Checkpoint-inhibitor induced Polyserositis with Edema.

BACKGROUND: As immune checkpoint inhibitors (ICI) are increasingly being used due to effectiveness in various tumor entities, rare side effects occur more frequently. Pericardial effusion has been reported in patients with advanced non-small cell lung cancer (NSCLC) after or under treatment with immune checkpoint inhibitors. However, knowledge about serositis and edemas induced by checkpoint inhibitors in other tumor entities is scarce. METHODS AND RESULTS: Four cases with sudden onset of checkpoint inhibitor induced serositis (irSerositis) are presented including one patient with metastatic cervical cancer, two with metastatic melanoma and one with non-small cell lung cancer (NSCLC). In all cases treatment with steroids was successful in the beginning, but did not lead to complete recovery of the patients. All patients required multiple punctures. Three of the patients presented with additional peripheral edema; in one patient only the lower extremities were affected, whereas the entire body, even face and eyelids were involved in the other patients. In all patients serositis was accompanied by other immune-related adverse events (irAEs). CONCLUSION: ICI-induced serositis and effusions are complex to diagnose and treat and might be underdiagnosed. For differentiation from malignant serositis pathology of the punctured fluid can be helpful (lymphocytes vs. malignant cells). Identifying irSerositis as early as possible is essential since steroids can improve symptoms.

Extracorporeal Photopheresis as a Treatment Option for Immune-Related Adverse Events: Two Case Reports and a Prospective Study.

The wide use of immune checkpoint inhibitors has increased the frequency of immune-related adverse events (irAEs). While many are managed with corticosteroids or hormone substitution, up to 14.9% of irAEs are steroid-refractory or steroid-dependent and thus require second-line treatment. These should reduce irAE-related morbidity and mortality and induce a few side effects of their own while maintaining the antitumor response. There is little comparative data on second-line therapies for irAEs. Two cases of irAEs could not be sufficiently managed with corticosteroids and subsequently received treatment with extracorporeal photopheresis (ECP), including one patient with immune-related erosive oral lichen planus and one patient with immune-related colitis. In both cases, the irAE resolved with ECP in combination with immunosuppressive drugs, that is 4 weeks and 10 weeks after the start of ECP, respectively. To investigate this approach, a prospective clinical study that compares ECP and other second-line therapies for the treatment of steroid-refractory and steroid-dependent irAEs with regard to immunophenotype and therapy response has been designed. ECP could be a treatment option for steroid-refractory and steroid-dependent irAEs, given its good safety profile and lack of adverse effects on antitumor response. Comparative prospective studies are needed to generate an evidence base.

Checkpoint inhibitor-induced lichen planus differs from spontaneous lichen planus on the clinical, histological, and gene expression level.

Background: Although highly efficacious, immune checkpoint inhibitors induce a multitude of immune-related adverse events including lichenoid skin reactions (irLP) that are often therapy-resistant. Objectives: To compare the clinical, histological, and transcriptional features of irLP with spontaneous lichen planus (LP). Methods: Clinical and histological presentations of irLP and LP, as well as the gene expression profiles of irLP and LP lesional and healthy skin were assessed. Results: irLP differed considerably from LP with regard to the distribution pattern of skin lesions with irLP appearing mostly in an exanthematous form, whereas lesions were more localized in the LP group. Histologically, dermal lymphocyte infiltration was significantly lower in irLP compared with LP, whereas lymphocyte exocytosis and apoptotic keratinocytes were significantly higher in irLP. Gene expression analysis revealed irLP to have a more inflammatory profile with elevated IFNG levels and a possible role of phagosome signaling compared with LP. Limitations: The study is descriptive and necessitates further investigation with larger cohorts and broader analyses. Conclusion: irLP differs from spontaneous LP on the clinical, histopathological, and gene expression level. The inflammatory gene signature in irLP suggests that topical JAK inhibitors could be an effective treatment, targeting local skin inflammation without systemic immunosuppression.

