Therapeutics Rheumat/Immun Witt Flashcard

Rheumatoid Arthritis is what type of Hypersensitivity Reaction?
Type III Immune-Complex Reaction
Rheumatoid Factor (RF or RhF)

  • An Autoantibody against the Fc portion of IgG
  • They bind together to form immune complexes which contribute to the disease process
  • Not everyone has detectable RF

Pannus

  • The inflamed, proliferating synovium characteristic of rheumatoid arthritis
  • The pannus eventually invades the cartilage and eventually the bone surface, producing erosions of bone and cartilage –> destruction of the joint

Pathophysiology of Rheumatoid Arthritis

  • Hyperplasia of synovial membrane
  • Increased vascularity (angiogenesis)
  • Production of enzymes that cause tissue damage
  • Presence of inflammatory cells (CD4+ T-cells, B cells, Macrophages, Neutrophils)

What are B-cells’ role in Rheumatoid Arthritis?

  • B lymphocytes produce IgG and IgM which become deposited in the tissue
  • This subsequently leads to the activation of the serum complement cascade and the recruitment of the phagocytic arm of the immune response
  • This further exacerbates the inflammation of the synovium, leading to edema, vasodilation, and infiltration by activated T-cells

Early and intermediate molecular mediators of inflammation in Rheumatoid Arthriti

  • TNF-;
  • IL-1, IL-6, IL-8, IL-15
  • TGF-;
  • fibroblast growth factor
  • platelet-derived growth factor

;

;

What are APCs’ role in Rheumatoid Arthritis?

  • Synovial macrophages and dendritic cells further function as antigen presenting cells by expressing MHC II molecules, leading to an established local immune reaction in the tissue
  • Macrophages are stimulated to produce prostaglandins and cytotoxins

HLA-DR

  • MHC II
  • An αβ heterodimer, cell surface receptor
  • N-terminal domain forms an alpha-helix that constitutes the exposed part of the binding groove
  • C-terminal cytoplasmic region interacts with the other chain forming a beta-sheet under the binding groove spanning to the cell membrane
  • Constitutes a ligand for the TCR
  • Upregulated in response to signalling

Cytokine Signaling Pathways in Rheumatoid Arthritis

Th1 responses lead to stimulation of macrophages

Macrophages produce pro-inflammatory cytokines (TNF-α, IL-1, IL-6)

Stimulate the expression of adhesion molecules on endothelial cells

Increased recruitment of Neutrophils into joints

Neutrophils release elastase and proteases

Degradation of proteoglycans in superficial layer of cartilage

Immune complexes can now precipitate in the superficial layer of collagens and chondrocytes are now exposed

Chondrocytes and synovial fibroblasts release matrix metalloproteinases when stimulated by IL-1, TNF-α, or activated CD4+ T-cells

CD4+ T-cells also express osteoprotegerin ligands (RANKL) that stimulate osteoclastogenesis in osteoclasts

Bone destruction

Major Prostaglandins Involved in Inflammatory Response

  • PGE2
  • PGF
  • TxA2

 

Aspirin: MOA

  • Non-Competitive and Irreversibly acetylates specific serine moieties of COX-1 and COX-2

Result in irreversible inhibition of:

  • TXA2 — leads to blood-thinning
  • PGI2 — increased gastric acid secretion
  • PGE2 and PGF2α– decreased protective mucus lining in stomach and intestine, sodium and water retention

Decreases PGE2 at nerve endings, which normally sensitizes nerve endings to the action of bradykinin, histamine, and other chemical mediators

  • Antipyretic (resets thermoregulatory set point)
  • Inhibits NFKB activation (decreases pro-inflammatory cytokines)

Salicylate Poisoning: Symptoms

  • Mild (nausea, vomiting, mental confusion, dizziness, and tinninitus)
  • Severe (restlessness, delirium, respiratory and metabolic acidosis, convulsions, coma, death from respiratory failure)

Salicylate Poisoning: Treatment

  • Alkalinize (blood, urine)
  • IV fluids
  • Dialysis

Prednisone: MOA

  • Interfere with APCs to T-lymphocytes
  • Inhibit PG and leukotriene synthesis
  • Impair cell migration blunting inflammatory responses

