Myasthenia gravis

Myasthenia Gravis (MG) is an autoimmune disease where the immune system produces autoantibodies that attack the neuromuscular junction (NMJ), the connection between nerves and muscles. === THE COMPLEMENT CASCADE (Key Biology) === The complement system is a collection of ~30 proteins circulating in blood in inactive form, primarily made by the liver. Three activation pathways exist: CLASSICAL PATHWAY (antibody-triggered, dominant in MG/CIDP/MMN): Autoantibodies cluster on target → C1q binds Fc tails → C1r activates → C1s activates (CLASEPRUBART/RILIPRUBART BLOCK HERE) → C4 cleaved → C2 cleaved (EMPASIPRUBART BLOCKS HERE) → C3 convertase forms (AMPLIFICATION: each generates 100s of C3b) → C5 convertase → C5 cleaved (ECULIZUMAB/RAVULIZUMAB BLOCK HERE) → MAC punches hole in cell membrane → cell damage/death. LECTIN PATHWAY (sugar-pattern-triggered, NOT major in autoimmune diseases): Lectins detect microbial carbohydrate patterns → MASP-2 (similar to C1s) cleaves C4 → shares downstream cascade with classical pathway. ALTERNATIVE PATHWAY (always-on surveillance, PRESERVED by C1s/C2 inhibitors): C3 spontaneously breaks down → fragments land on surfaces lacking complement regulators (bacteria) → amplifies via Factor B/Factor D → forms MAC. This pathway is why C1s and C2 inhibitors DON'T require meningococcal vaccination — bacteria are still killed. C5 inhibitors block MAC from ALL pathways, requiring vaccination. ANALOGY: Three alarm systems — motion detector (classical, antibody-triggered), heat sensor (lectin, sugar-triggered), 24/7 cameras (alternative, always-on). C1s inhibitors disconnect the motion detector only. C2 inhibitors disconnect motion detector + heat sensor. C5 inhibitors disable the response team that ALL alarms dispatch. In autoimmune disease, the motion detector is producing false alarms — C1s and C2 turn it off while keeping cameras running for real threats. === DISEASE MECHANISMS IN MG === THREE mechanisms of NMJ damage: 1. COMPLEMENT-MEDIATED: MAC forms on muscle membrane → destroys post-synaptic folds (where AChR concentrates) → fewer receptors 2. ANTIGENIC MODULATION: Antibodies cross-link AChR → cell internalizes/digests receptors faster 3. RECEPTOR BLOCKADE: Antibodies physically block acetylcholine binding site FcRn inhibitors (Vyvgart) address ALL THREE by eliminating autoantibodies. Complement inhibitors (C1s, C2, C5) only block mechanism #1. This is Vyvgart's key advantage — broader mechanism coverage. === DRUG MECHANISMS COMPARED === C1s inhibitors (claseprubart, riliprubart): Block classical pathway only. Preserve lectin + alternative. No vaccination needed. C2 inhibitors (empasiprubart): Block classical + lectin pathways. Preserve alternative. No vaccination needed. C5 inhibitors (eculizumab, ravulizumab): Block terminal MAC from ALL pathways. Meningococcal vaccination REQUIRED (REMS). FcRn inhibitors (Vyvgart): Accelerate IgG degradation — lowers ALL autoantibodies regardless of subclass. Addresses all three damage mechanisms. IVIg: Works through 5+ mechanisms simultaneously (FcRn saturation, anti-idiotypic antibodies, FcγR modulation, anti-complement, macrophage regulation). Broad but non-specific. BAFF/APRIL inhibitors (telitacicept, povetacicept): Kill B cells AND plasma cells that produce autoantibodies — attacks root cause. Could enable treatment-free remission.

Generalized Myasthenia Gravis

Ocular Myasthenia Gravis

Generalized myasthenia gravis (AChR+)

Pediatric myasthenia gravis

Generalized myasthenia gravis (AChR-Ab+)