Second-line therapies for steroid-refractory immune-related adverse events in patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICI) induce adverse events (irAEs) that do not respond to steroids, i.e. steroid-refractory (sr) irAEs, and irAEs in which steroids cannot be tapered, i.e. steroid-dependent (sd) irAEs, in about 10% of cases. An evidence-based analysis of the effectiveness of second-line immunosuppressive agents with regard to irAE and tumor control is lacking. METHODS: The international web-based Side Effect Registry Immuno-Oncology (SERIO; http://serio-registry.org) is a collaborative initiative with the Paul-Ehrlich-Institute to document rare, severe, complex or therapy-refractory immunotherapy-induced side effects. The registry was queried on August 1, 2023 for cases of irAEs which were treated with second-line therapies. RESULTS: From a total of 1330 cases, 217 patients (16.3%) received 249 second-line therapies. A total of 19 different second-line therapies were employed, including TNF-alpha antagonists (46.5%), intravenous immunoglobulins (IVIG; 19.1%), mycophenolate mofetil (15.9%), and methotrexate (3.6%). Therapy choices were determined by the type of irAE. The time to onset of sr-/sd-irAEs after ICI initiation did not consistently differ from steroid-responsive irAEs. While 74.3% of sr-/sd-irAEs resolved and 13.1% had improved, 4.3% persisted, 3.9% resulted in permanent sequelae, and 4.3% in death with ongoing symptoms. Infliximab exhibited potential for earlier symptom improvement compared to mycophenolate mofetil or IVIG. Tumor response in patients with second-line treated sd-/sr-irAE was similar to patients with irAEs treated with steroids only. CONCLUSION: Several second-line therapies are effective against sr-/sd-irAEs, the second-line therapies show no clear negative impact on tumor response, and infliximab shows potential for faster improvement of symptoms. However, prospective comparative data are needed.

Steroid-Refractory Immune-Related Adverse Events Induced by Checkpoint Inhibitors.

The occurrence, second-line management and outcome of sr/sd-irAEs was investigated in patients with skin cancer. All skin cancer patients treated with immune checkpoint inhibitors (ICIs) between 2013 and 2021 at a tertiary care center were analyzed retrospectively. Adverse events were coded by CTCAE version 5.0. The course and frequency of irAEs were summarized using descriptive statistics. A total of 406 patients were included in the study. In 44.6% (n = 181) of patients, 229 irAEs were documented. Out of those, 146 irAEs (63.8%) were treated with systemic steroids. Sr-irAEs and sd-irAEs (n = 25) were detected in 10.9% of all irAEs, and in 6.2% of ICI-treated patients. In this cohort, infliximab (48%) and mycophenolate mofetil (28%) were most often administered as second-line immunosuppressants. The type of irAE was the most important factor associated with the choice of second-line immunosuppression. The Sd/sr-irAEs resolved in 60% of cases, had permanent sequelae in 28% of cases, and required third-line therapy in 12%. None of the irAEs were fatal. Although these side effects manifest in only 6.2% of patients under ICI therapy, they impose difficult therapy decisions, especially since there are few data to determine the optimal second-line immunosuppression.

Persistent immune-related adverse events after cessation of checkpoint inhibitor therapy: Prevalence and impact on patients' health-related quality of life.

BACKGROUND: Immune checkpoint inhibitors (ICIs) may induce persistent immune-related adverse events (irAEs). We investigated persistent irAEs and implications on patients' lives compared to non-ICI-induced autoimmune diseases (AIs). METHODS: The multicentre, cross-sectional study comprised 200 patients with cancer ≥12 weeks after ICI cessation (ICI-patients) and 2705 patients with AIs (AI-patients), recruited in German outpatient clinics and support groups. The prevalence of persistent irAEs subdivided in long-term (12 weeks to <12 months) and chronic irAEs (≥12 months) since ICI discontinuation, health-related quality of life (HRQoL) using the EuroQol 5D-5L (EQ-Index/VAS score), and burden of autoimmune symptoms and respective therapies were assessed. RESULTS: Long-term/chronic irAEs occurred in 51.9%/35.5% of outpatient ICI-patients, including arthralgia (16.7%/16.1%), myalgia (13.0%/14.0%), hypothyroidism (11.1%/10.8%), xerostomia (7.4%/8.6%), vitiligo (13.0%/7.5%) and hypophysitis (9.3%/7.5%). ICI-patients with long-term/chronic irAEs reported clinically significantly reduced HRQoL compared to ICI-patients without long-term/chronic irAEs (EQ-Index score: 0.767/0.752 versus 0.920/0.923, p < 0.001/0.001; EQ-VAS score: 52.2/52.0 versus 63.6/74.7, p =/< 0.040/0.001). Multiple linear regression analyses confirmed clinically significant reductions in HRQoL scores by chronic irAEs (EQ-Index/VAS score: -0.163/-23.4, p < 0.001/0.001). HRQoL, burden of autoimmune symptoms and burden of respective therapies in ICI-patients with chronic irAEs were similar to AI-patients with non-exacerbated AIs. Patients with chronic irAEs felt inadequately informed about side-effects compared to patients without chronic irAEs (p < 0.001). CONCLUSION: Persistent irAEs impose a significant burden on patients after ICI cessation. Especially in early tumour stages, risk-benefit ratios must be carefully evaluated, and patients need to be informed about potential long-term sequelae.

