Autoimmune Diseases and Treatment Strategies

Autoimmune Diseases

• Two types: organ-specific and non-organ specific
• Solutions: reducing immune response (immunosuppressants), blocking consequences (anti-inflammatories), replacing/bypassing function (where possible)
• Management principles: controlling disease, managing flare-ups, limiting drug toxicity

Drug Groups in Autoimmune Patients

• Anti-proliferative agents (e.g., cyclophosphamide, methotrexate)
• Immune cell-depleting agents (e.g., rituximab)
• Cytokine inhibitors
• Inhibitors of cell signaling functions
• Precision medicine

Cyclophosphamide

• Inactive form of nitrogen mustard, metabolized to active form in the liver
• Alkylating agent, binds DNA causing DNA/RNA crosslinking
• Inhibition of protein synthesis
• Side effects: alopecia, nausea, bone marrow suppression

Methotrexate (MTX)

• Mechanism of action in oncology (high dose): interferes with dihydrofolate reductase (DHFR), reducing DNA synthesis
• Mechanism of action in autoimmunity (low dose): blocks AICAR transformylase, increases adenosine levels, multiple anti-inflammatory effects via adenosine receptors. Inhibits DHFR, preventing purine and pyrimidine biosynthesis.
• MTX inhibits DHFR, preventing purine/pyrimidine biosynthesis, blocking DNA/RNA. Accumulates AICAR, broken down into adenosine, inhibiting neutrophil degranulation.
• Role: inhibits replication of B & T cells; used with cyclosporine to prevent GvHD
• Side effects: alopecia, bone marrow suppression
• Autoimmune dose lower than cancer dose
• Teratogen (causes malformation in embryo)
• Adenosine receptors: G-protein coupled receptors (A1, A2A, A2B, A3)

B Cell-depleting agents

• Used to treat B-cell lymphoma; certain autoimmune conditions (e.g., rituximab)
• Depletion via ATG or anti-CD25 usually for transplant patients to prevent organ rejection

Rituximab

• Chimeric anti-CD20 monoclonal antibody (MAb)
• Kills normal and malignant B cells expressing CD20
• Mechanism: ADCC, complement activation, apoptosis.
• Side effects: reactivation of hepatitis B, progressive multifocal leukoencephalopathy (PML), systemic inflammatory response syndrome (SIRS)
• Mechanism of action in B cell killing: Complement-mediated cytotoxicity, antibody-dependent cellular cytotoxicity (macrophage), direct lysis (NK cells)

Plasmapheresis (Plasma Exchange)

• Removal, treatment, and return of blood plasma
• Exchanging blood plasma for donor plasma (or other fluids)
• Used in autoimmune patients
• Risks: leakage, clotting, bleeding

Intravenous Immunoglobulin (IVIG)

• Purified, pooled, sterilized IgG from the plasma of >1,000 donors

Inhibitors of Cell Function

• Goal: reduce pro-inflammatory signaling from immune cells

Precision Medicine in Autoimmunity

• Goal: to target molecular pathways driving disease in individual patients

Autoimmune Diseases - General

• Heterogeneous group of conditions
• Natalizumab prevents activated T cells migrating into the CNS

RA (Rheumatoid Arthritis) Treatment Failure

• Add additional DMARDs and continue anti-inflammatory drugs
• Potential for synthetic or biologic DMARDs
• Combination failure may mean different treatment approach

IVIG Mechanisms

• Blocks Fc receptors
• Interferes with complement activation
• Inhibits T and B cell function
• Alters immunoglobulin degradation

RA Immune Mechanisms

• Multiple mechanisms
• Anti-rheumatoid factor, anti-CCP antibodies are often found
• Immune complexes lead to inflammation, increased TNF-alpha production

RA Management

• Early diagnosis, specialist care, early initiation of DMARDs
• Tight control monitoring disease progression
• NSAIDs and glucocorticoids as adjunctive therapy

RA Pharmacological Management

• Start with monotherapy ASAP with oral methotrexate
• Use anti-inflammatories to accelerate control
• Once DMARDs effective, reduce and only use glucocorticoids for flare-ups