Drugs that cause de novo myasthenia gravis (MG) do so primarily by disrupting immune homeostasis and promoting autoimmunity against components of the neuromuscular junction. Immune checkpoint inhibitors (ICIs), including PD-1 inhibitors (pembrolizumab, nivolumab), PD-L1 inhibitors (avelumab, atezolizumab), and CTLA-4 inhibitors (ipilimumab), are the most clearly implicated agents. These drugs enhance T-cell activation by blocking inhibitory pathways that normally maintain self-tolerance, increasing the effector-to-regulatory T-cell ratio, stimulating B-cell activation, and promoting autoantibody production and proinflammatory cytokines such as IL-17. ICI-associated MG may occur de novo or as an exacerbation of pre-existing MG, with symptom onset typically within weeks of treatment initiation. It is frequently severe, often associated with respiratory failure, and may overlap with myositis and myocarditis, contributing to high morbidity and mortality. [1]
Alemtuzumab, an anti-CD52 monoclonal antibody, has also been associated with secondary autoimmunity following lymphocyte depletion and repopulation. Although most commonly linked to thyroid disease, rare cases of acetylcholine receptor (AChR) antibody–positive MG have been reported after treatment, suggesting that immune reconstitution may precipitate autoimmune neuromuscular disease. D-penicillamine is a well-established cause of drug-induced MG, occurring in approximately 1–7% of treated patients. The condition is typically mild and often ocular, with AChR antibodies present in the majority of cases. Symptom onset usually occurs months after initiation, and most patients experience remission within months of drug discontinuation. The proposed mechanism involves modification of major histocompatibility complex (MHC) molecules or related immune targets, promoting loss of tolerance and autoantibody formation. [1]
Tyrosine kinase inhibitors (TKIs) have been associated with MG through two possible mechanisms: immune dysregulation leading to autoantibody production and, in certain cases (e.g., tandutinib), direct interference with neuromuscular transmission via inhibition of muscle-specific kinase (MuSK) signaling. Reported cases include AChR antibody–positive MG developing during treatment with agents such as lorlatinib, nilotinib, imatinib, and BRAF/MEK inhibitors, although causality is not always definitively established. Interferon-α therapy has also been linked to de novo MG and exacerbation of pre-existing disease, likely through cytokine-mediated immune activation and alterations in lymphocyte profiles. The type I interferon pathway is broadly implicated in autoimmune pathogenesis, and interferon treatment may promote antibody-mediated autoimmunity at the neuromuscular junction. [1]
Finally, statins have been reported to induce de novo MG or exacerbate established disease. Proposed mechanisms include immune modulation with shifts in T-cell polarization toward a humoral immune response, mitochondrial toxicity affecting neuromuscular junction function, or superimposed myopathy. Although most patients tolerate statins without difficulty, rare cases of AChR antibody–positive MG have been documented, sometimes recurring upon rechallenge. Overall, these agents induce MG by promoting autoimmune responses rather than directly impairing neuromuscular transmission, distinguishing them mechanistically from drugs that cause MG-like symptoms through pharmacologic interference at the neuromuscular junction. [1]