09: Systemic Lupus Erythematosus Flashcards
What is the incidence rate of SLE?
5.5 per 100K
What is the prevalence rate of SLE?
72.8 per 100K
1 per 537 black females
What is the F:M ratio for SLE?
10-15:1
(Suggests chromosome and/or hormonal influence.)
What is the peak age for SLE?
15-44yrs
What is the major health disparity in SLE?
Compared to whites, blacks have:
- Earlier age at dx
- More than 2-fold ↑ in SLE prevalence and incidence
- ↑proportion renal dz, progression to end-stage renal dz
What is the disease concordance with SLE?
2-5% dizygotic twins
24-58% monozygotic twins
10-12% familial prevalence if one FDR
(Genes important but not whole answer.)
What is the overview of pathogenesis in SLE?
- Genetic, environmental and gender factors lead to defective immune regulation
- Break in self-tolerance leads to the production of autoantibodies
- Autoantibodies lead to immune complexes –> complement activation –> tissue damage
What occurs during the induction/expansion phase of SLE pathogenesis?
- ↓clearance apoptotic cells
- Deficiency of **C1q **(attachment to the complement fixing sites in immune complexed immunoglobulin)
- Abnormalities of T cells:
- Hyperactivation of helper cells
- Recognition of self antigens
- Autoreactive clones escape tolerance
- T cell repertoire skewed toward help
- Defective T cell regulatory circuits
- Abnormalities of B cells:
- Hyperactivation
- Recognition of self antigens (RNA/protein particles)
- Abnormalities of Ig repertoire
- Altered cytokine production
What is the role of apoptotic cells in SLE?
- Surface blebs present autoAg to immune system: snRNP, SSA/Ro, SSB/La
- ↑rates of apoptosis in lymphocytes
- ↓rates of phagocytosis of apoptotic bodies (C1q must coat apoptotic blebs for clearance)
What is the role of B cells in SLE?
- Antigen presentation
- Regulate T cell function
- Cytokine production: TNF, IL-6, LTalpha, IL-12, IL-10
- Regulate follicular dendritic cells and lymphoid organization
- Antibody/autoantibody production
What is BLyS (BAFF)?
- B Lymphocyte Stimulator/B-cell activating factor
- Cytokine expressed in B cell lineage cells and acts as a potent B cell activator
- Plays role in:
- B cell development
- B cell proliferation
- Ig production
- Novel pharmaceutical/neutralizing Ab against BLys: LymphoStat-B (Benlysta)
What are the clinical features (diagnostic criteria) of SLE?
- Cutaneous manifestations (80-90%)
- Butterfly/malar rash (face)
- Discoid rash (anywhere on body)
- Photosensitivity
- Oral (usually hard palate) or nasal ulcers (50-75%)
- Arthritis (76-100%)
- Serositis:
- Pleuritis: Convincing history of pleuritic pain or rubbing heard by a clinician or evidence of pleural effusio
- Pericarditis
- Kidney dz (50%)
- Brain dz (seizures or psychosis) (30-60%)
What are the laboratory features (diagnostic criteria) of SLE?
- Low blood cell counts (white, red, platelets)
- Antinuclear antibodies
- Specific autoantibodies (anti-DNA, anti-Sm, antiphospholipid)
How is SLE definitively diagnosed?
- Satisfy 4 criteria:
- At least one clinical
- At least one immunologic
OR:
- Have bx-proven lupus nephritis in presence of antinuclear antibodies or anti-Ds DNA antibodies
What are common supporting features of SLE?
- Alopecia
- Fatigue
- Fevers
- Raynaud’s
What is a common comorbidity with SLE?
Premature atherosclerosis
50x greater incidence of MIs in women w/ SLE 2/2 endothelial activation and inflammation (vasculitis)
What does this image show?
Malar (buttefly) rash: fixed erythema, flat or raised, sparing the nasolabial folds; will not cause scarring.
What does this image show?
Discoid rash: raised patches, adherent keratotic scaling, folicular plugging; older lesions may cause scarring.
What are the characteristics of arthritis in SLE?
