Diarrhea/nausea
Hypersensitivity reactions
Infection
Psychiatrics disturbances
Infusion related reactions
Belimumab monitoring
Hypersensitivity and/or infusion related reactions
Infections
Worsening depression, mood changes, suicidal thoughts
Belimumab and pregnancy
Should be discontinued if pregnancy is confirmed
Belimumab place in therapy for SLE
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])
Rituximab place in therapy for SLE
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
TNF alpha inhibitor place in therapy for SLE
Infliximab
-some data for lupus nephritis
Etanercept
-long term treatment of refractory lupus arthritis
Cyclophosphamide MOA
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
Cyclophosphamide can cause what? How can this be prevented?
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)
Cyclophosphamide place in therapy
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
Cyclophosphamide pregnancy considerations
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
Cyclophosphamide monitoring
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
Azathioprine MOA
prodrug of mercaptopurine
acts as an antimetabolites - purine analog
Interferes with purine nucleic acid metabolism, destroying lymphoid cells
Azathioprine DDI consideration
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)
AZA adrs
Bone marrow suppression
Skin rashes
Fever
N/v/d
hepatic dysfunction
What genetic testing should be done before AZA use
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)
AZA pregnancy consideration
Category D risk, but may be continued in pregnancy if there are no other choices (risk v benefit decision)
Mycophenolate mofetil (MMF) MOA
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
mycophenolate mofetil (MMF) ADRs
Blood pressure changes - can increase or decrease
Hyperglycemia
Hypercholesteremic
CNS effects
Rash
Liver toxicity
GI
Infection
Increased SCr
MMF monitoring
CBC
renal and liver function
Infection signs
MMF pregnancy considerations
Avoid if safer options are available
(but risk vs benefit decision - may be continued if no other options)
MMF place in therapy
Most studied for lupus nephritis
●may also be useful for arthritis, cutaneous lupus, and hematologic and cardiorespiratory involvement, and can be steroid sparing
Methotrexate place in therapy
Can be used for arthritis and skin disease associated with SLE
-can be steroid sparing
Intravenous Immune Globulin (IVIG)
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
3 last line therapy options for SLE
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
What is the backbone treatment for lupus that is used for all manifestations?
Hydroxychloroquine
Non pharm therapy
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)
What are the only 4 FDA approved drugs for lupus
Aspirin
Hydroxychloroquine
Prednisone
Belimumab
So a lot of preferred therapies are actually off label use
Cutaneous lupus drug therapy
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
Joint pain drug therapy
If intermittent joint pain: NSAIDs
If severe or persistent: prednisone (10 mg or less daily) + hydroxychloroquine
If inadequate response: methotrexate + hydroxychloroquine
Lupus nephritis drug therapy
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
Neuropsychiatric lupus drug therapy
therapy
Treatment is specific to symptomatic presentation
If seizures - anticonvulsants
If depression - antidepressants
Which drug is associated with ovarian failure and infertility?
Cyclophosphamide
-can consider harvesting eggs before starting
Contraception considerations
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
Dealing with pregnancy and lupus
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
Antiphospholipid syndrome management in pregnancy
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)
Neonatal lupus
Baby can get antibodies from mom and present with lupus manifestations, but this usually resolves
Which antihypertensives can be used in pregnancy (4)
Labetalol
Hydralazine
Methyldopa
Nifedipine
(these are old drugs so they have the most data)
Which drug should be used for lupus flares in pregnancy and why?
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
Antiphospholipid syndrome drug therapy
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
Immunizations and lupus
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)
