• 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

• 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

• 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)

• 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

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

• 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

• 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

Th1 responses lead to stimulation of macrophages

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

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Stimulate the expression of adhesion molecules on endothelial cells

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Increased recruitment of Neutrophils into joints

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Neutrophils release elastase and proteases

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Degradation of proteoglycans in superficial layer of cartilage

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

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

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

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Bone destruction

• PGE₂
• PGF_2α
• TxA₂

• 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)

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

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

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

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

• TNF
• IL-1

• sTNF-R
• IL-10
• IL-1ra

• 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

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

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

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

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

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

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

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

• 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

• 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

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

• 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

• Infection
• Malignancy

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

• 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

• 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

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

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

• 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

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

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

• 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

Monosodium urate crystals initiate the inflammatory response

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Activation of Classic Complement Pathways

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Cleavage products (C3a and C5a) are generated

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Neutrophil chemoattraction and transmigration to the synovium

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Phagocytosis, Degranulation, Free radical generation, Release of proteases

Monosodium urate crystals initiate the inflammatory response

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Synovial macrophages phagocytose crystals

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

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Increased expression of adhesion molecules on vessel endothelial cells

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Facilitation of Neutrophil adhesion and transmigration

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Phagocytosis, Degranulation, Free radical generation, Release of proteases

• 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

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

• 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

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

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

• 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

• 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)

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