Spontaneous development of myasthenia gravis and myositis following treatment with pembrolizumab: a case report.

BACKGROUND: Immune checkpoint inhibitors are a relatively new advancement in the world of cancer therapy. As such, their adverse effects have yet to be fully understood, with only recent literature documenting autoimmune phenomena secondary to their utilization. Specific immune checkpoint inhibitors have recently been linked with the development of myasthenia gravis, which is classically known to manifest spontaneously in patients. Given the relative rarity of this presentation, the risk of misdiagnosis and subsequent mortality and morbidity is concerning. CASE PRESENTATION: We discuss the case of a 73-year-old male who presented with clinical symptoms of myasthenia gravis and myositis shortly after beginning treatment with Pembrolizumab. The diagnosis of myasthenia gravis was initially missed at an outside hospital, which delayed initiation of proper treatment. CONCLUSION: While the incidence of "de-novo" diseases secondary to immune checkpoint inhibitors might be increasing, guidelines regarding best treatment options do not yet exist, leaving many providers at a loss when faced with making clinical decisions surrounding patients with De novo myasthenia gravis. Thus, our goal is to underscore the importance of early recognition of this disease, and emphasize the need for a standard of care as immune checkpoint inhibitors usage becomes more prevalent.

Managing suspected myasthenia gravis and myositis induced by pembrolizumab in a Jehovah's Witness sarcoma patient.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) can cause a spectrum of adverse events known as immune-related adverse events (irAEs) that resemble autoimmune responses. Immune-mediated myasthenia gravis (MG) is a rare and serious neurologic adverse event that has been associated with ICIs requiring prompt treatment. In the Jehovah's Witness population, typical management of these adverse events may not be options, and alternative treatment choices would be needed. CASE REPORT: 73-year-old Jehovah's Witness patient with high-grade undifferentiated pleiomorphic sarcoma who developed immune-mediated MG approximately 4 weeks after initiation of pembrolizumab. On the day of admission, the patient presented with a three-day history of worsening ptosis, right greater than left. He was later found to be seronegative for MG. MANAGEMENT AND OUTCOME: The patient required therapy with pyridostigmine, steroids, and agreed to plasma exchange (PLEX) prior to discharge. He achieved near resolution of his neurologic symptoms, and pembrolizumab was discontinued. He later underwent radical resection of the left thigh soft tissue sarcoma and superficial inguinal lymph node dissection. He is now on active surveillance. DISCUSSION: While neurologic adverse events typically present 6 weeks after initiation of ICIs, MG has been reported occurring as early as 4 weeks after initiation. This rare and serious adverse event requires prompt treatment, and clinicians need to be aware of the alternative treatment options in this unique patient population. Early conversations regarding blood products and factions must be had to develop a treatment plan in accordance with the patient's personal decisions.

Novel uses of complement inhibitors in myasthenia gravis-Two case reports.

INTRODUCTION/AIMS: Myasthenia gravis (MG) is a rare, life-threatening immune-related adverse effect (irAE) of immune checkpoint inhibitor (ICI) treatment. C5-complement inhibitors are effective treatments for acetylcholine receptor antibody (AChR ab) positive generalized MG. We describe the use of eculizumab/ravulizumab in two patients with MG receiving concomitant pembrolizumab. METHODS: This was a retrospective review of two medical records. RESULTS: Patient 1: An 80-year-old male with recurrent, non-muscle invasive transitional cell carcinoma of the bladder developed ICI-induced AChR ab positive MG (ICI-MG), myositis, and myocarditis 2 weeks after the first dose of pembrolizumab. Myositis responded to corticosteroids. MG responded to eculizumab, followed by ravulizumab. He died of metastatic cancer 8 months later. Patient 2: A 58-year-old male had refractory thymoma-associated AChR ab-positive MG, which responded to eculizumab. He developed metastatic Merkel cell cancer necessitating pembrolizumab. MG remained stable on eculizumab. He had no irAEs for 22 months, with positron emission tomographic resolution of cancer. He then developed mild, indolent retinal vasculitis, which responded to prednisone. Discontinuation of pembrolizumab for 5 months resulted in cancer recurrence; pembrolizumab was resumed with peri-infusion pulse prednisone. MG remained stable and he continues eculizumab. DISCUSSION: In the first patient, eculizumab, followed by ravulizumab, improved ICI-MG. In the second patient, eculizumab treatment may have had a prophylactic effect on the development of ICI-induced irAEs. The effect of complement inhibition on cancer outcomes of ICI therapy is unknown. A possible biologic basis for complement inhibitors in reducing irAEs of ICI, especially in the presence of underlying autoimmune disease, merits evaluation.

