Autoantibody profiles in patients with immune checkpoint inhibitor-induced neurological immune related adverse events

Abstract

BackgroundNeurological immune-related adverse events (irAE-n) are severe and potentially fatal toxicities of immune checkpoint inhibitors (ICI). To date, the clinical significance of neuronal autoantibodies in irAE-n is poorly understood. Here, we characterize neuronal autoantibody profiles in patients with irAE-n and compare these with ICI-treated cancer patients without irAE-n.MethodsIn this cohort study (DRKS00012668), we consecutively collected clinical data and serum samples of 29 cancer patients with irAE-n (n = 2 pre-ICI, n = 29 post-ICI) and 44 cancer control patients without irAE-n (n = 44 pre- and post-ICI). Using indirect immunofluorescence and immunoblot assays, serum samples were tested for a large panel of neuromuscular and brain-reactive autoantibodies.ResultsIrAE-n patients and controls received ICI treatment targeting programmed death protein (PD-)1 (61% and 62%), programmed death ligand (PD-L)1 (18% and 33%) or PD-1 and cytotoxic T-lymphocyte-associated protein (CTLA-)4 (21% and 5%). Most common malignancies were melanoma (both 55%) and lung cancer (11% and 14%). IrAE-n affected the peripheral nervous system (59%), the central nervous system (21%), or both (21%). Prevalence of neuromuscular autoantibodies was 63% in irAE-n patients, which was higher compared to ICI-treated cancer patients without irAE-n (7%, p <.0001). Brain-reactive autoantibodies targeting surface (anti-GABABR, -NMDAR, -myelin), intracellular (anti-GFAP, -Zic4, -septin complex), or unknown antigens were detected in 13 irAE-n patients (45%). In contrast, only 9 of 44 controls (20%) presented brain-reactive autoantibodies before ICI administration. However, seven controls developed de novo brain-reactive autoantibodies after ICI initiation, therefore, prevalence of brain-reactive autoantibodies was comparable between ICI-treated patients with and without irAE-n (p = .36). While there was no clear association between specific brain-reactive autoantibodies and clinical presentation, presence of at least one of six selected neuromuscular autoantibodies (anti-titin, anti-skeletal muscle, anti-heart muscle, anti-LRP4, anti-RyR, anti-AchR) had a sensitivity of 80% (95% CI 0.52-0.96) and a specificity of 88% (95% CI 0.76-0.95) for the diagnosis of myositis, myocarditis, or myasthenia gravis.ConclusionNeuromuscular autoantibodies may serve as a feasible marker to diagnose and potentially predict life-threatening ICI-induced neuromuscular disease. However, brain-reactive autoantibodies are common in both ICI-treated patients with and without irAE-n, hence, their pathogenic significance remains unclear.

Plasma Exchange in Patients With Myositis due to Immune Checkpoint Inhibitor Therapy

“…Patients with neuromuscular disorders secondary to ICI agents are much more likely to have neuromuscular disease-specific antibodies compared with patients without ICI-related neuromuscular diseases. 12 In contrast, in a small sample of patients with irAE-MG, extensive evaluation of antibodies obtained from these patients were shown to be different from AChR antibodies from autoimmune MG in the degree and extent of complement fixation, raising questions about potential mechanisms of pathogenicity. 13 Although the potential side effects of PLEX, including coagulopathy and catheterrelated complications, should carefully be considered, the potential benefits of rapid recovery and steroid sparing effect may justify its use in severe neurologic syndromes.…”

What Is in the Neuromuscular Junction Literature?

“…The role of AChR Abs may also differ in ICI-related MG compared with typical idiopathic MG. For instance, in 2 of 3 seropositive patients with ICI-related MG evaluated by Masi et al, 21 the Abs did not activate complement or have modulating/blocking potency. The Abs could be an epiphenomenon because “neuromuscular antibodies” were detected in 15/24 (63%) patients with any type of immune-related adverse event versus 7% in controls in the study by Müller-Jensen et al 22…”

Immune checkpoint inhibitors induced side effects of the peripheral nervous system

“…It is clinically important that patients are evaluated for overlapping irMyositis and cardiomyositis. Overall, a retrospective cohort study of ICI-treated cancer patient with irNAE ( n = 29) and without ( n = 44) reported detection rates of up 80% of pathognomonic antibodies in patients suffering from irMyositis, irMyocarditis or irMG [18 ▪ ]. Routine autoantibody testing in suspicion of MG is warranted but nevertheless when negative, irMG can still be likely if typical clinical features and other supportive examinations findings are present [13].…”

“…Routine autoantibody testing in suspicion of MG is warranted but nevertheless when negative, irMG can still be likely if typical clinical features and other supportive examinations findings are present [13]. Of note, some patients carry preexisting low-titre neuromuscular antibodies before initiation of ICI-treatment, which raises the question, if irNAEs evolve de novo or are triggered in the context of an underlying subclinical autoimmune disorder [7,16,18 ▪ ]. Compared to the classic form, irMG does not show a female preponderance (in younger patients) and occurs mostly in male, elderly patients (without associated thymoma) [19], and has a higher overall mortality.…”