09: Systemic Lupus Erythematosus Flashcards
1
Q
What is the incidence rate of SLE?
A
5.5 per 100K
2
Q
What is the prevalence rate of SLE?
A
72.8 per 100K
1 per 537 black females
3
Q
What is the F:M ratio for SLE?
A
10-15:1
(Suggests chromosome and/or hormonal influence.)
4
Q
What is the peak age for SLE?
A
15-44yrs
5
Q
What is the major health disparity in SLE?
A
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
6
Q
What is the disease concordance with SLE?
A
2-5% dizygotic twins
24-58% monozygotic twins
10-12% familial prevalence if one FDR
(Genes important but not whole answer.)
7
Q
What is the overview of pathogenesis in SLE?
A
- 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
8
Q
What occurs during the induction/expansion phase of SLE pathogenesis?
A
- ↓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
9
Q
What is the role of apoptotic cells in SLE?
A
- 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)
10
Q
What is the role of B cells in SLE?
A
- 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
11
Q
What is BLyS (BAFF)?
A
- 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)
12
Q
What are the clinical features (diagnostic criteria) of SLE?
A
- 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%)
13
Q
What are the laboratory features (diagnostic criteria) of SLE?
A
- Low blood cell counts (white, red, platelets)
- Antinuclear antibodies
- Specific autoantibodies (anti-DNA, anti-Sm, antiphospholipid)
14
Q
How is SLE definitively diagnosed?
A
- 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
15
Q
What are common supporting features of SLE?
A
- Alopecia
- Fatigue
- Fevers
- Raynaud’s
16
Q
What is a common comorbidity with SLE?
A
Premature atherosclerosis
50x greater incidence of MIs in women w/ SLE 2/2 endothelial activation and inflammation (vasculitis)
17
Q
What does this image show?
A
Malar (buttefly) rash: fixed erythema, flat or raised, sparing the nasolabial folds; will not cause scarring.
18
Q
What does this image show?
A
Discoid rash: raised patches, adherent keratotic scaling, folicular plugging; older lesions may cause scarring.
19
Q
What are the characteristics of arthritis in SLE?
A
- 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)
20
Q
What are the cardiac manifestations in SLE?
A
- 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
21
Q
What are the pulmonary manifestations in SLE?
A
- 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.
22
Q
What histologies are present in renal involvement of SLE, and waht are their clinical manifestations?
A
- 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
23
Q
What are the classes of lupus nephritis?
A
- 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
24
Q
What does this image show?
A
- Diffuse proliferative LN (class IV)
- Extensive immune complex deposition in mesangium and subendothelial side of capillary BM
25
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
26
What are the indications for renal biopsy?
1. Clinical parameters misleading (low C, high DNA Abs, inactive sediment, protein excretion abnl but \<1g/24hr)
2. Tx issues
3. Evaluation of tx response
4. Research
27
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
28
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
29
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
30
What are the features of **pathogenic autoantibodies**?
* IgG
* Monospecific
* High affinity
* Somatically mutated
31
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
32
Where are the various SLE AAbs found?
* Nuclear (screen w/ **ANA**)
* dsDNA
* Smith
* nRNP
* Cytoplasmic
* SSA/Ro
* SSB/La
* Membrane
* Phospholipids
33
How do AAbs cause tissue damage?
1. AAbs form immune complexes w/ their antigen
1. Activation of classical (C1) or alternative (C3) pathway produces complement products
2. **C3a, C5a**: chemotactic factor, anaphylotoxin
3. Leads to glomerulonephritis and fetal loss
34
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
35
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.
36
Hydroxychloroquine:
1. Pharma
2. Efficacy
3. Toxicity
4. MOA
1. PO
2. Mild-moderate
3. Rare retinal dz (schedule biannual retinal exams)
4. Unknown; may a) alter lysosomal granule pH, b) modify antigen presentation, c) alter TLRs
37
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)
38
Cyclophosphamide
1. Pharma
2. Efficacy
3. Toxicity
4. MOA
1. IV for lupus, PO for other uses (Wegener's dz, granulomatosus dz)
2. High rate of remission in combo w/ prednisone; T cells particularly sensitive
3. N/V, severe immunosupp, infx, infertility/sterility, marrow failure, bladder toxicity, bladder Ca, other malignancies (including lymphoma)
4. Alkylating agent: effective in rapidly dividing cells
39
Mycophenolate Mofetil (MMF)
1. Pharma
2. Efficacy
3. Toxicity
4. MOA
1. Fungal derivative; prodrug converted in liver
2. Comparable to other drugs
3. (Not mentioned)
4. Inhibits guanine synthesis, targeting lymphocytes
40
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)
41
What is the treatment regimen for an SLE pt p/w renal dz?
* Hydroxychloroquine
* High dose prednisone
* Cyclophosphamide IV
* MMF
* Biologics/rituxamab
42
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)
43
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
44
What is the mortality risk for 15-25yo pts w/ SLE?
20x more than sex/age-matched individuals.
45
What is the risk of mortality in a pt diagnosed w/ SLE at 20yo?
1-in-6 by age 35 (by lupus or infx)
46
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.
47
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
48
What does this image show?
Parotid swelling 2/2 Sjogren's syndrome
49
What is the **Schrimer test**?
Measure of amount of tears produced; used in the dx of Sjogren's sydnrome.
50
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)
51
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
52
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**
53
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
54
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
55
What are the three distinct types of APS?
1. **Primary **(absence of any comorbidity)
2. **Secondary **(pre-existing autoimmune condition, most frequently SLE)
3. **Catastrophic**: (simultaneous multi-organ failure w/ small vessel occlusion)
56
How is catastrophic APS diagnosed?
Must have all four of the following:
1. Evidence of involvement of three or more organs, systems, and/or tissues
2. Development of manifestations simultaneously or in less than a week
3. Confirmation by histopathology of small vessel occlusion in at least one organ or tissue
4. Laboratory confirmation of the presence of antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin antibodies)
57
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**).
58
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
* For CAPS:
* Plasmapheresis/IVIG/**rituxan**