Efficacy and safety of iscalimab, a novel anti-CD40 monoclonal antibody, in moderate-to-severe myasthenia gravis: A phase 2 randomized study.

BACKGROUND: Increased morbidity in many patients with myasthenia gravis (MG) on long-term immunosuppression highlights the need for improved treatments. The aim of this study is to investigate the safety and efficacy of iscalimab (CFZ533), a fully human anti-CD40 monoclonal antibody, in patients with moderate-to-severe MG receiving standard-of-care (SoC) therapies. METHODS: In this double-blind, placebo-controlled phase 2 study, symptomatic patients (n = 44) despite SoC were randomized 1:1 to receive intravenous iscalimab (10 mg/kg; n = 22) or placebo (n = 22) every 4 weeks for 6 doses in total. Patients were followed up for 6 months after the last dose. The total duration of the study was 52 weeks. RESULTS: In total, 34 of 44 patients (77.3 %) completed the study. The primary endpoint, Quantitative MG score, did not change significantly between baseline and week 25 for iscalimab (median [90 % CI], -4.07 [-5.67, -2.47]) versus placebo (-2.93 [-4.53, -1.33]); however, non-thymectomized patients (n = 29) showed more favorable results (iscalimab, -4.35 [-6.07, -2.64] vs placebo, -2.26 [-4.16, -0.36]). A statistically significant difference between iscalimab and placebo groups was observed in MG Composite score (adjusted mean change: -4.19 [-6.67, -1.72]; p = 0.007) at week 13, and MG-Activities of Daily Living score (-1.93 [-3.24, -0.62]; p = 0.018) at week 21. Adverse events were comparable between the iscalimab (91 %) and placebo (96 %) groups. CONCLUSION: Iscalimab showed favorable safety and improvements compared with placebo in non-thymectomized patients with moderate-to-severe MG. It did not show any protective effect in patients with moderate-to-severe MG.

Safety update: statins and myasthenia gravis.

Overview of: Medicines and Healthcare products Regulatory Agency. Statins: very infrequent reports of myasthenia gravis.Drug Safety Update 2023;17(2):1.

Pembrolizumab-induced Myopathy with Anti-striated Muscle Antibodies Successfully Treated by Plasma Exchange.

A 70-year-old woman with advanced endometrial cancer developed right ptosis and muscle weakness in the right quadriceps after pembrolizumab administration. Serum creatine kinase (CK) levels were elevated, and anti-striated muscle antibodies were positive. On magnetic resonance imaging, the right vastus lateral muscle showed an abnormal signal. She was diagnosed with pembrolizumab-induced myopathy. We initiated plasma exchange (PE), and the ptosis immediately resolved. We then introduced oral corticosteroids, which improved her muscle weakness. We were able to rapidly diagnose her with ocular symptoms and serum CK level elevation. The early initiation of PE might prevent the exacerbation of pembrolizumab-induced myopathy.

Anti-Kv1.4 Antibody-positive Nivolumab-induced Myasthenia Gravis and Myositis Presenting with Bilateral Ptosis and Demonstrating Different Pathophysiologies.

