Emerin self-assembly and nucleoskeletal coupling regulate nuclear envelope mechanics against stress.

Emerin is an integral nuclear envelope protein that participates in the maintenance of nuclear shape. When mutated or absent, emerin causes X-linked Emery-Dreifuss muscular dystrophy (EDMD). To understand how emerin takes part in molecular --scaffolding at the nuclear envelope and helps protect the nucleus against mechanical stress, we established its nanoscale organization using single-molecule tracking and super-resolution microscopy. We show that emerin monomers form localized oligomeric nanoclusters stabilized by both lamin A/C and the SUN1-containing linker of nucleoskeleton and cytoskeleton (LINC) complex. Interactions of emerin with nuclear actin and BAF (also known as BANF1) additionally modulate its membrane mobility and its ability to oligomerize. In nuclei subjected to mechanical challenges, the mechanotransduction functions of emerin are coupled to changes in its oligomeric state, and the incremental self-assembly of emerin determines nuclear shape adaptation against mechanical forces. We also show that the abnormal nuclear envelope deformations induced by EDMD emerin mutants stem from improper formation of lamin A/C and LINC complex-stabilized emerin oligomers. These findings place emerin at the center of the molecular processes that regulate nuclear shape remodeling in response to mechanical challenges.

Mortality and Autopsy Findings in Patients with Pyoderma Gangrenosum: A Multi-Institutional Series.

INTRODUCTION: Pyoderma gangrenosum (PG) is a rare ulcerative skin condition with an increased risk of mortality compared to the general population. The causes of this increased risk are not well understood. Misdiagnosis is common in PG, and many studies are limited by the inclusion of misdiagnosed cases. The goal of this study was to review autopsy findings, identify causes of death, and identify factors that may worsen outcomes among deceased patients confirmed to have PG. METHODS: Data was retrospectively reviewed from the electronic medical records at five academic hospitals. A search was conducted for deceased patients with a diagnosis of PG who had an autopsy performed between 2010 and 2020. We report a descriptive analysis of 11 patients and their clinical characteristics, causes of death, and autopsy findings. RESULTS: The average age of death was 62.9 years. Seven patients had at least one underlying condition known to be associated with PG including inflammatory bowel disease, inflammatory arthritis, or a hematologic disorder. The most common cause of death was infection (n = 6, 54.5%), followed by pulmonary embolism (n = 3, 27.3%), and myelodysplastic syndrome (n = 2, 18.2%). Six patients (54.5%) were taking systemic steroids at the time of death. CONCLUSION: The development of PG may shorten life expectancy among those with underlying conditions associated with PG, and common treatments for PG may contribute to the risk of fatal complications. Awareness of the risk of infection, thrombosis, and malignancy among those with PG is necessary for proper management. Further research is needed to explore the relationship between PG and thromboembolism.

Efficacy and safety of repository corticotropin injection for refractory cutaneous dermatomyositis: a prospective, open-label study.

OBJECTIVES: Cutaneous dermatomyositis (DM) is often refractory to multiple medications. Repository corticotropin injection (RCI) is FDA-approved for DM, but little is known about its efficacy and safety for treating cutaneous DM. We conducted a prospective, open-label trial assessing efficacy and safety of RCI for treating refractory cutaneous DM. METHODS: DM patients with moderate-to-severe cutaneous activity [Cutaneous Dermatomyositis Disease Area and Severity Index activity (CDASI-A)] >14 despite prior treatment with ≥2 systemic agents were enrolled. Patients were initiated on 80 u RCI twice weekly for 6 months. Primary outcomes included significant decreases in CDASI-A and Physician's Global Assessment (PGA) scores at 6 months. RESULTS: Of nineteen patients enrolled, fifteen patients (11 females, 4 males) with DM (7 classic, 8 amyopathic) completed 6 months of RCI treatment. Patients were treated with a median 3.0 systemic medications prior to enrolment and were taking a median of 2.0 systemic medications at enrolment. Median baseline CDASI-A score was 19.0 and median PGA activity score was 2.5/10. For patient-reported outcomes, baseline median patient global skin score (PtGSS) was 3.0/10 and median dermatology life quality index (DLQI) score was 7.0/10. At 6 months, there were statistically significant improvements in CDASI-A scores (median= 10.0), PGA scores (median= 0.8/10), PtGSS scores (median= 7.0) and DLQI scores (median= 2.0), among others. Adverse effects were mild. CONCLUSIONS: RCI treatment resulted in statistically significant and clinically meaningful improvement in cutaneous DM activity and quality of life. Our results suggest RCI is an effective, safe, and well-tolerated treatment for patients with refractory cutaneous dermatomyositis. CLINICAL TRIAL REGISTRATION: This clinical trial was registered with ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT01906372).

