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Pembrolizumab-Induced Myasthenia Gravis Case Points To Need For Treatment Standardization

This case report details an incident of pembrolizumab-induced myasthenia gravis in an elderly male patient being treated for urothelial cell bladder cancer.

Researchers are calling for further investigation of the adverse effects (AEs) of pembrolizumab and other members of its drug class following a case of pembrolizumab-induced myasthenia gravis in an 87-year-old male patient being treated for urothelial cell bladder cancer.1 Doing so, they believe, holds potential to help identify future patients who may have a high risk of poor outcomes with these medications.

"It is evident that although immune checkpoint inhibitors have provided effective treatment for devastating diseases, they also present the risk of untoward AEs," the study authors published in Cureus. "This case highlights the importance of maintaining a high level of suspicion for immune-related myasthenia gravis and other immune-related AEs in patients on pembrolizumab and drugs in the same class."

Following a 2-week history of worsening right-sided ptosis, new left-sided blurred vision, dysarthria, cervical myalgia, and ambulatory dysfunction secondary to fatigue, the patient presented to his emergency department. In addition to the urothelial cell bladder cancer, he had a history of brain tumor resection with residual right-sided cranial nerve VII palsy and immunoglogulin A (IgA) deficiency. At this point, he had been on pembrolizumab for his bladder cancer for 4 weeks.

There was no evidence of stroke, but preliminary lab results showed elevate troponins, creatine kinase, and transaminases, all of which were attributed to the pembrolizumab and indicated by a Naranjo Scale score of 6. The Naranjo Adverse Drug Reaction Probability Scale score scale ranges from –4 to 13, with a 9 and higher indicating a definite adverse drug reaction; 5 to 8, a probable reaction; 1 to 4, a possible reaction; and 0, doubtful.2 Stoppage of pembrolizumab was recommended.

At his cardiology-oncology follow-up appointment, new lab evaluations showed troponin levels remained elevated, that liver function tests and creatine phosphokinase were high, and that he had borderline tachyarrhythmia. Balance and weakness had worsened. A third hospital visit revealed new-onset atrial fibrillation, with rapid ventricular response via EKG. Repeat EKG results were unchanged.

A diltiazem infusion was started after which he was switched to metoprolol, "with good response," the case report authors noted. However, the patient at this point exhibited bilateral restricted eye movements, decreased neck strength secondary to pain, and diminished deltoid strength. These findings alarmed this physicians, who ordered myasthenia gravis–specific antibody tests.

Myasthenia gravis diagnosisImage Credit: Andrii - stock.Adobe.Com

"Anti-acetylcholine (ACh)-binding, anti–ACh-blocking, anti–muscle-specific kinase, anti–acetylcholine receptor-modulating, and anti–ENS-2 antibodies were within normal limits," the authors wrote, following immunochemial testing.

Due to a 12% incidence of seronegativity, his clinicians still thought he may have myasthenia gravis. Because of this, the patient was initiated on a calcium channel blocker for heart rate control, pyridostigmine, and steroids. When that regimen failed, he was prescribed 10 plasma exchange sessions every other day.

"Intravenous immunoglobulin was not considered a viable treatment option given the patient's history of IgA deficiency," the case report authors noted.

By week 4, he had slight improvement, and was prescribed physical therapy plus weekly plasma exchange on an outpatient basis. Just 1 week later, his symptoms remained at only mildly improved. The weekly plasma exchange sessions continued for 1 more month until the patient died from acute hypoxic respiratory failure following pneumonia and pulmonary edema.

The investigators noted that although the complications in this case are rare, they may start to become more prevalent with wider use of immunomodulator medications. This and the lack of insight on how to best manage immune-related myasthenia gravis has them recommending standardizing treatment guidelines for the condition, with further investigation.

"By doing so, we will gain better insight into specific immune-related AEs and thereby be able to recognize those who are most susceptible to poor outcomes," the authors concluded. "As a result, there will be a future in which clinicians are more prepared to provide optimized therapy to patients treated with pembrolizumab or related medications."

