Case #4 SLE Flashcards
ACR diagnostic criteria for SLE 4 out of 11
SOAP BRAIN MD
Serositis
Oral ulcers
Arthritis
Photosensitivity
Blood disorders
Renal involvement
Antinuclear antibodies
Immunologic phenomena (eg, dsDNA; anti-Smith [Sm] antibodies)
Neurologic disorder
Malar rash
Discoid rash
GBM disruption
(Nephritic/Nephrotic)?
Nephritic
Podocyter disruption
(Nephritic/Nephrotic)?
NephrOtic
POdOcyte
Proteinuria (less than 3.5 g/day)
(Nephritic/Nephrotic)?
Nephritic
Proteinuria (>3.5g/day)
(Nephritic/Nephrotic)?
NephrOtic = Massive prOteinuria
Acute poststreptococcal glomerulonephritis (Nephritic/Nephrotic)?
Nephr”I“tic - “I“nflammatory process
Frequently seen in children.
Occurs 2 weeks after an infeciton
Acute Post-streptococcal glomerulonephritis
What type of hypersensitivity reaction is seen in Acute poststreptococcal glomerulonephritis?
Type III Hypersensitivity
ACID
Anaphylatic & atopic - Type I
Cytotoxic (antibody mediated) - Type II
Immune Complex (Type III)
Delayed (tcell mediated) - Type IV
What type of hypersensitivity reaction is seen in Goodpasture syndrome?
Type II
Rapidly progressing (crescentic) glomerulonephritis
(Nephritic/Nephrotic)?
Nephritic
- Goodpastures
- Granulomatosis with polyangitis (Wegener - cANCA)
Diffuse proliferative glomerulonephritis
(Nephritic/Nephrotic)?
Nephritic
- SLE (loopy lupus - wire looping in capillary)
- Membranoproliferative glomerulonephritis
Berger disease
(Nephritic/Nephrotic)?
Nephritic
IgA nephropathy
Alport syndrome
(Nephritic/Nephrotic)?
Nephritic
mutation in type IV (A) collagen
retinopathy, lens dislocation, glomerulonephritis, sensorineural deafness
x-linked
“can’t see, can’t pee, can’t hear a buzzing bee”
Membranoproliferative glomerulonephritis (MPGN)
(Nephritic/Nephrotic)?
Nephritic
Type I - may be 2ary to Hep B or C
Type II - C3 nephritic factor
(often copresents with nephrotic syndrome)
Focal Segmental glomerulosclerosis
(Nephritic/Nephrotic)?
Nephrotic FOcal
most common cause of nephrotic syndrome in:
African Americans
Hispanics
Minimal Change Disease
(Nephritic/Nephrotic)?
Nephrotic
- most common cause of nephrotic syndrome in children
Membranous nephropathy
(Nephritic/Nephrotic)?
Nephrotic
Amyloidosis
(Nephritic/Nephrotic)?
Nephrotic
Congo Red stain - apple green birefringence
Associated with:
TB
multiple myeloma
rheumatoid arthritis
Diabetic glomerulonephropathy
(Nephritic/Nephrotic)?
Nephrotic
Kimmelstiel Wilson lesions
Explain the mechanism of action of antimalarials.
Chlorquine and hydroxychloroquine are nonbiologic drugs and it has been proposed that they:
suppress T-lymphocyte responses in mitogen
inhibit leukocyte chemotaxis
stabalize lysosomal enzymes
inhibit DNA/RNA synthesis
trap free radicals
Explain the mechanism of action of glucocorticoids.
Interact with glucocorticoid receptors preventing NF-KB from activating and forming proinflammatory cytokines. It also activates anti-inflammatory and immuno-suppressive effects.
Glucocorticoids also inhibit the functions of tissue macrophages and other APCs.
Glucocorticoids dramatically reduce the manifestations of inflammation due to their effect on concentration, distribution and function of peripheral leukocytes and suppressive effects on inflammatory cytokines.
Explain the mechanism of action of cyclophosphamide.
CyCLophosphamide is a synthetic nonbiologic DMARD.
Its major active metabolite is phsphoramide mustard which Cross-Links DNA to prevent cell replication.
It suppresses Tcell and Bcell funcion by 30-40%.
Explain the mechanism of action of Mycophenolate mofetil (MMF).
MYCOPHENOLate mefetil (MMF) is a semi-synthetic DMARD
Converted to MYCOPHENOLic acid which inhibits inosine monophospate dehydrogenase leading to suppression of T and B lymphocyte proliferation.
It interferes with leukocyte adhesion to endothelial cells by inhibiting:
E-selectin,
P-selectin
and intercellular adhesion molecule 1.
Explain the mechanism of action of azathioprine.
AzaTHIOprine is a synthetic nonbiologic DMARD.
Its major metabolite is 6-THIOguanine which suppresses:
inosinic acid synthesis
B cell and T cell function
immunoglobulin production
IL2 secretions
What is the mechanism of Type I Hypersensitivity?
Production of IgE antibody –> immediate release of vasoconstrictive amines and other mediators from mast cells.
Mast cells release mediators that act on vessels and smooth muscles and proinflammatory cytokines.
Later recruitement of inflammatory cells
What is the mechanism of Type II Hypersensitivity?
