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BACKGROUND: The Myasthenia Gravis-Activities of Daily Living scale (MG-ADL) is an 8-item outcome measure to assess symptoms and functional limitations in myasthenia gravis (MG) patients. The MG-ADL score is an equally weighted level sum score that is used as primary outcome measures in clinical trials, in clinical practice, and as an end-point in health economic evaluation. This data analysis aims to obtain detailed knowledge of measurement properties of MG-ADL items and the MG-ADL score. METHODS: Cross-sectional data from a real-world prospective study (MRW) were combined with longitudinal data from the ADAPT trial. Outcome measures included were MG-ADL, Quantitative Myasthenia Gravis score (QMG), MG 15-item Quality of Life (MG-QOL15r) and EQ-5D-5L. Patients were categorized by their Myasthenia Gravis Foundation of America (MGFA) clinical classification. The following measurement properties were assessed: distributional characteristics, inter-item correlation, convergent, known groups and construct validity and internal factor structure. RESULTS: Correlations of items within MG-ADL dimensions were moderate, while MG-ADL correlations between comparable MG-QOL15r and QMG items were mixed. Known groups validity for the MG-ADL score was demonstrated for MGFA class. Mean MG-ADL item level scores by MGFA class demonstrated construct validity. PCA, including all four outcome measures, resulted in a nine factor solution. DISCUSSION: Psychometric properties of individual MG-ADL items were moderate to good. This study showed that the MG-ADL adequately captures the multidimensional heterogeneous nature of MG. This is, however, accompanied by mixed psychometric performance of the MG-ADL score, which may complicate health economic modelling. REGISTRATION: MyRealWorld-MG was registered on November 25, 2019, with registration numberNCT04176211. The ADAPT randomized clinical trial is registered atClinicalTrials.gov(NCT03669588).
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BACKGROUND/OBJECTIVES: The phase 3 REGAIN study and its open-label extension demonstrated the efficacy of the complement C5 inhibitor eculizumab in patients with treatment-refractory, acetylcholine receptor antibody-positive generalized myasthenia gravis (gMG). The aim of the ELEVATE study was to assess the effectiveness of eculizumab in clinical practice in adults with MG in the United States. METHODS: A retrospective chart review was conducted in adults with MG who initiated eculizumab treatment between October 23, 2017 and December 31, 2019. Outcomes assessed before and during eculizumab treatment using a pre- versus post-treatment study design included Myasthenia Gravis-Activities of Daily Living (MG-ADL) total scores; minimal symptom expression (MSE); physician impression of clinical change; minimal manifestation status (MMS); and concomitant medication use. RESULTS: In total, 119 patients were included in the study. A significant reduction was observed in mean MG-ADL total score, from 8.0 before eculizumab initiation to 5.4 at 3 months and to 4.7 at 24 months after eculizumab initiation (both p < 0.001). At 24 months after eculizumab initiation, MSE was achieved by 19% of patients. MMS or better was achieved by 30% of patients at 24 months. Additionally, 64% of patients receiving prednisone at eculizumab initiation had their prednisone dosage reduced during eculizumab treatment and 13% discontinued prednisone; 32% were able to discontinue nonsteroidal immunosuppressant therapy. DISCUSSION: Eculizumab treatment was associated with sustained improvements in MG-ADL total scores through 24 months in adults with MG. Prednisone dosage was reduced in approximately two-thirds of patients, suggesting a steroid-sparing effect for eculizumab.