- Non-erosive, non-deforming (correctable)
- 2/2 ligament loosening
- Frequently precedes other manifestations of SLE
- Morning stiffness
- Evanescent (quickly fading) or persistent
- Knees, small joints of hands (PIPs)
- Objective evidence of inflammation (tenderness, swelling, effusion)
What are the cardiac manifestations in SLE?
- Primary lupus carditis:
- Pericarditis (ACR criterion for SLE dx)
- Myocarditis
- Endocarditis
- Conduction defects
- Secondary heart disease:
- Ischemic
- HTN:
- Systemic
- Pulmonary
- Infecive
NB: Seen in 25% of SLE pts.
NB: Pericarditis p/w chest pain worse w/ deep breath or lying down
What are the pulmonary manifestations in SLE?
- Pleuritis/pleural effusion (ACR criterion for SLE dx)
- Pneumonitis
- Pulmonary hemorrhage
- Pulmonary HTN
- Pulmonary embolism
- Shrinking lung syndrome (unexplained dyspnea, a restrictive pattern on pulmonary function tests, and an elevated hemidiaphragm)
NB: Seen in >30% of SLE pts.
What histologies are present in renal involvement of SLE, and waht are their clinical manifestations?
- Predominantly mesangial: nl U/A, nl function
- Predominantly membranous: U/A >2+ protein, no sediment; nl function
-
Predominantly proliferative:
- Focal: U/A >2+, active sediment; nl function
- Diffuse: U/A >2+, active sediment; abnl BUN/creatinine, ↑BP
- Sclerosis: markedly abnl BUN/creatinine
What are the classes of lupus nephritis?
- Class I: Minimal mesangial LN
- Class II: Mesangial proliferative LN
- Class III: Focal LN
- A: active lesions (focal proliferative)
- B: active + chronic lesions
- C: chronic (inactive) lesions + scars
- Class IV: Diffuse LN (>50% of glomeruli)
- S: Segmental
- G: Global
- Class V: Membranous LN
- If proliferative lesions present, “V + III” or “V + IV”
- Class VI: Advanced sclerotic LN
NB: Proliferative lesions dictate therapy
What does this image show?
- Diffuse proliferative LN (class IV)
- Extensive immune complex deposition in mesangium and subendothelial side of capillary BM
What does this image show?
- Membranous LN (class V)
- Immune complex deposition confined to intramembranous and subepithelial area of capillary BM
- Thickening of capillary walls and irregularity due to “spikes” in the external aspect of the BM
What are the indications for renal biopsy?
- Clinical parameters misleading (low C, high DNA Abs, inactive sediment, protein excretion abnl but <1g/24hr)
- Tx issues
- Evaluation of tx response
- Research
What are the primary neuropsychiatric manifestations of SLE?
- Organic mental syndrome (psychosis) (20%)
- Seizure (15%)
- Cranial neuropathy
- Peripheral neuropathy
- Stroke
- Movement disorder
- Transverse myelitis
- Aseptic meningitis
What are the hematologic abnormalities in SLE?
- Anemia (Hct <35%):
- Of chronic dz: 57-78%
- Hemolytic: 5-40%
-
Leukopenia (<4K/mm)** **(60%)
- **Lymphopenia **(<1.5K/mm) (60-84%)
- Neutropenia
-
Thrombocytopenia (<100K/mm) (60%)
- Spontaneous bleeding at <10K
What are the features of natural antibodies?
- IgM
- Polyreactive (bind to a variety of different and structurally unrelated self and non-self foreign antigens)
- Low affinity
- Germline-encoded
- Protective
What are the features of pathogenic autoantibodies?
- IgG
- Monospecific
- High affinity
- Somatically mutated
What are the common autoantibodies in SLE? What is their frequency? What are their clinical associations?
- Anti-dsDNA (40-70%): SLE-specific, renal dz
- Anti-Sm (14-55%): SLE-specific, CNS dz
- Anti-RNP (30-80%): Also seen in MCTD, PSS, arthritis
- Anti-SSA/Ro (35-60%): Also seen in SS, dry eyes + mouth, neonatal lupus
- Anti-SSB/La (10-15%): Also seen in SS, dry eyes + mouth, neonatal lupus
- Antiphospholipid (25-50%): Associated w/ thrombosis, stroke, fetal loss, thrombocytopenia
Where are the various SLE AAbs found?