Development of Lymphopenia during Therapy with Immune Checkpoint Inhibitors Is Associated with Poor Outcome in Metastatic Cutaneous Melanoma.

Predictive markers for immune checkpoint inhibitor (ICI) therapy are needed. Thus, baseline blood counts have been investigated as biomarkers, showing that lymphopenia at the start of therapy with (ICI) is associated with a worse outcome in metastatic melanoma. We investigated the relationship between the occurrence of lymphopenia under ICI and disease outcome. Patients with metastatic melanoma who had undergone therapy with ICI were identified in our database. Only patients with a normal lymphocyte count at baseline were included in this retrospective study. Progression-free survival (PFS) and overall survival (OS) were compared between patients in which lymphopenia occurred during ICI therapy and those who did not develop lymphopenia. In total, 116 patients were analyzed. Lymphopenia occurred in 42.2% of patients, with a mean onset after 17 weeks (range 1-180 weeks). The occurrence of lymphopenia during immunotherapy was significantly associated with a shorter PFS and OS. Patients who developed lymphopenia (n = 49) had a mean PFS of 13.3 months (range 1-67 months) compared to 16.9 months (range 1-73 months) for patients who did not develop lymphopenia (n = 67; p = 0.025). Similarly, patients with lymphopenia had a significantly shorter OS of 28.1 months (range 2-70 months) compared with 36.8 months (range 4-106 months) in patients who did not develop lymphopenia (p = 0.01). Patients with metastatic melanoma who develop lymphopenia during ICI therapy have a worse prognosis with significantly shorter PFS and OS compared with patients who do not develop lymphopenia.

Health-related quality of life (EuroQol 5D-5L) in patients with autoimmunity in the context of immunotherapy: A large dataset comprising cancer patients after cessation of checkpoint inhibitor therapy and patients with autoimmune diseases.

This dataset contains demographic, clinical, and health-related quality of life (HRQoL) data from 2905 patients including 200 cancer patients after immune checkpoint inhibitor (ICI) cessation and 2705 patients with a wide variety of autoimmune diseases. Within this multicenter, cross-sectional survey study data were collected questionnaire-based in cancer patients (ICI-patients) ≥ 18 years of age who had received at least one dose of ICI with ≥ 12 weeks since ICI discontinuation. Patients with autoimmune diseases (AI-patients) were ≥ 18 years, had at least one autoimmune disease and had never received ICI. ICI-patients were recruited in three skin cancer centers and via support groups. AI-patients were recruited in an outpatient clinic for internal medicine and via support groups. Specific questionnaires for ICI-patients/AI-patients were provided paper-based for patients from outpatient clinics and online for patients from support groups. Both questionnaires contained sections with demographic information, clinical data, and the standardized patient-reported outcome measure EuroQol 5D-5L (EQ-5D-5L) to assess HRQoL. Clinical data focused on autoimmunity and therapy of autoimmunity in (1) ICI-patients referring to particularly persistent immune-related adverse events (persistent irAEs) and in (2) AI-patients referring to respective autoimmune diseases. Additionally, specific items on cancer and cancer therapy were included in ICI-patients, and AI-patients were asked about the presence of acute exacerbations of autoimmune diseases. This dataset contains the raw data for ICI-patients and AI-patients, analyzed data on patient demographics, clinical characteristics and HRQoL scores among ICI-patients with/without persistent irAEs and among AI-patients. The data provide a basis for further investigations within the cohort of ICI-patients after ICI cessation and/or for AI-patients with different autoimmune diseases with regard to HRQoL, autoimmunity and therapy of autoimmunity.

Characteristics of immune checkpoint inhibitor-induced encephalitis and comparison with HSV-1 and anti-LGI1 encephalitis: A retrospective multicentre cohort study.

AIM: Immune checkpoint inhibitor-induced encephalitis (ICI-iE) is a rare but life-threatening toxicity of immune checkpoint inhibitor treatment. We aim to identify the characteristics of ICI-iE and describe factors that discriminate it from herpes simplex virus (HSV)-1 encephalitis and anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis, as two alternative entities of encephalitis. METHODS: In this retrospective multicentre cohort study, we collected patients with ICI-iE reported to the Side Effect Registry Immuno-Oncology from January 2015 to September 2021 and compared their clinical features and outcome with 46 consecutive patients with HSV-1 or anti-LGI1 encephalitis who were treated at a German neurological referral centre. RESULTS: Thirty cases of ICI-iE, 25 cases of HSV-1 encephalitis and 21 cases of anti-LGI1 encephalitis were included. Clinical presentation of ICI-iE was highly variable and resembled that of HSV-1 encephalitis, while impairment of consciousness (66% vs. 5%, p = .007), confusion (83% vs. 43%; p = .02), disorientation (83% vs. 29%; p = .007) and aphasia (43% vs. 0%; p = .007) were more common in ICI-iE than in anti-LGI1 encephalitis. Antineuronal antibodies (17/18, 94%) and MRI (18/30, 60%) were mostly negative in ICI-iE, but cerebrospinal fluid (CSF) showed pleocytosis and/or elevated protein levels in almost all patients (28/29, 97%). Three patients (10%) died of ICI-iE. Early immunosuppressive treatment was associated with better outcome (r = 0.43). CONCLUSIONS: ICI-iE is a heterogeneous entity without specific clinical features. CSF analysis has the highest diagnostic value, as it reveals inflammatory changes in most patients and enables the exclusion of infection. Early treatment of ICI-iE is essential to prevent sequelae and death.