References

1. Kosick TI, Patel K, Jasinski J, Dada B. A case of pembrolizumab-induced myasthenia gravis. Cureus. 2023;15(9):e45455. Doi:10.7759/cureus.45455

2. Adverse drug reaction probability scale (Naranjo) in drug-induced livery injury. National Institutes of Health. May 4, 2019. Accessed October 26, 2023. Https://www.Ncbi.Nlm.Nih.Gov/books/NBK548069/

Bridging The Gap Between Mental And Physical Health

Today, we welcome John M. Samuels, MPH, and Lipi Roy, M.D., MPH, FASAM, to discuss the importance of addressing mental health and physical health.

Taylor Swift, Prince Harry, Ryan Reynolds, Selena Gomez, Michael Phelps. What do these high-profile figures have in common? They have all been open about their mental health issues. In fact, a worldwide survey published in The Lancet, covering 150,000 responses across 29 nations, revealed that one out of two individuals across the globe will encounter a mental health disorder in their lifetime. The burden on society of this unmet mental health need is unacceptable. We need urgent, evidence-based, and compassionate responses.

Poor physical health in individuals with mental illness is a global concern. The risk of medical conditions such as heart disease and cancer increases in people with depression, PTSD, and other mental health disorders. Healthcare access is also limited, leading to disparities worldwide. In the United States, African American and indigenous communities receive subpar healthcare compared to white populations in approximately 40 percent of healthcare indicators. Within the Latino community, this disparity rises to 60 percent. High medical and psychiatric comorbidity reduces life expectancy and escalates personal, social, and economic burdens.

Coordinated care between physical and mental health is clearly and urgently needed.

One solution? A health advisor acting as a quarterback or consigliere can help bridge this gap, fostering collaboration between medical professionals, therapists, and mental health experts to empower individuals and enhance their overall well-being.

As the leader of a health advocacy firm (JS), I have observed first-hand how mental health organizations seek assistance in addressing their clients' complex and unmet medical issues. This intertwined need became vividly evident through the experience of one of my clients who was deeply anxious about seeing a doctor to get his relentless cough treated. I arranged an assessment and treatment by a specialist. Afterward, it was concluded that my client required treatment at an inpatient facility that specialized in both substance use disorders and mental health. Once his alcoholism and mental health condition were stabilized, further workup revealed a diagnosis of pulmonary fibrosis. Thankfully, my client received the comprehensive care that he needed.

Another client had a history of multiple hospitalizations due to severe stomach pain. During one particularly intense episode, my team and I had strongly advised him to go to the emergency department. Following admission, the medical team discovered he was struggling with alcoholism, which he had not disclosed to his family.

After discharge, my client made the courageous decision to enroll in an inpatient rehabilitation facility and, afterward, an outpatient program. Since then, I have facilitated regular sessions with a mental health therapist and a career coach. These steps have resulted in a profound life transformation. His stomach pain has subsided, and he has achieved significant milestones, including securing a full-time job and improving relationships with family and friends.

In the realm of healthcare, personal experiences like the ones shared underscore the importance of understanding the intricate connections between physical and mental health. Researchers have similarly shed light on these links, revealing significant associations between conditions such as depression and psoriatic arthritis, as well as their potential broader implications. This connection may extend beyond psoriatic arthritis due to elevated cortisol levels associated with depression, contributing to inflammation and related conditions like diabetes and heart disease.

The other key solution to the poor coordination between physical and mental health? Major investment in primary care.

As a former primary care physician (LR), I have diagnosed and treated a wide variety of acute and chronic conditions, ranging from upper respiratory infections to congestive heart failure. I have evaluated patients with weight loss and night sweats, ordered the appropriate lab and imaging tests, diagnosed them with cancer, and then referred them to specialists. Of note, before the last step, I reminded my patient that "we will get through this together." I also diagnosed and treated many patients with depression and anxiety and referred countless others to psychiatrists and therapists. This level of coordinated care and compassion so expertly provided by primary care providers is sorely lacking in the U.S. Healthcare system.