Nivolumab blocks inhibitors of T-cell activation and restores antitumor immunity but promotes T-cell activity in host tissues by blocking inhibition of the T-cell function, resulting in immune-related adverse effects. We herein report an 80-year-old man presenting with nivolumab-related myasthenia gravis with anti-muscular voltage-gated potassium channel-complex (Kv1.4) antibodies. On day 29 after nivolumab administration, he simultaneously developed rapidly progressing right ptosis and left facial paralysis. Nivolumab administration was discontinued. He subsequently presented with bulbar paralysis, dyspnea, and muscle weakness and received intravenous immunoglobulin, methylprednisolone, and plasma exchange. The severity of nivolumab-related myasthenia gravis with anti-Kv1.4 antibodies presented with diverse clinical findings.

Suspected Fluoroquinolone-Induced Exacerbation of Myasthenia Gravis in Dogs.

Acquired myasthenia gravis (MG) in dogs can present with focal or generalized weakness and is diagnosed by the presence of circulating antibodies to the acetylcholine receptor. Megaesophagus is the most common focal form of MG. Although exacerbation of MG has been associated with the use of fluoroquinolones in humans, it has not been previously described in dogs. The medical records of 46 dogs diagnosed with MG based on acetylcholine receptor antibody testing from 1997 to 2021 were retrospectively evaluated to identify any dogs who demonstrated exacerbation of MG after the administration of a fluoroquinolone. Exacerbation of MG, from focal to generalized, occurred in a median of 4.5 days after initiation of fluoroquinolone therapy in six dogs. In addition, one dog with generalized MG and megaesophagus developed pyridostigmine resistance subsequent to fluoroquinolone therapy. Marked improvement in generalized weakness was reported 36 hr after discontinuation of fluoroquinolone therapy alone in one dog and in combination with pyridostigmine in two dogs. Fluoroquinolone therapy was never stopped in three dogs who were euthanized because of severe weakness and one dog who died of respiratory arrest.

Analysis on the risk of myasthenia gravis related to immune checkpoint inhibitors based on the US FDA Adverse Event Reporting System.

OBJECTIVE: To evaluate the risk of myasthenia gravis (MG) associated with immune checkpoint inhibitors (ICI). METHODS: Adverse event (AE) reports related to MG, myasthenic syndrome, and MG crisis for durvalumab, atezolizumab, pembrolizumab, nivolumab, avelumab, and ipilimumab in the US FDA Adverse Event Reporting System (FAERS) from Q1 2004 to Q3 2022 were collected. The proportional reporting odds ratio (PRR) method was used to evaluate the correlation between the six drugs and the three AEs. Statistical significance was defined as having reports ≥3, PRR ≥ 2, and chi-square (χ2 ) ≥ 4. RESULTS: A total of 36, 78, 276, 380, 5, and 53 AE reports were collected for durvalumab, atezolizumab, pembrolizumab, nivolumab, avelumab, and ipilimumab, respectively. For myasthenic syndrome, the PRR values reflecting the correlation with the drugs were 27.83 (χ2 = 102.66), 26.20 (χ2 = 235.67), 44.17 (χ2 = 1313.98), 32.09 (χ2 = 1229.54), 21.31 (χ2 = 151.15), and 0 for durvalumab, atezolizumab, pembrolizumab, nivolumab, avelumab, and ipilimumab, respectively. For MG, the PRR values reflecting the correlation with the drugs were 24.21 (χ2 = 682.04), 18.34 (χ2 = 900.27), 39.32 (χ2 = 7945.15), 26.93 (χ2 = 6636.45), 14.73 (χ2 = 566.47), and 15.69 (χ2 = 54.77) for durvalumab, atezolizumab, pembrolizumab, nivolumab, avelumab, and ipilimumab, respectively. For MG crisis, there were no data for durvalumab, atezolizumab, avelumab, and ipilimumab; the PRR values reflecting the correlation with the drugs were 16.54 (χ2 = 225.23) and 9.20 (χ2 = 119.14) for pembrolizumab and nivolumab, respectively. All six drugs were statistically correlated with their corresponding AEs. CONCLUSIONS: ICI may lead to ICIs-associated MG during therapy. Analysis of FAERS data identified signals for AEs of MG with ICI regimens. Practitioners should consider the factors that may increase the likelihood of MG. The findings support a continued surveillance and risk factor identification.

