Background Immune checkpoint inhibitor (ICI)-related myocarditis is an uncommon but potentially fatal immune-related adverse event. Corticoid-resistant myocarditis induced by ICI is an important therapeutic challenge. Case Summary Here we present a case of steroid-refractory ICI-related myocarditis and myositis treated with abatacept and mycophenolate mofetil (MMF). A 57-year-old male with metastatic renal cell carcinoma was diagnosed with immune-related myocarditis and myasthenia gravis-like myositis after first dose of combination immune checkpoint inhibitors with nivolumab (anti-programmed cell death-1) plus ipilimumab (anti-cytotoxic T-lymphocyte-associated antigen-4). Twelve days after ICI he was admitted to the hospital due to palpitations, headache, and pain in the extremities. Laboratory findings revealed elevated inflammatory markers and cardiac enzymes. Electrocardiogram showed first-degree AV-block and right bundle branch block which developed into complete heart block within 48 hours. Because of clinical and paraclinical deterioration despite immediate initiation of methylprednisolone abatacept and MMF was added. Following, gradual subjective improvement and termination of arrythmia led to discharge of the patient from the hospital 6 weeks after introduction of ICI. Discussion The key treatment of ICI-related myocarditis is glucocorticoid. For steroid-refractory myocarditis supplementary immune suppressive agents are recommended. Yet, data still relies on case reports and case series, due to lack of prospective studies. In this case the use of abatacept and MMF led to resolution of steroid-resistant ICI-related myocarditis and myositis.

A 63-year-old male with metastatic non-small cell lung cancer developed longitudinal extensive transverse myelitis (LETM) following two cycles of Pembrolizumab, an immune checkpoint inhibitor (ICI) targeting the programmed cell death receptor 1 (PD-1). Magnetic resonance imaging (MRI) showed centromedullary contrast enhancement at several levels, cerebrospinal fluid (CSF) cytology showed lymphocytic pleocytosis, and indirect immunofluorescence assay (IFA) on the primate cerebellum, pancreas, and intestine revealed strong binding of neuronal autoantibodies to unknown antigens. CSF C–X–C motif ligand 13 (CXCL13) was elevated. The patient was treated with plasma exchange (PEX) and intravenous (i.v.) methylprednisolone (MP) 1 g/day for 5 days followed by oral (p.o.) MP 100 mg/day for 10 days with clinical and radiological response. However, after discontinuation of MP, LETM relapsed and the patient developed paralytic ileus presumably due to autoimmune enteropathy and suffered a fatal gastrointestinal sepsis. Findings of novel neuronal autoantibodies and highly elevated CXCL13 in CSF suggest that the severe neurological immune-related adverse event (nirAE) was B-cell mediated contrary to the commonly assumed ICI-induced T-cell toxicity. An individual evaluation of the underlying pathophysiology behind rare nirAEs is essential for choosing treatment regimens and securing optimal outcome.

IntroductionBorrelia burgdorferi sensu lato complex (B. burgdorferi) can cause a variety of clinical manifestations including Lyme neuroborreliosis. Following the tick-borne transmission, B. burgdorferi initially evade immune responses, later symptomatic infection is associated with occurrence of specific antibody responses. We hypothesized that B. burgdorferi induce immune hyporesponsiveness or immune suppression and aimed to investigate patients with Lyme neuroborreliosis ability to respond to immune stimulation.MethodsAn observational cohort study investigating the stimulated immune response by standardized whole blood assay (TruCulture®) in adult patients with Lyme neuroborreliosis included at time of diagnosis from 01.09.2018-31.07.2020. Reference intervals were based on a 5-95% range of cytokine concentrations from healthy individuals (n = 32). Patients with Lyme neuroborreliosis and references were compared using Mann-Whitney U test. Heatmaps of cytokine responses were generated using the webtool Clustvis.ResultsIn total, 22 patients with Lyme neuroborreliosis (19 definite, 3 probable) were included. In the unstimulated samples, the concentrations of cytokines in patients with Lyme neuroborreliosis were comparable with references, except interferon (IFN)-α, interleukin (IL)-17A, IL-1β and IL-8, which were all significantly below the references. Patients with Lyme neuroborreliosis had similar concentrations of most cytokines in all stimulations compared with references. IFN-α, IFN-γ, IL-12 and IL-17A were lower than references in multiple stimulations.ConclusionIn this exploratory cohort study, we found lower or similar concentrations of circulating cytokines in blood from patients with Lyme neuroborreliosis at time of diagnosis compared with references. The stimulated cytokine release in blood from patients with Lyme neuroborreliosis was in general slightly lower than in the references. Specific patterns of low IL-12 and IFN-γ indicated low Th1-response and low concentrations of IL-17A did not support a strong Th17 response. Our results suggest that patients with Lyme neuroborreliosis elicit a slightly suppressed or impaired immune response for the investigated stimulations, however, whether the response normalizes remains unanswered.