Patients with checkpoint-induced myositis, overlap syndrome face worse outcomes
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Myositis due to immune checkpoint therapy is rare yet severe, with more than half of patients developing overlapping myasthenia gravis and/or myocarditis, leading to extended hospitalizations and respiratory failure, researchers noted.
“Immune checkpoint inhibitors (ICIs) have revolutionized cancer care,” Jeffrey Aldrich, MD, of the University of Texas MD Anderson Cancer Center, in Houston, and colleagues wrote in Arthritis & Rheumatology. “The ability of ICIs to stimulate the immune system provides a powerful anti-tumor effect, but these benefits can be hindered by the development of inflammatory and autoimmune adverse events (irAEs). Neuromuscular irAEs have rarely been reported in clinical trials, with incidence of ICI-related myositis (ICI-myositis) of less than 1%.”
“However, as the use of ICIs has grown, an increasing number of reports describing ICI-myositis have been published primarily as case reports and small case series,” they added. “Importantly, cases of ICI-myositis with concomitant myasthenia gravis (MG), myocarditis or both have been reported, often with poor outcomes. Rheumatologists may often be confronted with such cases with overlapping syndromes.”
To examine the incidence of myositis as a result of immune checkpoint inhibitor therapy among individuals with cancer, and to analyze the associated clinical manifestations, treatments and outcomes, Aldrich and colleagues reviewed data from a retrospective cohort of patients at the University of Texas MD Anderson Cancer Center. In all, the researchers included 9,088 patients with cancer who received immune checkpoint inhibitors between 2016 and 2019.
The researchers identified cases of checkpoint therapy-related myositis by reviewing available electronic medical records and pathology. ICD-10 codes of interest included those for myositis, dermatopolymyositis, dermatopolymyositis in neoplastic disease and rhabdomyolysis. Outcomes were assessed using electronic health records through November 2019 or until patient death. Mortality was attributed to myositis if the disease — or overlap syndrome or infection as a result of myositis treatment — was directly responsible for the death.
According to the researchers, 36 patients, or 0.4% of the total, had myositis due to immune checkpoint inhibitors. Among those patients, 47% presented with myositis alone while 53% demonstrated overlap manifestations, including five patients with myocarditis, five with myasthenia gravis, and nine with both.
The incidence rate of myositis was 0.31% among patients who received immune checkpoint monotherapy, and 0.94% in those treated with combination immune checkpoint therapy (RR = 3.1; 95% CI, 1.5‐6.1). Twenty-five patients received at least one additional therapy to corticosteroids. Among those patients, 47% were treated with plasmapheresis, 33% received intravenous immune globulin and 31% received biologics.
Patients with overlap conditions demonstrated worse outcomes compared with those who presented with myositis alone, with 79% of them developing respiratory failure. Eight patients died as a result of checkpoint therapy-related myositis, with all demonstrating overlap syndrome with myasthenia gravis or myocarditis (P < .05). Among the patients who died, 75% had a concomitant infection.
“Our study shows that ICI-myositis alone can be successfully treated,” Aldrich and colleagues wrote. “However, in more than half of patients, overlapping MG and/or myocarditis results in significant morbidity and mortality. Concomitant use of multiple agents targeting B cells, T cells, and cytokines may be needed in severe cases, which could result in reduced duration of corticosteroids.”
“As death was frequently attributed to infection, the risks and benefits of immunosuppression will need to be weighed,” they added. “Future progress will require translational research to elucidate the underlying mechanisms of ICI-myositis. Large multi-center studies are needed to identify predictive biomarkers and determine optimal treatments that minimize risk of infection.”
Perspective
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David A. McLain, MD, MACR, FACP, FRCP
Since the approval and use of immune checkpoint inhibitors for the treatment of cancer beginning in 2014, there have been a number of rheumatologic and non-rheumatologic immune-related adverse events (irAEs) reported. Checkpoint inhibitor drugs that target PD-1 or PD-L1 include pembrolizumab (Keytruda, Merck), nivolumab (Opdivo, Bristol Myers Squibb) and cemiplimab (Libtayo; Sanofi, Regeneron).
Rheumatic irAEs from these agents include sicca syndrome, polymyalgia rheumatica, sarcoidosis, vasculitis, inflammatory arthritis, myositis and scleroderma. Non-rheumatic irAEs include uveitis, neuropathy, demyelination, myasthenia gravis, Guillain-Barre, acute interstitial nephritis, psoriasis, Sweet’s syndrome and bullous pemphigoid. The recognition and treatment of these conditions related to immune checkpoint inhibitor use has been an active area of study and publication; this article is another in a series of these articles that will elucidate these irAEs and their natural history.
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