SLE Flashcards
SLE
Systemic Lupus Erythematosus
Inflammatory autoimmune disorder
Chronic with relapses and remission
Can affect all organ systems
Malar rash = facial rash
Woman of childbearing potential and black/hispanic most commonly affected
DLE
Discoid Lupus Erythematosus
Inflammatory autoimmune disorder
Chronic, with relapses and remission
Primarily affects skin
Discoid rash of face
Can progress to SLE
Etiology of SLE - Environment
Ultraviolet Light - sunlight is #1 SLE trigger
Stress
Smoking
Medications (over 100)
-Hydralazine, Procainamide, Sulfa Drugs
Viruses or Virus-Like elements (EBV)
Etiology of SLE - Hormones
Estrogen - higher risk in oral contraceptive users and post menopausal women using estrogen
Prolactin - paradoxical decreased risk during pregnancy
SLE Pre-Clinical Phase: Autoimmune Proliferation
Overactive B cell and T cell activation
Elevated CD4:CD8 T cell ratio
Impaired tolerance/immune complex clearance
Dysregulation of cellular apoptosis via impaired/deficient macrophages which causes danger ligands to activate and mature dendritic cells
These dendritic cells release BLyS which prevents B cell apoptosis and increases B cell proliferation. Auto antibodies are also produced during this time (leads to clinical phase)
SLE Clinical Phase: Autoantibody Production
Increased self-exposure
Self-recognition
Foreign Ab cross-reaction
SLE Timeline
Pre-Clinical Phase:
Ab bind to soluble auto-Ag -> immune complexes
Immune complexes deposit in vasculature and tissues
Clinical Phase:
Type III hypersensitivity reaction -> Inflammation
Neutrophils and complement activate to destroy Ab-Ag complex
IFN-α, TNF, immune reaction leads to tissue damage
Organ involvement -> Remissions -> Relapses -> Further organ damage -> comorbidities (infection, malignancy)
SLE Most Common Clinical Presentation
Fever, arthralgias, and rash in a woman of childbearing age
Can impact any organ system so symptoms vary widely
ACR SLE Diagnostic Criteria
Initial criterion:
Antinuclear antibodies ≥ 1:80
AND
≥ 10 total points of criterion points met with at least one clinical criterion
Serologic Testing
Antinuclear Autoantibodies:
•Low positive predictive value
•Very high negative predictive values (97%)
•Good for excluding lupus, but not a 100% guarantee if clinical features of lupus exist (Caution: 10-15% of patients without SLE positive for ANA)
Anti-dsDNA Ab:
•Target genetic material in nucleus causing organ damage
•Perform after ANA titer to confirm
•Part of extractable nuclear antigen (ENA) panel
-High negative predictive value
Anti-SM Ab:
• Smith proteins help RNA keep its 3D structure
• Part of ENA panel
Lupus Nephritis (LN)
Kidney inflammation due to either:
-intravascular deposition of immune complexes in glomeruli
-formation of immune complexes on self-antigens on glomerular basement membrane
Used to be most common cause of death, but now beaten by infections
Diagnosed via persistent proteinuria and/or cellular casts +/- renal biopsy and histology to confirm
Clinical Presentation: foamy urine, peripheral edema, concomitant hypertension
Six classes based on type of LN. More severe forms (III, IV, VI) require immunosuppression or preparation for transplant
Antiphospholipid Syndrome (APS)
Antiphospholipid Antibody (aPL):
• ~50% of SLE patient are aPL (+)
• Anticardiolipin and lupus anticoagulant
• Hypercoagulable state - clot risk!
Secondary APS:
• aPL(+) plus thrombotic event = APS
• 50-70% of aPL(+) SLE patients will have an event
Significant morbidity/mortality concerns!!
Topical Steroid
Dose more important than drug
Face vs. arms/legs/trunk consideration
Steroid concern? Use topical CNI (tacrolimis)
High -> Low Potency:
• Clobetasol, fluocinonide high-dose, halobetasol
• desoximetasone, fluocinonide medium-dose
• betamethasone valerate ointment, fluticasone ointment
• mometasone cream, triamcinolone medium-dose ointment
• fluticasone cream, most triamcinolone products
• most desonide products, low-dose triamcinolone cream
• most hydrocortisone products
NSAIDs
MOA: reversibly inhibits COX-1 and COX-2 enzymes
BBW: serious cardiovascular thrombotic events, serious gastrointestinal bleeding, ulcerations, and perforation
Hydroxychloroquine
MOA: antimalarial and anti-inflammatory, interferes with lysosomal degradation of hemoglobin
FDA indications: SLE, malaria, rheumatoid arthritis
DMARD for long-term management in all SLE and DLE
-Reduces flares, risk of major organ involvement, and death
-Recommended for ALL patients diagnosed with SLE, unless CI
-Low risk in pregnancy, continue to reduce risk of flare
Dosing
-Suppression: 400 mg QD-BID
-Maintenance: 200-400 mg QD
Little to no immediate effect
-Usually takes 2-4 months to work
-Can use NSAIDs to control symptoms in meantime
-Adequate trial period is 6 months
Adverse Effects: Flu-Like Symptoms and Ocular Toxicity
Ocular Toxicity Risk factors: dose, length of therapy, CKD, previous retinal or macular disease
-Reduced risk if daily dose <5 mg/kg ABW
- Eye exam at baseline, in 5 years, then annually
Other ADE include Skin and hair pigmentation changes, Hematological changes
DMARD
Disease Modifying Anti-Rheumatic Drug
Glucocorticoids
MOA: suppression of polymorphonuclear leukocytes and reversal or increased capillary permeability, decreases activity and volume of lymphatic system, suppresses adrenal function
Adjunctive treatment reserved for:
-Moderate-severe initial presentation
-Organ-threatening or life-threatening SLE
-Inadequate response to HCQ or NSAIDs
-Poor quality of life without
Rapid symptoms relief
-Use suppressive dose (prednisone 20-60 mg/d) or IV pulse (dose by weight/severity) followed by oral taper
-May allow for lower initial PO dose upon transition
-PO taper 10-20% q 5-7 days, minimize daily dose ≤7.5 mg/day prednisone equivalent to reduce side effects, ideally, taper off
Adverse reactions from long-term use (many)
Belimumab (Benlysta)
MOA: IgG1-lambda monoclonal antibody that prevents survival of B lymphocytes by blocking the binding of soluble human B lymphocyte stimulator protein (BLyS) to receptors on B lymphocytes.