Production of IgG, IgM –> binds to antigen on target cell or tissue –> phagocytosis or lysis of target cell by activated compleemnt or Fc receptors;
The deposited anibodies activate complement generating by-producs including chemotactic agents (mainly C5a) which direct the migration of pmn leukocytes and monocytes and anaphylatoxins.
A-Opsonization and phagocytosis
B- Complement and Fc receptor mediated inflammation
C - Antibody-mediated cellular dysfunction
What is the mechanism of Type III Hypersensitivity?
Deposition of antigen-antibody complexes –> complement activation –> recruitment of leukocytes by complement products and Fc receptors –> release of enzymes and other toxic molecules
What is the mechanism of Type IV Hypersensitivity?
activated T lymphocytes –> release of cytokines(IL2, IFN gamma) by CD4+, inflammation and macrophage activation
Tcell (CD8+) mediated cytotoxicity
What are the disease associations of Type I Hypersensitivity?
Hay Fever
Insect venom sensitivity
anaphylaxis to drugs
atopic dermatitis
some food allergies
allergies to animals and animal products
asthma
What are the disease associations of Type II Hypersensitivity?
Cytotoxic
HDNB (erythroblastosis fetalis - Rh- mother with Rh+ child)
Goodpasture disease
rheumatic fever
Autoimmune or drug induced hemolytic anemia
transfusion reactions
NonCytotoxic
Myasthenia Gravis (2 mice in a grave)
Graves disease
Type II Diabetes Mellitus
What are the disease associations of Type III Hypersensitivity?
SLE
Poststreptococcal glomerulonephritis
polyarteritis nodosa
Arthus reaction
Serum sickness
What are the disease associations of Type IV Hypersensitivity?
Ms. Tuberculosis has Contact dermatitis.
MS
Tuberculin test/Tuberculosis
Hashimoto thyroiditis
Contact dermatitis (poison ivy)
GVHD
RA
Crohn disease
leprosy
acute graft rejection
Explain the immunologic basis for Rituximab and other anti CD-20 monoclonal antibodies.
[Off label use] Rituximab and other anti-CD20 monoclonal antibodies (eg, ocrelizumab, ofatumumab, epratuzumab)
Rituximab is a B-cell targeted therapy. This anti-CD20 antibody is a chimeric murine/human monoclonal antibody which causes cell lysis when the Fab domain binds to CD20. Rituximab binds to the antigen on the cell surface, activating complement-dependent B-cell cytotoxicity; and to human Fc receptors, mediating cell killing through an antibody-dependent cellular toxicity. Reducing B-cell response reduces autoimmune response.
Explain the immunologic basis for Belimumab.
BLyS Blockers - The B-cell survival molecule B-lymphocyte stimulator (BLyS) also known as B-cell activation factor of the TNF family (BAFF) plays a key role in the activation and differentiation of B cells. High serum levels of soluble BLyS, and its homolog APRIL (a proliferation inducing ligand), are found in SLE patients and in murine lupus. Selective blockade of BLyS reduces transitional type 2 follicular and marginal-zone B cells and significantly attenuates immune activation.
Belimumab (Benlysta) - Belimumab is an IgG1-lambda monoclonal antibody that prevents the survival of B lymphocytes by blocking the binding of soluble human B lymphocyte stimulator protein (BLyS) to receptors on B lymphocytes. This reduces the activity of B-cell mediated immunity and the autoimmune response.
Explain the immunologic basis for Atacicept.
c. Atacicept - Atacicept (also known as TACI-Ig) is a soluble transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) receptor, which binds both BAFF and APRIL (Figure 1). Atacicept is of interest in SLE because of its profound effects on plasma cells, but its use leads to significant decrease in IgM and IgG immunoglobulin levels and increased infection.
Explain the immunologic basis for Abatacept.
T-cell target
Costimulatory molecules provide the necessary second signal for T-cell activation by antigen-presenting cells. An antigen-independent signal for T-cell activation is the CD28:B7 costimulatory interaction. CD28 is expressed on T cells, whereas the ligands B7-1 and B7-2 (CD80 and CD86) are found on antigen-presenting cells.. CTLA4 inhibits T-cell activation by binding to B7-1 and B7-2 (CD80 and CD86) expressed on antigen-presenting cells. Therefore CTLA4 interacts with B7 but inhibits T-cell activation, by preventing the costimulatory signal CD28-B7 interaction necessary for T-cell activation.
d. Abatacept - Abatacept is a soluble receptor or fusion protein encoded by fusion of CTLA-4 with the Fc portion of IgG1. Abatacept blocks CD28-B7 interaction and subsequent T-cell-dependent B-cell function.
Explain the immunologic basis for anticytokine therapies (monoclonal antibodies directed against IL-1, IL-6 and TNF-alpha)
Cytokines such as tumor necrosis factor alpha (TNF-α), interferon alpha and gamma (IFN-α/-γ) and interleukins (IL) 1, 6, 10, 15, and 18 are upregulated in SLE and play important roles in the inflammatory processes that leads to tissue and organ damage. These cytokines have been considered potential targets for the reduction of chronic inflammation in SLE.
TNF-alpha - Infliximab, Adalimumab, GOLimumab, certolizumab pegol and a fusion protein that acts as a “decoy receptor” for TNF-α Etanercept
IL-1 - Anakinra (A is #1)
IL-6 - Tocilizumab (toll is $6)