Strategies for Inhibition of Cytokine Action

1.  Neutralization of Cytokines

  • Monoclonal antibodies or soluble receptors are targeted against specific cytokines — prevents their actions

2.  Receptor Blockade

  • Monoclonal antibodies or receptor antagonists are directed against cytokine receptor, thereby preventing their binding and actions

3.  Activation of Anti-Inflammatory Pathways

  • Synthetic anti-inflammatory cytokines are used to suppress the action of inflammatory cytokines

Pro-Inflammatory Cytokines

  • TNF
  • IL-1

Anti-Inflammatory Cytokines

  • sTNF-R
  • IL-10
  • IL-1ra

TNFα

  • Pro-Inflammatory cytokine
  • Key regulator of the inflammatory response
  • Produced mostly by monocytes and macrophages
  • Increases expression of adhesion molecules
  • Implicated in joint damage in RA
  • Potent stimulator of synovial fibroblasts, osteoclasts, and chondrocytes

Etanercept: MOA

  • Dimeric fusion protein
  • Consists of the extracellular ligand-binding portion of the p75 TNF receptor — TNFα recognizes this, binds to it, and becomes inactivated

Etanercept: Adverse Effects
Mild-moderate injection site reaction
Infliximab: MOA

  • Chimeric mouse-human antibody
  • Directed against TNF-α
  • Binds and inhibits TNF-α from interacting with its receptor

Adalimumab: MOA

  • Human-derived antibody
  • Antibody directed against TNF-α
  • Binds and inhibits TNF-α from interacting with its receptor

Golimumab: MOA

  • Antibody directed against TNF-α
  • Binds and inhibits TNF-α from interacting with its receptor

Infliximab: Adverse Effects

  • Generation of antibodies against infliximab (methotrexate reduces antibody development against infliximab)
  • Local injection-site reaction

IL-1

  • Pro-Inflammatory cytokine
  • Produced mostly by monocytes and macrophages
  • Causes release of metalloproteases from fibroblasts and chondrocytes

IL-1RA

  • Endogenous IL-1 antagonist
  • Binds to IL-1 receptor, but produces no signal

Anakinra: MOA

  • Recombinant IL-1 receptor antagonist
  • Effectiveness in RA is limited:

– TNFα may play a more significant role as a cytokine involved in RA

– Anakinra may not reach diseased tissues in sufficient concentrations

– 10-100x excess of IL-1RA is needed to effectively block IL-1

Anakinra: Adverse Effects
Infection
Rituximab: MOA

  • Chimeric (human-mouse) monoclonal antibody targeted against CD20 B lymphocytes
  • Binding of monoclonal antibody to CD20 generates transmembrane signals –> autophosphorylation and activation of serine/tyrosine protein kinases and induction of c-myc oncogene expression and MHC II molecules
  • Produces complement-mediated cytotoxicity
  • Produced antibody-dependent cell-mediated cytotoxicity
  • Induces apoptosis

CD20
Regulates early steps in the activation process for cell cycle initiation and differentiation of B-cells
Rituximab: Adverse Effects

  • Infusion reactions (cytokine release syndrome)
  • Increased incidence of infections

Abatacept: MOA

  • Fusion protein composed of the extracellular domain of CTLA-4 and a fragment of the Fc domain of human IgG1
  • Mimics endogenous CTLA-4 and competes with CD28 for CD80 and CD86 binding
  • By blocking the engagement of CD28, Abatacept prevents the delivery of the secondary costimulatory signal that is required for optimal T-cell activation
  • This prevents the release of TNF-α, IL-2, IL-6

Abatacept: Adverse Effects

  • Infection
  • Malignancy

Tocilizumab: MOA

  • Humanized monoclonal antibody against the IL-6 (CD126) receptor

IL-6

  • Pro-inflammatory and anti-inflammatory cytokine
  • Secreted by T-cells and macrophages
  • Role as an anti-inflammatory cytokine is mediated through its inhibitory effects on TNF-α and IL-1, and activation of IL-1ra and IL-10

IL-6 Receptor
Mediator of fever and the acute phase inflammatory responses
Methotrexate: MOA

  • Competitively inhibits Dihydrofolate Reductase
  • Structurally related to folic acid and acts as an antagonist of that vitamin by inhibiting DHFR
  • Slows erosion in joints
  • Reduces lymphocyte and cytokine levels