The principal task is finding a dedicated primary care physician (PCP) and visiting them at least once a year. A PCP is truly essential in first diagnosing and treating acute and chronic health issues and, second, in coordinating care with other specialists, including mental health providers. Another key factor is having appropriate health insurance coverage: understanding which mental health services are covered can alleviate financial concerns and any reluctance you may have about seeking assistance.

Access to timely mental healthcare remains a major challenge. A long under-addressed health issue, it that has garnered the attention of the White House amid the COVID-19 pandemic. Even access to overall medical care is shrinking. While urgent care centers are popping up across the country, the availability of primary care doctors is shrinking, further splintering any coordination between physical and mental health services.

When physical and mental health conditions (including substance use disorders) co-occur, treatment planning can become very challenging, leading to disease progression and higher morbidity and mortality. Conditions often go undiagnosed among patients with co-occurring physical and mental illnesses. For example, COPD and heart failure may mask or mirror symptoms of depression, anxiety, and post-traumatic stress disorder, making their recognition and diagnosis less likely.

In other circumstances, you might need to be your own care coordinator. You need to advocate for your own health and well-being by asking your doctors and specialists if they're communicating with one another, especially during transitions in care. Maintaining readily accessible medical records is a key component of this. Fortunately, many hospital systems have established portals that allow you to access these records easily.

In case of an emergency, have a plan in place. The COVID-19 pandemic reinforced the need for contingency plans for both the general population as well as healthcare systems. Finding an expert advocate and PCP can assist with all of the above. They can coordinate care and find the right hospitals and doctors, rather than you resorting to nonspecific and not-always-accurate "Dr. Google." They can also mitigate risk and may even be able to secure more reasonable rates at mental health and addiction facilities.

In today's era of war, violence, job and food insecurity, and other traumas, we are all struggling in some way or another. We need to work together to get people the health and support they need and deserve… urgently.

In Acute Myocardial Infarction Patients, Does Adding A Traditional Chinese Medicine Compound To Standard Treatments Improve Outcomes?

In a recent study published in JAMA, researchers investigated whether Tongxinluo, a Chinese medicinal compound, could improve clinical outcomes among ST-segment elevation myocardial infarction (STEMI) patients.

Study: Traditional Chinese Medicine Compound (Tongxinluo) and Clinical Outcomes of Patients With Acute Myocardial Infarction The CTS-AMI Randomized Clinical Trial. Image Credit: Image Point Fr/Shutterstock.Com Background

STEMI is a major life-threatening condition worldwide. Despite reperfusion treatment and optimal medical management, STEMI patients face increased risks of cardiovascular disease recurrences and in-hospital deaths. Tongxinluo has demonstrated promising potential in animal, in vitro, and small-scale trials among myocardial infarction patients.

Studies have indicated that ingredients such as peoniflorin, ginsenoside Rg1, and ginsenoside Rb1 in Tongxinluo have cardioprotective properties. Large randomized controlled trials (RCTs) are required to facilitate drug development and clinical translation.

About the study

In the present study, researchers evaluated the impact of Tongxinluo use by STEMI patients treated with STEMI guideline-directed medications such as coronary reperfusion and dual antiplatelet treatment.

The placebo-controlled, double-blinded RCT [The China Tongxinluo Study for Myocardial Protection in Patients with Acute Myocardial Infarction (CTS-AMI)] included adults diagnosed with ST-segment elevation myocardial infarction within a day of symptomatic onset. Patients were recruited from 124 hospitals across China between 23 May 2019 and 8 December 2020 and followed through 15 December 2021. ST-segment elevation ≥was 0.2 mV in more than two adjacent leads or new left bundle-branch blocks among the participants.