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Purpose: To describe the early experience of ravulizumab use in acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR+ve gMG). Methods: This multicenter retrospective study included AChR+ve gMG patients who were treated with ravulizumab and had both pre- and post-ravulizumab myasthenia gravis activities of daily living (MG-ADL) scores. Clinical information regarding MG history, concomitant treatment(s), MG-ADL, other MG-specific measures, and adverse events were recorded. Results: A total of 18 patients with mean age of 61.83 (±16.08, n = 18) years were included in this cohort. In 10 complement inhibitor naive patients, a clinically meaningful reduction in mean Mg-ADL (baseline: 6.6 (±3.58) vs. 4.4 (±2.28), post ravulizumab) was seen. 6 out of 10 patients (60%) had clinically meaningful reduction post ravulizumab and two achieved minimum symptom expression (MSE). In 8 patients switched from eculizumab to ravulizumab, further reduction was noted in post ravulizumab mean MG-ADL (Baseline: 3.25 (±3.34) vs. 1.5 (±2.34) post ravulizumab). None of the patients who switched from eculizumab to ravulizumab experienced worsening symptoms. Eleven out of 14 (78.5%) patients on prednisone therapy were able to reduce their prednisone dose post-ravulizumab. None of the patients experienced any major side effects. Conclusion: In our clinical practice, 60% of AChR+ve gMG complement inhibitor naive patients experienced a clinically meaningful improvement in MG-ADL scores with ravulizumab. Patients were safely switched from eculizumab to ravulizumab and had further improvement in their mean MG-ADL scores. Of those on prednisone therapy, the majority were able to reduce their prednisone dosage.
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PURPOSE: Immune-mediated seizures are rare but are increasingly recognized as an etiology of seizures resistant to anti-seizure medications (ASMs). Antibody Prevalence in Epilepsy 2 (APE2) and Response to Immunotherapy in Epilepsy 2 (RITE2) scores were developed recently to identify patients who may be seropositive for serum central nervous system (CNS) specific antibodies (Ab) and may benefit from immunotherapy (Dubey et al. 2018). The goal of this study was to apply APE2 and RITE2 scores to an independent cohort of patients with seizures secondary to autoimmune encephalitis (AE) and to further verify the sensitivity and specificity of the scores. PRINCIPAL RESULTS: We conducted a retrospective study at Stanford University Hospital between 2008 and 2021 and included patients who had acute seizures and AE using diagnostic criteria from Graus (n = 34 definite AE, 10 probable AE, and 12 possible AE) (Graus et al. 2016). Patients were excluded if they did not have a serum Ab panel investigated or had alternate diagnoses (n = 55). APE2 and RITE2 scores were calculated based on clinical and diagnostic data (n = 56). Serum Ab were positive in 73 % of patients, in which 63 % cases carried CNS specific Ab. An APE2 score ≥ 4 had a sensitivity of 97 % and specificity of 14 % to predict a positive serum CNS specific Ab. A RITE2 score ≥ 7 had a sensitivity of 93 % and specificity of 60 % to predict seizure responsiveness to immunotherapy. CONCLUSION: APE2 and RITE2 scores had high sensitivities but low specificities to predict seropositivity and seizure responsiveness to immunotherapy in patients with autoimmune encephalitis with seizures.
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Encefalite , Convulsões , Humanos , Feminino , Masculino , Adulto , Convulsões/sangue , Convulsões/etiologia , Convulsões/diagnóstico , Pessoa de Meia-Idade , Estudos Retrospectivos , Encefalite/complicações , Encefalite/sangue , Encefalite/imunologia , Encefalite/diagnóstico , Doença de Hashimoto/complicações , Doença de Hashimoto/sangue , Idoso , Sensibilidade e Especificidade , Autoanticorpos/sangue , Adulto Jovem , Imunoterapia/métodos , AdolescenteRESUMO
ABSTRACT: Immune checkpoint inhibitors used to treat malignancies may lead to various immune-related adverse events (irAEs) including conditions such as myositis and myasthenia gravis (MG). Here, we describe 2 cases of myositis treated effectively with therapeutic plasma exchange (PLEX). A 64-year-old man with thymic cancer developed leg weakness and dyspnea 1 month after the second dose of nivolumab with moderate weakness in proximal and distal muscles, with elevated creatine kinase levels. Another 77-year-old man with Stage IIIB squamous cell carcinoma of the lung developed progressive proximal muscle weakness and became nonambulatory after cycle 2 of durvalumab with persistently high creatine kinase levels despite prednisone treatment. Electrophysiology revealed irritative myopathy without evidence of neuromuscular junction dysfunction and MG antibody testing was nonrevealing. With PLEX, both patients noticed rapid improvement in strength. PLEX in conjunction with other immunosuppressive agents can result in rapid improvement in irAE-myositis even in patients without associated MG.