The capillary lobule variant of radiation-associated angiosarcoma in the setting of breast cancer: A diagnostic pitfall.

AIM: Post-radiation angiosarcoma is an iatrogenic event seen in the setting of breast cancer treatment. Histopathologically, there are morphologic variants of angiosarcoma that mimic benign entities, including the capillary lobule variant of post-radiation angiosarcoma. We present the largest case series to date of this histopathologic variant of post-radiation angiosarcoma. METHODS AND RESULTS: Cases of the capillary lobule variant of post-radiation angiosarcoma from institutional/consultation archives from 2008 to June 2022 were reviewed. For inclusion, tumors had to occur in irradiated skin and exhibit a multi-lobular proliferation of tightly packed capillary-like vessels, as previously described in this variant. Prior ancillary studies were also reviewed. Eight cases met the criteria. All occurred in women treated with radiation for breast cancer (median age 75 years). All cases had similar findings, including a multi-lobular proliferation of tightly packed vessels, infiltrative cords, and atypical single endothelial cells. A conventional angiosarcoma pattern was also seen in five cases. All cases tested were positive for vascular markers (CD31, CD34, and/or ERG) and MYC. MYC amplification was shown by FISH in all cases tested. Smooth muscle actin (SMA) was positive in pericytes in the capillary lobules in all five cases tested and areas of conventional angiosarcoma in two of three cases. CONCLUSIONS: The capillary lobule variant of angiosarcoma is a rare and therefore potentially under-recognized variant of post-radiation angiosarcoma. The lobular architecture and SMA positivity may mimic benign vascular proliferations. Careful attention to histopathologic features and ancillary tests may facilitate accurate diagnosis.

Sweet Syndrome Associated with Active Inflammatory Bowel Disease: A Case Series of a Rare Extra-intestinal Manifestation.

BACKGROUND: Cutaneous extra-intestinal manifestations (EIM) occur in up to 20% of patients with IBD. Information about Sweet syndrome (SS)'s clinical course as a rare cutaneous EIM in IBD is limited to case reports. We present the largest retrospective cohort on the occurrence and management of SS in IBD. STUDY: Electronic medical records and paper charts since 1980 were retrospectively reviewed at a large quaternary medical center to identify all adult IBD patients with histopathology-proven SS. Patient characteristics and clinical outcomes were evaluated. RESULTS: 25 IBD patients with SS were identified; 3 patients were assessed to have AZA-induced SS. The majority of SS patients were female. Median age at diagnosis was 47 years (IQR 33-54 years) and SS appeared at a median of 6.4 years after IBD diagnosis. IBD patients with SS had a high rate of complicated IBD phenotypes (75% extensive colitis in UC and 73% stricturing or penetrating disease in CD, with 100% colonic involvement), as well as frequent co-occurring EIMs (60%). SS correlated with global IBD disease activity. Corticosteroids were an effective therapy for SS in IBD. Recurrence rate of SS was 36%. CONCLUSION: Contrary to previous case reports, SS was a cutaneous EIM occurring late after diagnosis of IBD in our cohort, with occurrences paralleling global IBD disease activity. Although AZA-induced and IBD-associated SS were both effectively treated with corticosteroids, distinguishing them is relevant for future IBD treatment strategies.