Individuals were randomized in a 1:1 ratio to receive Tongxinluo or a placebo drug orally for one year [loading dosage was 2.1 grams post-randomization (eight capsules), and maintenance dosage was 1.0 grams, thrice daily (four capsules)], in conjunction with STEMI therapies.

The primary study endpoint was one-month majorly adverse cardiovascular or cerebrovascular events (MACCEs), the composite measure of myocardial reinfarction, cardiac mortality, stroke, and emergent coronary artery revascularization. MACCE follow-ups were conducted every three to 12 months.

Baseline characteristics of participants, including clinical features, laboratory investigations, and electrocardiograms (ECGs), were obtained at hospitalization. In addition, ECG was performed at two hours, 24 hours, and several days post-hospitalization/reperfusion treatment. Exploratory analyses were performed based on onset-to-arrival (≤12 hours, more than 12 hours) and serological creatinine levels at hospitalization (≤0.5 or above 0.5 of the normal range).

In addition, a per-protocol analysis was performed, excluding individuals with major protocol deviations and those who failed to complete 30-day follow-up assessments or did not complete the predetermined minimal exposure to Tongxinluo (80% or higher adherence).

The team excluded individuals with severe STEMI complications, including mechanical complications, serious cardiogenic shock unresponsive to vasopressors, uncontrolled acute left-sided cardiac failure or pulmonary edema, and malignant arrhythmias that could not be controlled by anti-arrhythmic agents.

In addition, individuals with severe comorbidities, such as severe renal or hepatic dysfunction, severe infections, bleeding tendencies, cancers, and a life expectancy of below 12 months, were excluded from the analysis.

Results

Among 3,797 individuals, 3,777 (mean participant age of 61 years, and 77% men) were considered for the analysis, among whom 1,889 received Tongxinluo, and 1,888 received a placebo. The median duration of hospitalization was nine days. Most participants received statins, P2Y12 receptor inhibitors, and aspirin. Other therapies included β-blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs).

One-month MACCEs were reported among 64 Tongxinluo recipients (3.4%) versus 99 placebo recipients (5.2%) [relative risk (RR) of 0.6 and risk difference (RD) of −1.8%)]. In addition, individual MACCE components, including cardiovascular mortality [56 (three percent) versus 80 (four percent); RR of 0.7, and RD of −1.2%], were significantly lower among Tongxinluo recipients compared to the placebo recipients.

In one year, Tongxinluo recipients demonstrated lower MACCE rates [100 (five percent) versus 157 (eight percent); HR of 0.6, and RD of −3.0%] and cardiovascular mortality [85 (five percent) versus 116 (six percent); HR of 0.7, and RD of −1.6%].

The team observed non-significant alterations in secondary endpoints such as one-month stroke, major hemorrhage at one and 12 months, 12-month all-cause deaths, and coagulation in stents (within 24 hours; one to 30 days; one month to one year). Adverse side-effects were more frequent among Tongxinluo recipients than placebo recipients [40 (two percent) versus 21 (one percent)] and mainly included gastrointestinal symptoms such as nausea and stomach discomfort.

Tongxinluo has been demonstrated to increase myocardial microvascular perfusion while decreasing myocardial ischemic/reperfusion damage by protecting endotheliocytes and cardiomyocytes from ischemic/reperfusion-induced mortality. Tongxinluo may also stabilize and slow the evolution of coronary susceptible plaques by reducing intraplaque inflammation and neovascularization. Tongxinluo has been shown in studies to stabilize arterial plaques, minimize severe cardiovascular events, and postpone the commencement of the first event.

Conclusion

Overall, the study findings showed that among STEMI patients, the Tongxinluo compound, as an adjunct to STEMI therapies, significantly improved one- and 12-month cardiovascular outcomes. However, further investigations are required to elucidate the underlying biological mechanisms of Chinese medicine in STEMI.

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