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Miastenia Gravis , Miosite , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Inibidores de Checkpoint Imunológico , Troca Plasmática , Miosite/terapia , Miosite/tratamento farmacológico , Nivolumabe/efeitos adversos , Miastenia Gravis/terapia , Miastenia Gravis/tratamento farmacológico , Creatina QuinaseRESUMO
Objectives: Sensitivity and specificity of Repetitive Nerve Stimulation (RNS) is typically reported from outpatient centers, and we hypothesized that these values might not apply to hospitalized patients with higher grades of weakness. RNS may be helpful in rapidly confirming diagnosis of myasthenia gravis (MG) in the inpatient setting, as results from confirmatory antibody testing are often delayed. We sought to characterize the sensitivity and specificity of RNS in the inpatient setting to assist in the early diagnosis of MG. Methods: We performed a retrospective analysis of all adult patients who had inpatient RNS at our center from 2016 to 2021. Inclusion criteria included RNS performed at least at one site and a neurological evaluation which prompted an electrodiagnostic study to evaluate for neuromuscular junction (NMJ) pathology. Descriptive statistics and Fisher exact analysis were performed. Results: Of the 32 identified hospitalized patients, 6 had greater than 10% decrement on slow RNS, confirming NMJ dysfunction. Five were diagnosed with MG, and 1 with Lambert-Eaton myasthenic syndrome. Of the 26 patients with normal RNS, 25 ultimately had alternative causes of weakness. One was later diagnosed as seronegative MG based on clinical improvement with acetylcholinesterase inhibitors. In our inpatient population, the overall sensitivity and specificity of RNS were 83.3% and 96.2% respectively. There was a statistically significant association between a positive RNS and diagnosis of MG (P = .0002). Conclusions: RNS is a highly sensitive and specific test for the diagnosis of MG in an inpatient setting, and these results are likely more rapidly available compared to antibody testing.
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INTRODUCTION/AIMS: Multiple novel therapies have been approved for patients with myasthenia gravis. Our aim is to describe the early experience of efgartigimod use in acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR+ve gMG). METHODS: This multicenter retrospective study included AChR+ve gMG patients from five major neuromuscular centers who were treated with efgartigimod and had both pre- and post-efgartigimod myasthenia gravis activities of daily living (MG-ADL) scores. Information regarding MG history, concomitant treatment(s), MG-ADL and other MG-specific measures, laboratory data, and adverse events were recorded. RESULTS: A total of 37 patients (M:23, F:14) with a mean age of 65.56 (±14.74) y were included in this cohort. A total of 36/37 patients completed at least one cycle and 28 patients completed at least two cycles of efgartigimod. A total of 72% (26/36) of patients had a clinically meaningful reduction (≥2 point change) in MG-ADL after the completion of the first cycle of efgartigimod (mean pre-efgartigimod 8.02) (±3.09) versus post-efgartigimod 4.33 (±3.62). Twenty-five percent (9/36) achieved minimal symptom expression status after one cycle and 25% (7/28) after the second cycle. Treatment benefit was sustained after cycle 2. Three out of four patients with thymoma in this cohort had clinically significant reductions in MG-ADL scores. Immunoglobulin G (IgG) levels decreased by about 60% (n = 10). One patient had a relapse of Clostridium difficile infection resulting in the discontinuation of therapy. Four patients had mild side effects. DISCUSSION: Efgartigimod led to clinically meaningful improvement in MG-ADL in diverse AChR+ve gMG patients but treatment frequency to achieve optimal symptom control needs to be explored.