- Nuclear (screen w/ ANA)
- dsDNA
- Smith
- nRNP
- Cytoplasmic
- SSA/Ro
- SSB/La
- Membrane
- Phospholipids
How do AAbs cause tissue damage?
- AAbs form immune complexes w/ their antigen
- Activation of classical (C1) or alternative (C3) pathway produces complement products
- C3a, C5a: chemotactic factor, anaphylotoxin
- Leads to glomerulonephritis and fetal loss
How do AAb and complement protein levels vary over the course of SLE and its treatment?
- Emerging dz: ↑levels of AAbs, ↓levels of complement proteins
- Tx of dz: ↑levels of complement proteins, ↓levels AAbs
What are the widespread vascular manifestations of SLE?
- Vasculitis
- Vasospasm
- Vasculopathy (microvascular leuko-occlusive dz)
- Thromboembolism
- Accelerated atherosclerosis
NB: Demonstrates that endothelium is active participant in SLE pathology.
Hydroxychloroquine:
- Pharma
- Efficacy
- Toxicity
- MOA
- PO
- Mild-moderate
- Rare retinal dz (schedule biannual retinal exams)
- Unknown; may a) alter lysosomal granule pH, b) modify antigen presentation, c) alter TLRs
What drugs are used in the treatment of SLE?
- Glucocorticoids
- Hydroxychloroquine
- Methotrexate
- Azathioprine (use in place of long-term steroids)
- Cyclophosphamide
- Mycophenolate mofetil
- Belimumab
- Rituximab (Ab against CD20, primarily found on surface of B cells)
- Cyclosporine (lower activity of T cells and their immune response)
Cyclophosphamide
- Pharma
- Efficacy
- Toxicity
- MOA
- IV for lupus, PO for other uses (Wegener’s dz, granulomatosus dz)
- High rate of remission in combo w/ prednisone; T cells particularly sensitive
- N/V, severe immunosupp, infx, infertility/sterility, marrow failure, bladder toxicity, bladder Ca, other malignancies (including lymphoma)
- Alkylating agent: effective in rapidly dividing cells
Mycophenolate Mofetil (MMF)
- Pharma
- Efficacy
- Toxicity
- MOA
- Fungal derivative; prodrug converted in liver
- Comparable to other drugs
- (Not mentioned)
- Inhibits guanine synthesis, targeting lymphocytes
What is the treatment regimen for an SLE pt p/w malar rash, fatigue and arthralgia?
- Hydroxychloroquine
- NSAIDS
- Prednisone (if necessary; try to avoid if possible)
What is the treatment regimen for an SLE pt p/w renal dz?
- Hydroxychloroquine
- High dose prednisone
- Cyclophosphamide IV
- MMF
- Biologics/rituxamab
What is the treatment regimen for an SLE pt p/w severe skin rash and alopecia?
- High dose hydroxychloroquine or switch to chloroquine
- Quinacrine
- Prednisone
- Methotrexate
- Azathioprine (steroid sparing if need cont’d prednisone)
What is the treatment regimen for an SLE pt p/w arthritis w/ moderate loss of function?
- Hydroxychloroquine
- NSAIDS
- Prednisone
- Methotrexate
- Azathioprine or MMF (steroid sparing if need cont’d prednisone)
- Belimumab
What is the mortality risk for 15-25yo pts w/ SLE?
20x more than sex/age-matched individuals.
What is the risk of mortality in a pt diagnosed w/ SLE at 20yo?
1-in-6 by age 35 (by lupus or infx)
What is Sjogren’s Syndrome?
Chronic, slowly progressive autoimmune disease characterized by lymphocytic infiltration & destruction of the exocrine glands resulting in xerostomia and dry eyes.
What are the clinical signs of Sjogren’s syndrome?