Myasthenia gravis after the third dose of human papillomavirus 9-valent vaccine: A case report.

Human papillomavirus (HPV) infection is the main cause of cervical cancer. HPV vaccination is considered an effective way to prevent cervical cancer. Although the vast majority of people experience no obvious adverse reactions after being vaccinated with HPV vaccine, the continuous monitoring of adverse events following immunization is important. Herein, we report the case of a previously healthy young woman who developed unilateral extraocular muscle palsy after receiving the third dose of the Gardasil HPV 9-valent vaccine (9vHPV) and was diagnosed with myasthenia gravis (MG). The patient developed swelling of the left eye on the 3rd day after vaccination and ptosis of the left eyelid on the 18th day after vaccination. She was treated with oral pyridostigmine and methylprednisolone. Her symptoms began to improve after 2 weeks of treatment and resolved completely after 3 weeks. After excluding other possible causes and considering the close temporal relationship between the timing of the 9vHPV vaccination and the onset of symptoms, 9vHPV appears to have triggered MG. To our knowledge, this is the first documented case report of 9vHPV-associated MG in China. Although ocular MG may be a rare adverse event after vaccination with 9vHPV, there is currently no direct evidence establishing a causal relationship; therefore, the safety of 9vHPV remains unquestioned.

Immune checkpoint inhibitors induced side effects of the peripheral nervous system.

PURPOSE OF REVIEW: This review highlights recent knowledge on the diagnosis and treatment of immune checkpoint inhibitor-induced neurological side effects (irNAE) focussing on the neuromuscular system. RECENT FINDINGS: irNAEs mainly resemble sporadic neuromuscular autoimmune diseases and paraneoplastic neurological syndromes. However, neurological symptoms may be unspecific (muscle weakness, fatigue) in the oncological setting and carry the risk of misdiagnosis and delayed therapeutic intervention. The role of disease-specific neuromuscular autoantibodies in the diagnosis is controversial as preexisting autoantibodies may otherwise be present before immune checkpoint inhibitor (ICI) treatment without clinical symptoms and may not develop in case of irNAE manifestation. A new necrotising form of myositis (irMyositis) has been described presenting with facial weakness and ptosis mimicking myasthenia gravis. It comes along with a high rate of severe myocarditis accounting for a triad overlap syndrome (myasthenia/myositis/myocarditis). The role of modern biologicals in the treatment of irNAEs has to be determined. SUMMARY: irNAEs are rare but carry the risk of permanent morbidity and mortality. Early suspicion and diagnosis are key to prevent neurological sequelae. Beyond interruption of ICI administration, treatment corresponds to sporadic autoimmune diseases. The myasthenia/myositis/myocarditis overlap syndrome deserves special attention as it carries the highest risk of mortality. The role of neurotoxic pretreatment regimens, preexisting subclinical neurological autoimmune diseases and the risk of ICI-re-challenge after irNAEs has to be further investigated.

Improved outcomes with early immunosuppression in patients with immune-checkpoint inhibitor induced myasthenia gravis, myocarditis and myositis: a case series.