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Introduction: Gastrointestinal dysfunction, particularly constipation, is among the most common non-motor manifestations in Parkinson's Disease (PD). We aimed to identify high-resolution anorectal manometry (HR-ARM) abnormalities in patients with PD using the London Classification. Methods: We conducted a retrospective review of all PD patients at our institution who underwent HR-ARM and balloon expulsion test (BET) for evaluation of constipation between 2015 and 2021. Using age and sex-specific normal values, HR-ARM recordings were re-analyzed and abnormalities were reported using the London Classification. A combination of Wilcoxon rank sum and Fisher's exact test were used. Results: 36 patients (19 women) with median age 71 (interquartile range [IQR]: 69-74) years, were included. Using the London Classification, 7 (19%) patients had anal hypotension, 17 (47%) had anal hypocontractility, and 3 women had combined hypotension and hypocontractility. Anal hypocontractility was significantly more common in women compared to men. Abnormal BET and dyssynergia were noted in 22 (61%) patients, while abnormal BET and poor propulsion were only seen in 2 (5%). Men had significantly more paradoxical anal contraction and higher residual anal pressures during simulated defecation, resulting in more negative recto-anal pressure gradients. Rectal hyposensitivity was seen in nearly one third of PD patients and comparable among men and women. Conclusion: Our data affirms the high prevalence of anorectal disorders in PD. Using the London Classification, abnormal expulsion and dyssynergia and anal hypocontractility were the most common findings in PD. Whether the high prevalence of anal hypocontractility in females is directly related to PD or other confounding factors will require further research.
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N-glycanase 1 (NGLY1) deficiency is a debilitating, ultra-rare autosomal recessive disorder caused by loss of function of NGLY1, a cytosolic enzyme that deglycosylates other proteins. It is characterized by severe global developmental delay and/or intellectual disability, hyperkinetic movement disorder, transient elevation of transaminases, (hypo)alacrima and progressive, diffuse, length-dependent sensorimotor polyneuropathy. A prospective natural history study (NHS) was conducted to elucidate clinical features and disease course. Twenty-nine participants were enrolled (15 onsite, 14 remotely) and followed for up to 32 months, representing ~29% of the ~100 patients identified worldwide. Participants exhibited profound developmental delays, with almost all developmental quotients below 20 on the Mullen Scales of Early Learning, well below the normative score of 100. Increased difficulties with sitting and standing suggested decline in motor function over time. Most patients presented with (hypo)alacrima and reduced sweat response. Pediatric quality of life was poor except for emotional function. Language/communication and motor skill problems including hand use were reported by caregivers as the most bothersome symptoms. Levels of the substrate biomarker, GlcNAc-Asn (aspartylglucosamine; GNA), were consistently elevated in all participants over time, independent of age. Liver enzymes were elevated for some participants but improved especially in younger patients and did not reach levels indicating severe liver disease. Three participants died during the study period. Data from this NHS informs selection of endpoints and assessments for future clinical trials for NGLY1 deficiency interventions. Potential endpoints include GNA biomarker levels, neurocognitive assessments, autonomic and motor function (particularly hand use), (hypo)alacrima and quality of life.
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Defeitos Congênitos da Glicosilação , Qualidade de Vida , Humanos , Criança , Estudos Prospectivos , BiomarcadoresRESUMO
Neonatal Fc receptor (FcRn) blockade may represent a mechanism similar to plasma exchange (PLEX) in reducing immunoglobulin levels and thus have a broad implication for apheresis practitioners. Although only efgartigimod received FDA approval for myasthenia gravis in December 2021, multiple trials are currently underway with different FcRn therapies in a varied group of IgG antibody-mediated neurological and hematological disorders which are outlined in this review. In this review we discuss FcRn's mechanism of action, and its potential use in various neurological and non-neurological diseases. In addition, we further compare the kinetics and adverse events of PLEX and FcRn blockade. We encourage apheresis practitioners to be familiar with this class of drugs in order to better understand how these two therapies can be used either standalone, or in combination with other therapies as both FcRn antagonism and PLEX improve clinical state by reducing IgG levels and pathogenic antibodies.