-Antagonizes B-lymphocyte stimulator protein (BLyS) which activates, stimulates proliferation, and prevents normal apoptosis of B-cells
FDA indications: lupus nephritis ≥ 5 years of age, SLE ≥ 5 years of age
B lymphocyte stimulator antagonist
Route of administration: monthly IV infusion (approved ages 5+ or subcutaneous self-injection (approved adults only))
Adjunctive medication to be used in combination with standard
-Non-active-CNS, autoantibody-positive SLE
-Musculoskeletal or cutaneous disease unresponsive to HCQ/NSAID/steroid
-Lupus nephritis III, IV, or V
Takes 2-4 months to work
Alternative, adjunctive agent to immunosuppressants
-Useful to lower steroid doses
Belimumab (Benlysta) Adverse Effects
Most common: nausea, diarrhea, allergic reaction (up to 1 in 7 patients), infusion reaction (up to 1 in 6 patients)
Progressive multifocal leukoencephalopathy (PML)
Risk of serious infection with live vaccines and other biologics
Not tested in pregnant or breastfeeding women
Anifrolumab (Saphnelo)
MOA: IgG1-kappa monoclonal antibody that blocks biologic activity of type 1 interferon receptors (IFNAR) -> reduces inflammatory and immunological processes
FDA indications: SLE, moderate to severe
Adjunctive medication to be used in combination with standard SLE treatment
Interferon antagonist
-Reduce immune cell recruitment
-Symptomatic improvements
IV infusion q 4 weeks
Not indicated in active LN or CNS disease
Immunosuppressants
For poor symptom control refractory to HCQ/NSAID/steroid
Indicated for organ-threatening SLE, mainly lupus nephritis
-Often used in combination with steroids
Azathioprine, cyclophosphamide, cyclosporine, methotrexate, mycophenolate
Methotrexate (MTX)
Immunosuppressant
Concomitant RA or primary presentation of arthritis
More effective than AZA
MOA: folate antimetabolite that inhibits DNA synthesis, repair, & cellular replication
BBW: embryo-fetal toxicity, hypersensitivity, severe adverse reactions
AE: bone marrow suppression, GI toxicity, hepatotoxicity, nephrotoxicity, etc.
Azathioprine (AZA)
Immunosuppressant
Second-line after steroids for a more moderate disease course
Safest in class during pregnancy
MOA: antagonist of purine metabolism
BBW: malignancy
AE: bone marrow suppression, nausea, vomiting
Mycophenolate Mofetil / Sodium (MMF)
Immunosuppressant
Proliferative (II-IV) LN, second-line for membranous (V) LN
Also used in non-renal disease
MOA: reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) which inhibits de novo guanosine nucleotide synthesis and blocks DNA synthesis
BBW: HCP experienced in immunosuppressive therapy, serious infections, malignancies, embryo-fetal toxicity
FDA indications: organ transplantation
Adverse reactions:
-Most common: diarrhea, abdominal pain, anorexia, nausea
-Hematologic, cardiovascular, teratogenicity
Not used in pregnancy
Cyclophosphamide (CYC)
Immunosuppressant
Use for organ-threatening cardiopulmonary, renal, or neuropsychiatric disease
MOA: alkylating agent that prevents cell division by cross-linking DNA strands & decreasing DNA synthesis
Incredibly toxic
-Hematologic, cardiac, neurologic toxicity
-Can cause permanent infertility
Cyclosporine (CsA)
Immunosuppressant
MOA: inhibits production & release of interleukin II
BBW: experienced physician, immunosuppression, bioavailability, psoriasis, HTN/nephrotoxicity
Membranous (V) LN
Calcineurin Inhibitors
Immunosuppressant
Most commonly tacrolimus, for proliferative (V) LN alone or in combination with MMF
Rituximab (Rituxan)
MOA: binds to CD20 proteins on the surface of B-lymphocytes, activating complement-dependent B-cell cytotoxicity
BBW: infusion related reactions, mucocutaneous reactions, Hepatitis B reactivation, progressive multifocal leukoencephalopathy (PML)
2nd or 3rd line therapy
Voclosporin (Lupkynis)
Adjunct to immunosuppressants in active LN
Oral calcineurin inhibitor
Should not be used with CYC (cyclophosphamide)
Nephrotoxicity if eGFR <45 mL/min/1.73 m2
- 3A4 interactions, including grapefruit
Treatment Guidelines
HCQ always unless contraindicated
Glucocorticoids PRN for active disease then taper
Non-renal?
Second line therapies would be belimumab (Benlysta) or anifrolumab (Saphnelo®)
LN?
Immunosuppressants, voclosporin (Lupkynis®)
Last line: Rituximab (Rituxan)
See the following slides from SLE notes
Treatment of aPL(+) or APS
Lupus nephritis treatment - specifically targets on right hand side