- Sicca symptoms:
- Dry eyes (keratoconjuctivitis sicca)
- Xerostomia (may cause periodontal dz)
- Extraglandular involvement:
- Skin:
- Xerosis
- Cutaneous vasculitis
- Raynaud’s
- Photosensitivity
- Annular erythematous lesions
- MSK:
- Arthralgias
- Inflammatory myopathy
- Pulm:
- ILD
- Lymphocytic interstitial pneumonitis
- GU:
- Vaginal dryness
- Interstitial cystitis
- GI:
- Dysphagia
- GERD
- Gastritis
- Constipation
- Celiac dz
- Hepatitis, PBC
- Pancreatitis
- Renal:
- RTA, interstital nephritis
- Neuro:
- Neuropathy
- CNS vasculitis
- Skin:
What does this image show?
Parotid swelling 2/2 Sjogren’s syndrome
What is the Schrimer test?
Measure of amount of tears produced; used in the dx of Sjogren’s sydnrome.
What does this image show?
Rose bengal stain: stains damaged corneal and conjuctival cells purple (2/2 decreased tear formation –> corneal abrasions in Sjogren’s syndrome)
What labs and histology are useful in the diagnosis of Sjogren’s syndrome?
- ANA
- Anti-ENA
- SSA/SSB
- RF (40% of SS pts)
- Hypergammaglobulinemia
- Lip bx/minor salivary glands: focal lymphocytic sialoadenitis
- Salivary gland (parotid/submandibular) bx only useful in severe cases
What is the treatment for Sjogren’s syndrome?
- Replace saliva/tears
- Stimulate saliva/tear flow via secretagogues
- Pilocarpine
- Cevimeline
- Immunomodulation/suppression:
- Plaquenil
- Methotrexate
- If life-threatening systemic manifestations:
- Cytoxan
- Cellcept
- Imuran
- Rituxan
- Orencia
What is antiphospholipid syndrome?
Autoantibody-mediated acquired thrombophilia characterized by recurrent arterial or venous thrombosis and/or pregnancy morbidity in the presence of autoantibodies against phospholipid (PL)-binding plasma proteins, mainly a plasma apolipoprotein known as β2 glycoprotein I (β2GPI) and prothrombin
How is antiphospholipid syndrome diagnosed?
One clinical and one laboratory manifestation:
CLINICAL:
- Clot (arterial/venous/small vessel thrombosis)
- Pregnancy pathology:
- 1 or more unexplained fetal death of morphologically normal fetus at 10th week of gestation or later
- 3 or more unexplained consecutive spontaneous abortions before 10th week of gestation (r/o maternal/paternal abnl)
- 1 premature birth of morphologically normal neonate before 34 weeks 2/2 eclampsia or severe pre-eclampsia or placental insufficiency
LABORATORY:
- **Anti-cardiolipin IgG **and/or IgM on 2+ occasions not less than 12 weeks apart w/ medium/high titer
- **Anti-B2 glycoprotein I IgG **and/or IgM on 2+ occasions not less than 12 weeks apart w/ medium/high titer
- Lupus anticoagulant on 2+ occasions not less than 12 weeks apart
What are the three distinct types of APS?
- **Primary **(absence of any comorbidity)
- **Secondary **(pre-existing autoimmune condition, most frequently SLE)
- Catastrophic: (simultaneous multi-organ failure w/ small vessel occlusion)
How is catastrophic APS diagnosed?
Must have all four of the following:
- Evidence of involvement of three or more organs, systems, and/or tissues
- Development of manifestations simultaneously or in less than a week
- Confirmation by histopathology of small vessel occlusion in at least one organ or tissue
- Laboratory confirmation of the presence of antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin antibodies)
What is the VDRL test, and why is it important in APS?
Test which detects Abs against syphilis; aPL binds to lipid in the test, thus APS patients will have a false positive (resolve by using more specific **FTA-Abs **test).
What is the treatment for APS?
- Prophylaxis: aspirin (inhibit platelet activation)
- efficacy debated
- Treatment:
- **warfarin **(anticoagulant)
- must be kept on for life
- rx after thrombotic event
- teratogenic
- **LMW heparin **(in pregnancy)
- prevents miscarriage when taken in conjunction w/ low-dose aspirin
- **warfarin **(anticoagulant)
- For CAPS:
- Plasmapheresis/IVIG/rituxan