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OBJECTIVES: This study aims to explore the impact of myasthenia gravis (MG) - in terms of treatments, side effects, comorbidities, psychological health and work or study- in the real world from a patient perspective. DESIGN AND PARTICIPANTS: This is a prospective, observational, digital, longitudinal study. Adults diagnosed with MG residing in the USA, Japan, Germany, the UK, Italy, Spain or Canada were eligible to participate in the study. There were no other exclusion criteria. Participants used a bespoke smartphone application to confirm eligibility, provide consent and enter data about their MG into a profile, a tracker to record MG-related events and a series of patient-reported outcome instruments. 1693 participants completed at least 1 survey and were included in this analysis. RESULTS: Results are presented as a percentage of respondents to each survey question. The study population was largely female (69% of 1586 respondents), with an average age of 49.9 years (SD 14.8). In the previous 12 months, 83.7% of 1412 respondents confirmed that they had received one or more routine treatments for MG, and 67.1% of 255 respondents confirmed that they had experienced a side effect in the previous month. Commonly experienced comorbidities reported by 966 respondents were thyroid problems, hypertension and anxiety, experienced by 37.5%, 31.4% and 28.0% of respondents, respectively.According to 889 respondents to the Hospital Anxiety and Depression Scale survey, 52.7% and 43.2% had a score indicative of at least mild anxiety and mild depression, respectively. Of 257 respondents, 33.0% reported experiencing a work or study impact in the past month. CONCLUSIONS: This analysis of baseline characteristics of the MyRealWorld MG study population indicates that, despite current treatments, patients experience notable burden. Further scheduled analyses will develop a longitudinal picture of MG burden. TRIAL REGISTRATION NUMBER: NCT04176211.
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Miastenia Gravis , Adulto , Humanos , Feminino , Pessoa de Meia-Idade , Estudos Longitudinais , Miastenia Gravis/terapia , Miastenia Gravis/tratamento farmacológico , Inquéritos e Questionários , Ansiedade/epidemiologia , Estudos ProspectivosRESUMO
OBJECTIVES: Myasthenia gravis (MG) is a rare, chronic, autoimmune neuromuscular disease which can affect functional and mental aspects of health and health-related quality of life (HRQoL). This study aims to obtain detailed knowledge of the impact of MG on HRQoL in a broad population from the perspective of the patient. DESIGN: Prospective, observational, digital, longitudinal real-world study. SETTING: Adult patients with MG from seven countries (USA, Japan, Germany, UK, Italy, Spain and Canada) downloaded a mobile application onto their phones and entered data about themselves and their MG. OUTCOME MEASURES: Data was collected using the following general and disease-specific patient-reported outcome measurements: EuroQol 5 Domains Health-Related Quality of Life Questionnaire (EQ-5D-5L), Myasthenia Gravis Activities of Daily Living (MG-ADL), Myasthenia Gravis Quality of Life 15-item revised scale (MG-QoL-15r), Hospital Anxiety and Depression Scale (HADS) and Health Utilities Index III (HUI3). Patients were categorised by their self-assessed Myasthenia Gravis Foundation of America (MGFA) class (I-V). RESULTS: Baseline results of 841 participants (mean age 47 years, 70% women) are reported . The distribution across the MGFA classes was: 13.9%, 31.0%, 38.1%, 15.5% and 1.6% for classes I-V. The MGFA class was a strong predictor of all aspects of HRQoL, measured with disease-specific and with generic instruments. The domains in which patients with MG most frequently mentioned problems were usual activities, anxiety and depression, tiredness, breathing and vision. The mean total MG-ADL Score was positively associated with increasing MGFA classes: 2.7, 4.4, 6.3 and 8.4 for MGFA classes I-IV. Mean baseline EQ-5D-5L utility was also associated with MGFA classes and was 0.817, 0.766, 0.648 and 0.530 for MGFA class I-IV. CONCLUSIONS: MG has a large impact on key aspects of health and HRQoL. The impact of this disease increases substantially with increasing disease severity.