Dataset of a retrospective multicenter cohort study on characteristics of immune checkpoint inhibitor-induced encephalitis and comparison with HSV-1 and anti-LGI1 encephalitis.

Over the past decade, cancer immunotherapy with immune checkpoint inhibitors (ICIs) has significantly improved the outcome of many malignancies. However, with the broad use of ICIs, neurological immune related adverse events (irAE) are increasingly recognized. ICI-induced encephalitis (ICI-iE) is a particularly severe irAE, often leading to treatment termination, long-term sequalae or death. Despite its high morbidity and mortality, data on clinical features and diagnostic criteria are limited. We aimed to define clinical, radiologic and laboratory characteristics of ICI-iE and identify factors that discriminate it from anti-leucine-rich glioma-inactivated (anti-LGI)-1 encephalitis and herpes simplex virus (HSV)-1 encephalitis - two alternative causes of encephalitis - to increase the awareness of ICI-iE and improve its diagnosis and management. To that end, we retrospectively collected 30 cases of ICI-iE that were reported to the Side Effect Registry Immuno-Oncology (SERIO) and 46 cases of anti-LGI1 encephalitis or herpes simplex virus (HSV)-1 encephalitis that presented to a large German neurological referral center (Charité Universitätsmedizin Berlin) between January 2015 and September 2021. Signs and symptoms, imaging and electroencephalogram features, laboratory findings and outcome measures were assessed using standardized case report forms as well as patients' medical records and compared between the groups. The data reported here represents the largest primary cohort of patients with ICI-iE to date and the first comparison with other types of encephalitis. As all three disorders - ICI-iE, HSV-1 encephalitis and anti-LGI1 encephalitis - are rare neurological entities, this dataset can be used as a reference in future clinical studies on ICI-induced neurotoxicity, neurological autoimmune disorders, and central nervous system infections.

Brain-Derived Neurotrophic Factor Expression and Signaling in Different Perivascular Adipose Tissue Depots of Patients With Coronary Artery Disease.

Background Brain-derived neurotrophic factor (BDNF) is expressed in neuronal and nonneuronal cells and may affect vascular functions via its receptor, tropomyosin-related kinase B (TrkB). In this study, we determined the expression of BDNF in different perivascular adipose tissue (PVAT) depots of patients with established coronary atherosclerosis. Methods and Results Serum, vascular tissue, and PVAT surrounding the proximal aorta (C-PVAT) or internal mammary artery (IMA-PVAT) was obtained from 24 patients (79% men; mean age, 71.7±9.7 years; median body mass index, 27.4±4.8 kg/m2) with coronary atherosclerosis undergoing elective coronary artery bypass surgery. BDNF protein levels were significantly higher in C-PVAT compared with IMA-PVAT, independent of obesity, metabolic syndrome, or systemic biomarkers of inflammation. mRNA transcripts of TrkB, the BDNF receptor, were significantly reduced in aorta compared with IMA. Vessel wall TrkB immunosignals colocalized with cells expressing smooth muscle cell markers, and confocal microscopy and flow cytometry confirmed BDNF receptor expression in human aortic smooth muscle cells. Significantly elevated levels of protein tyrosine phosphatase 1B, a negative regulator of TrkB signaling in the brain, were also observed in C-PVAT. In vitro, inhibition of protein tyrosine phosphatase 1B blunted the effects of BDNF on smooth muscle cell proliferation, migration, differentiation, and collagen production, possibly by upregulation of low-affinity p75 neurotrophin receptors. Expression of nerve growth factor or its receptor tropomyosin-related kinase A did not differ between C-PVAT and IMA-PVAT. Conclusions Elevated expression of BDNF in parallel with local upregulation of negative regulators of neurotrophin signaling in perivascular fat and lower TrkB expression suggest that vascular BDNF signaling is reduced or lost in patients with coronary atherosclerosis.