Understanding subjective experience in psychedelic-assisted psychotherapy: The need for phenomenology.

Psychedelic-assisted psychotherapy is being investigated as a treatment for a range of psychiatric illnesses. Current research suggests that the kinds of subjective experiences induced by psychedelic compounds play key roles in producing therapeutic outcomes. To date, most knowledge of therapeutic psychedelic experiences are derived from psychometric assessments with scales such as the Mystical Experience Questionnaire. While these approaches are insightful, more nuanced and detailed descriptions of psychedelic-induced changes to subjective experience are required. Drawing on recent advancements in qualitative methods arising from the interdisciplinary field of phenomenological psychopathology, we propose a systematic and comprehensive investigation into how psychedelic-assisted psychotherapy alters subjective experience. This research programme aims to characterise the nature of therapeutic psychedelic experiences by drawing on concepts from philosophical phenomenology. Such characterisations should, moreover, contribute to our understanding of the mechanisms of psychedelic therapy, the role of integration therapy, and related philosophical debates.

Preferentially expressed antigen in melanoma and p16 expression in acral melanocytic neoplasms.

Acral melanocytic neoplasms often pose diagnostic difficulty. Preferentially expressed antigen in melanoma (PRAME) expression and loss of p16 expression have diagnostic utility in melanocytic tumors. We examined PRAME and p16 expression in 30 acral melanocytic neoplasms (n = 11 nevi; n = 2 dysplastic nevi; n = 7 Spitz nevi; n = 10 acral melanomas). PRAME was scored as % positive nuclei: negative = 0%; 1% to 25% = 1+; 25% to 50% = 2+; 50% to 75% = 3+, or positive: 75% to 100% = 4+. p16 expression was defined as retained (homogeneous or checkerboard) or lost (complete or partial/regionally). PRAME expression was negative in all benign, dysplastic, and Spitz nevi. Conversely, all acral melanomas were diffusely (4+) positive for PRAME expression. p16 expression was retained in all benign acral nevi (8/11 homogeneous, 3/11 checkerboard), completely lost in one dysplastic nevus, and retained in all acral Spitz nevi (3/7 homogeneous, 4/7 checkerboard). p16 was retained in five of 10 acral melanomas (3/10 homogeneous; 2/10 checkerboard), and negative in five of 10 acral melanomas (absent in 3/10, partially lost in 2/10). Our data suggest that 4+ PRAME expression is highly sensitive and specific in the setting of acral melanomas and is a more predictive diagnostic tool compared with p16 immunohistochemistry.

Development of sacral/buttock retiform purpura as an ominous presenting sign of COVID-19 and clinical and histopathologic evolution during severe disease course.

Retiform purpura has been described as a relatively frequent cutaneous finding in patients with coronavirus disease 2019 (COVID-19). The etiology is hypothesized to be related to thrombotic vasculopathy based on lesional biopsy specimen findings, but the pathogenesis of the vasculopathy is not completely understood. Here, we present a case of a retiform purpuric patch on the sacrum/buttocks in a hospitalized patient prior to subsequent diagnosis of COVID-19 and an eventual fatal disease course. Two lesional biopsy specimens at different time points in the disease course revealed thrombotic vasculopathy, despite therapeutic anticoagulation. Detailed histopathologic evaluation using immunohistochemical markers suggest the etiology of the vasculopathy involves both persistent complement activation and platelet aggregation, which possibly promote ongoing thrombus formation. This case highlights that sacral/buttock retiform purpuric patches may be a presenting sign of infection with SARS-CoV-2 virus and may represent an ominous sign supporting a future severe disease course. In addition, biopsy specimen findings at separate time points demonstrate that cutaneous vasculopathy may persist despite adequate systemic anticoagulation, possibly due to the combination of persistent complement and platelet activation. Finally, occlusive thrombi in sacral/buttock retiform purpuric patches may contribute to future ulceration and significant cutaneous morbidity in patients who survive COVID-19.