PURPOSE: Myasthenia gravis (MG) is a rare but life-threatening complication of immune-checkpoint inhibitor (ICI) therapy and often co-presents with myositis and myocarditis. Previous case series of ICI-related MG have reported high mortality rates. We present a series of ten patients from a tertiary oncology centre outlining outcomes of an early multi-modal immunosuppression strategy. METHODS: We reviewed The Christie Hospital database of immunotherapy-related toxicity from 2017 to 2020. Symptom severity was assessed using the Myasthenia Gravis Foundation of America (MGFA) classification. RESULTS: Ten patients with ICI-related MG were identified. All patients presented following 1 (n = 4) or 2 (n = 6) cycles of ICI. Symptom progression was rapid with a median of 3 days from onset of symptoms to admission. Concomitant myositis and myocarditis were observed in nine patients. AChR or MuSK autoantibodies were positive in six patients. All patients received urgent treatment with intravenous methylprednisolone (IVMP) and eight received intravenous immunoglobulin (IVIG). A single patient died from myasthenia-related symptoms; the remaining 9 patients were successfully discharged. CONCLUSION: In our cohort, we demonstrate good outcomes associated with early intensive immunosuppressive treatment with IVIG and IVMP. An agreed national treatment protocol or clinical discussion forum would be beneficial.

Real-world safety profile of eculizumab in patients with paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, or generalized myasthenia gravis: an integrated analysis of post-marketing surveillance in Japan.

Eculizumab is a C5 inhibitor approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and anti-acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR + gMG) in Japan. We report integrated safety data from post-marketing surveillance in these three indications, focusing on commonly occurring adverse events (AEs) and infection-related AEs. Of 1219 patients registered, 1055 (PNH: 780; aHUS: 192; AChR + gMG: 83) had available safety data. Total eculizumab exposure was 3977.361 patient-years. AEs were reported in 74.03% of patients. AEs with an incidence of  ≥ 1.0 per 100 patient-years included hemolysis, headache, nasopharyngitis, renal impairment, anemia, pneumonia, upper respiratory tract inflammation, influenza, condition aggravated, and infection. The incidence of infection-related AEs was 21.30 per 100 patient-years, the most frequent types (≥ 1.0 per 100 patient-years) being nasopharyngitis, pneumonia, influenza, and infection. Meningococcal infections were reported in four patients (0.10 per 100 patient-years). Two patients died from meningococcal sepsis, with a mortality rate of 0.05 per 100 patient-years. This is the largest safety dataset on eculizumab in Japan derived from more than 10 years of clinical experience. No new safety signals were observed and the safety profile of eculizumab was consistent with that in previous clinical trials and international real-world safety analyses.

Mogamulizumab-Associated Myositis With and Without Myasthenia Gravis and/or Myocarditis in Patients With T-Cell Lymphoma.

Mogamulizumab is being increasingly prescribed for the treatment of T-cell lymphomas (MF/SS/ATLL). We conducted a retrospective cohort study to identify muscular immune-related adverse events (irAEs) associated with mogamulizumab in patients with T-cell lymphoma followed at Dana-Farber Cancer Institute from January 2015 to June 2022. We identified 5 cases of mogamulizumab-associated myositis and/or myocarditis (MAM/Mc), 2 additionally affected by myasthenia gravis, among 42 patients with T-cell lymphoma. Three cases experienced -mogamulizumab-associated rash (MAR) prior to developing MAM/Mc. The incidence (n = 5/42, 11.9%) of muscular mogamulizumab-associated irAEs may be higher than has been previously reported in clinical trials and may be of late onset (a median of 5 cycles and as late as 100 days from the last infusion). We highlight the utility of IVIG, together with systemic corticosteroids, for the treatment of these potentially fatal side effects associated with mogamulizumab therapy.

Cogan's sign in a patient with suspected post-COVID-19 vaccine-associated myasthenia gravis.

The Cogan's sign is indicative of myasthenia gravis. This is the first report of neurological signs in a patient with post-COVID-19 vaccine-associated myasthenia gravis in Brazil. In this case, a previously healthy 68-year-old woman presented with proximal limb weakness, left ptosis, and diplopia 1 month after receiving her fourth dose of the COVID-19 vaccine. Neurological examination revealed the presence of Cogan's sign, and she recovered rapidly after treatment. To our knowledge, this is the first reported case of myasthenia gravis associated with the COVID-19 vaccine in Brazil.