Methotrexate: Adverse Effects

  • Nausea
  • Mucosal ulcers
  • Dose related hepatotoxicity
  • Folic acid deficiency

Fleucovorin: MOA

  • Reduced folate
  • Used to rescue cells exposed to folate antagonists (methotrexate, pyrimethamine, trimethoprim)

Leflunomide: MOA

  • Exhibits essentially all of its pharmacologic activity via its primary metabolite A77 1726 (M1)
  • Inhibits Dihyroorotate Dehydrogenase –> inhibits pyrimidine synthesis
  • Suppressed pyrimidine synthesis in T and B lymphocytes interferes with RNA and protein synthesis within the cells, which inhibits B and T-cell proliferation

Leflunomide: Adverse Effects

  • Paresthesias
  • Peripheral neuropathy
  • vomiting, diarrhea, abdominal pain
  • Hepatotoxicity
  • Hair loss

Leflunomide: Interactions

  • Inhibits CYP2C9 which is responsible for NSAID metabolism
  • Can result in NSAID toxicity with concurrent NSAID use

Gout Pathophysiology

  • Disease in which high plasma levels of uric acid (hyperuricemia) cause for urate crystals to form in joints –> leading to inflammatory reaction
  • The end product of purine metabolism is uric acid and this is increased in the body through decreased excretion or increased ingestion
  • Most frequently occurs at the metatarsophalangeal joint

Complement Cascade Pathway of Gout

Monosodium urate crystals initiate the inflammatory response

Activation of Classic Complement Pathways

Cleavage products (C3a and C5a) are generated

Neutrophil chemoattraction and transmigration to the synovium

Phagocytosis, Degranulation, Free radical generation, Release of proteases

Cytokine Pathway of Gout

Monosodium urate crystals initiate the inflammatory response

Synovial macrophages phagocytose crystals

Proinflammatory cytokines (TNFα, IL-1, IL-8) are released

Increased expression of adhesion molecules on vessel endothelial cells

Facilitation of Neutrophil adhesion and transmigration

Phagocytosis, Degranulation, Free radical generation, Release of proteases

Colchicine: MOA

  • Inhibits microtubule polymerization by binding to tubulin — this inhibits the migration of neutrophils into the area of inflammation
  • Inhibits synthesis and release of leukotrienes (LTB4)
  • Not an analgesic and does not affect uric acid cleavage

LTB4’s role in Gout
Neutrophils amplify their own recruitment by releasing leukotriene LTB4 on phagocytized urate crystals, resulting in a positive feedback loop that results in further recruitment of neutrophils
Colchicine: Adverse Effects

  • N/V/D
  • Decreases body temp
  • Suppresses the respiratory center
  • Vasomotor stimulation leading to hypertension
  • Kidney failure
  • Myelosuppressive
  • Alopecia

Allopurinol: MOA

  • Xanthine Oxidase Inhibitor
  • Blocks the metabolism of hypoxanthine and xanthine to uric acid
  • Metabolite is Oxypurinol and is responsible for pharmacological effects
  • Indirectly inhibits purine biosynthesis by stimulating negative feedback
  • Interferes with metabolism of 6-mercaptopurine and azathioprine
  • Dose dependent

Reabsorption of Urate is is mediated by:

  • The URAT1 antiport on the apical membrane
  • The OAT antiport on the basolateral membrane

When giving a patient a drug that increases uric acid elimination, what is an important to consider?

  • Urate can cystallize and form kidney stones
  • In order to increase solubility of urate, urine must be alkaline

Probenecid: MOA

  • Competitively inhibits the active reabsorption of uric acid, via binding to OAT;
  • Prevents uric acid reabsorption to the blood
  • No anti-inflammatory or analgesic activity

Sulfinpyrazone: MOA

  • Similar to probenecid
  • Competitively inhibits the active reabsorption of uric acid
  • No anti-inflammatory or analgesic activity
  • Sulfinpyrazone and its metabolite have anti-platelet effects (mediated through inhibition of COX)

Sulfinpyrazone: Adverse Effects

  • dyspepsia, epigastric pain, N/V, gastric bleeding
  • CI in peptic ulcer
  • agranulocytosis, anemia, aplastic anemia, leukopenia, thrombocytopenia

Get instant access to
all materials

Become a Member