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Miastenia Gravis , Qualidade de Vida , Adulto , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Atividades Cotidianas , Estudos Prospectivos , Medidas de Resultados Relatados pelo PacienteRESUMO
Background: Autonomic dysfunction is a known complication of post-acute sequelae of SARS-CoV-2 (PASC)/long COVID, however prevalence and severity are unknown. Objective: To assess the frequency, severity, and risk factors of autonomic dysfunction in PASC, and to determine whether severity of acute SARS-CoV-2 infection is associated with severity of autonomic dysfunction. Design: Cross-sectional online survey of adults with PASC recruited through long COVID support groups between October 2020 and August 2021. Participants: 2,413 adults ages 18-64 years with PASC including patients who had a confirmed positive test for COVID-19 (test-confirmed) and participants who were diagnosed with COVID-19 based on clinical symptoms alone. Main measures: The main outcome measure was the Composite Autonomic Symptom 31 (COMPASS-31) total score, used to assess global autonomic dysfunction. Test-confirmed hospitalized vs. test-confirmed non-hospitalized participants were compared to determine if the severity of acute SARS-CoV-2 infection was associated with the severity autonomic dysfunction. Key results: Sixty-six percent of PASC patients had a COMPASS-31 score >20, suggestive of moderate to severe autonomic dysfunction. COMPASS-31 scores did not differ between test-confirmed hospitalized and test-confirmed non-hospitalized participants [28.95 (15.62, 46.60) vs. 26.4 (13.75, 42.10); p = 0.06]. Conclusions: Evidence of moderate to severe autonomic dysfunction was seen in 66% of PASC patients in our study, independent of hospitalization status, suggesting that autonomic dysfunction is highly prevalent in the PASC population and independent of the severity of acute COVID-19 illness.
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Sleep apnea is a common disorder that represents a global public health burden. KCNK3 encodes TASK-1, a K+ channel implicated in the control of breathing, but its link with sleep apnea remains poorly understood. Here we describe a new developmental disorder with associated sleep apnea (developmental delay with sleep apnea, or DDSA) caused by rare de novo gain-of-function mutations in KCNK3. The mutations cluster around the 'X-gate', a gating motif that controls channel opening, and produce overactive channels that no longer respond to inhibition by G-protein-coupled receptor pathways. However, despite their defective X-gating, these mutant channels can still be inhibited by a range of known TASK channel inhibitors. These results not only highlight an important new role for TASK-1 K+ channels and their link with sleep apnea but also identify possible therapeutic strategies.
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Mutação com Ganho de Função , Síndromes da Apneia do Sono , Criança , Deficiências do Desenvolvimento , Humanos , Mutação/genética , Proteínas do Tecido Nervoso , Canais de Potássio de Domínios Poros em Tandem , Síndromes da Apneia do Sono/genéticaRESUMO
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several advanced malignancies leading to durable remission in a subset of patients. Their rapidly expanding use has led to an increased frequency of immune-related adverse events (irAEs). The pathogenesis of irAEs is poorly understood but may involve aberrant activation of T cells leading to inflammatory cytokine release or production of pathogenic antibodies leading to organ damage. Severe irAEs can be extremely debilitating and, in some cases, life threatening. IrAEs may not always be corticosteroid responsive or may require excessively high, often toxic, corticosteroid doses. Therapeutic plasma exchange (PLEX) is a treatment modality that has shown promising results for the management of certain severe irAEs, including irAEs that are not mentioned in current treatment guidelines. PLEX may attenuate ongoing irAEs and prevent delayed irAEs by accelerating clearance of the ICI, or by acutely removing pathogenic antibodies, cytokines, and chemokines. Here, we summarize examples from the literature in which PLEX was successfully used for the treatment of irAEs. We posit that timing may be a critical factor and that earlier utilization of PLEX for life-threatening irAEs may result in more favorable outcomes. In individuals at high risk for irAEs, the availability of PLEX as a potential therapeutic mitigation strategy may encourage life-saving ICI use or rechallenge. Future research will be critical to better define which indications are most amenable to PLEX, particularly to establish the optimal place in the sequence of irAE therapies and to assess the ramifications of ICI removal on cancer outcomes.