Patient-Specific Targeted Therapies Could Mitigate Immune-Related Adverse Events

Researchers emphasized the value of personalized treatment approaches in mitigating neuromuscular immune-related adverse events (irAEs) in a case report of myasthenia-myositis-myocarditis published in Neurology Neuroimmunology & Neuroinflammation.

The development of neuromuscular irAEs, such as myasthenia gravis (MG), among others, have become an associated consequence of immune checkpoint inhibitors (ICI) in cancer-treatment therapy. IrAEs occur in approximately 2%-4% of patients administered ICIs, and managing these instances is important for preventing long-term sequelae, morbidity, and mortality in affected patients. Although less severe irAEs can be reduced by discontinuing the administration of glucocorticoids and ICIs, more intense cases necessitate more specialized treatment approaches.

Patient-Specific Therapy Model | image credit: vrx123 - stock.adobe.com

Authors of the present report note that current perspectives highlight the need for personalized treatment algorithms to inform therapeutic approaches. They believe considering the unique immunopathology of patients can lead to improved outcomes. However, acquiring the necessary target tissue to study impacted organs is a difficult endeavor that hinders researchers’ abilities in these cases. The hurdles in this process have contributed to the insufficient, limited knowledge available for managing irAEs.

To address this gap in knowledge, researchers reported on the case of a 47-year-old female patient who arrived at their clinic presenting with severe tetraparesis. A muscle biopsy would later reveal substantial complement deposition and reinforce the use of complement inhibition as a specialized therapy.

The patient had been diagnosed with MG at 30 years of age and arrived experiencing difficulties with swallowing, speaking, and muscle weakness that was progressively worsening. Following their MG diagnosis, a related thymoma had be resected; they began treatment of azathioprine and subsequent recurrent administration of IV immunoglobulins. During this treatment, the patient reported minimal muscle weakness, her quantitative MG (QMG) scores fell between 2 and 4 points, and her MG activities of daily living (ADL) scoring fell between 3 and 6 points.

Four months prior to their admittance, they had been diagnosed with triple-negative breast cancer and were treated with paclitaxel, epirubicin/cyclophosphamide, and pembrolizumab. Their QMG and ADL scores were not 17 and 18 points and they had proximal tetraparesis with a manual muscle testing (MMT)-8 score of 124/140. The patient also exhibited increased creatine kinase levels (3300 U/I) and reported muscle pain—which clinicians suspected overlapped with underlying neuromuscular irAEs. In response, ICI was stopped immediately and the patient began treatment of 2 mg of methylprednisolone/kg.

The patient’s condition was not improving, and magnetic resonance imaging (MRI) identified active myositis in the gastrocnemius muscle after abnormal spontaneous activity had been observed. As their condition progressed, the patient developed dysphagia, their QMG score rose to 22 points, and therapy was escalated to continual use of neostigmine and 7 immunoadsorption cycles. No clinical improvement was observed in the month following their admission as the patient exhibited elevated troponin (1071 ng/L) and N-terminal prohormone of brain natriuretic peptide (1025 ng/L). Furthermore, echocardiography and a cardiac MRI revealed pericardial effusion and myocarditis. Clinicians subsequently performed a muscle biopsy of the right gastrocnemius muscle.

In the muscle biopsy the clinicians also utilized staining for terminal complement. Their analysis found evidence of considerable complement deposition throughout capillaries and muscle fibers, as well as scant CD8 T-cell infiltration encompassing damaged muscle fibers.

In response, complement was deemed the therapeutic target, and the patient began an intervention with eculizumab. The patient’s symptoms drastically—and quickly—improved. The QMG score decreased from 17 to 6 points after 2 weeks. A follow-up MRI of the lower thigh exhibited diminished myositis and a later cardiac MRI no longer showed the presence of myocarditis. Four months after discharge, QMG and MMT8 scores were still stable.

The development of neuromuscular irAEs remain associated with increased rates of in-hospital mortality, and the utilization of personalized treatment strategies represent an unmet need. In this case report, clinicians were able to use muscle biopsy as a tool for implementing a targeted therapy. Because more mainstream treatment approaches were ineffective, this result represents the value and importance of applying patient-specific strategies. The authors conclude by encouraging further studies in this realm be conducted to develop a more holistic understanding of how personalized therapies can benefit patient outcomes with neuromuscular irAEs.

Reference

Nelke C, Pawlitzki M, Kerkhoff R, et al. Immune checkpoint inhibition-related myasthenia-myositis-myocarditis responsive to complement blockade. Neurol Neuroimmunol Neuroinflamm. 2023 Oct 26;11(1):e200177. doi: 10.1212/NXI.0000000000200177