Abnormal Body Phenomena in Persons with Major Depressive Disorder.

BACKGROUND: Depressive disorders, despite being classified as mood or affective disorders, are known to include disturbances in the experience of body, space, time, and intersubjectivity. However, current diagnostic manuals largely ignore these aspects of depressive experience. In this article, we use phenomenological accounts of embodiment as a theoretical foundation for a qualitative study of abnormal body phenomena (ABP) in depressive disorders. METHODS: 550 patients affected by schizophrenic and affective disorders were interviewed in a clinical setting. Interviews sought to uncover the qualitative features of experiences through self-descriptions. Clinical files were subsequently digitized and re-examined using consensual qualitative research. RESULTS: Ninety-nine out of 100 patients with MDD reported at least one ABP. From cross-analysis of the MDD sample, we obtained 4 general categories of ABP, 3 of which had additional subcategories. The 4 categories include slowed embodied temporality (N = 90), anomalous vital rhythms (N = 82), worries about one's body (N = 22), and body deformation (N = 47). CONCLUSIONS: The results provide empirical evidence in support of theoretical discussions of embodiment in MDD found in the work of classical and contemporary phenomenologists. The findings also provide nuanced insight into the experience of persons living with MDD. Some categories of ABP, like slowed embodied temporality, can help to finely characterize psychomotor retardation or the so-called "medically unexplained symptoms" (MUS). This fine-tuned characterization can help to connect MUS to neuropsychological and neurobiological (e.g., alterations of interoceptive processes linked to anomalies of the brain resting-state hypothesis) and inflammatory (e.g., studies linking environmental stressors, inflammation mediators, and neurovegetative and affective symptoms) models of MDD. Our results can also support a pathogenic model of MDD, which posits, on the phenomenal level, ABP as the point of departure for the development of secondary symptoms including cognitive elaborations of these, namely, delusions about the body. Moreover, some of the categories, when contrasted with phenomenological qualitative studies of other disorders, provide conceptual resources of differential diagnosis and of identifying a "depressive core syndrome." For example, findings within category 4, deformation of the body, provide resources for using ABP to distinguish between MDD and schizophrenia.

Histologic comparison of tumor necrosis factor-α inhibitor-induced psoriasis and psoriasis vulgaris.

BACKGROUND: Tumor necrosis factor-α inhibitor (TNFi)-induced psoriasis is a paradoxic reaction characterized by the development of a psoriasiform rash that mimics idiopathic psoriasis subtypes both clinically and histologically. Few studies have investigated the histologic features of TNFi-induced psoriasis skin lesions, and most of these are limited by inclusion of few specimens. OBJECTIVE: We aimed to characterize histologic features of TNFi-induced psoriasis and identify histologic differences between TNFi-induced psoriasis and idiopathic psoriasis. METHODS: We characterized 60 biopsy specimens obtained from 47 unique patients at a single tertiary care referral center between 2004 and 2016 who developed TNFi-induced psoriasis, and we compared histologic features to those of 85 biopsy specimens from a control group of 85 patients with idiopathic psoriasis. RESULTS: The most common histologic reaction pattern in TNFi-induced psoriasis biopsy specimens was psoriasiform (80.0%). Five histologic parameters were significantly different in TNFi-induced psoriasis biopsy specimens compared with idiopathic psoriasis biopsy specimens: at least 3 dermal eosinophils per histologic section, neutrophils in the stratum corneum, neutrophils in the epidermis, papillary plate thinning, and absence of parakeratosis. LIMITATIONS: Inability to exclude lesion selection bias as a potential reason for some significant histologic differences. CONCLUSIONS: This study supports the idea that histologic differences exist between TNFi-induced psoriasis and idiopathic psoriasis may help distinguish between these conditions, especially for dermal eosinophil counts of 3 or greater.

TNF-α inhibitor-induced psoriasis: A decade of experience at the Cleveland Clinic.

BACKGROUND: Tumor necrosis factor-α (TNF-α) inhibitor (TNFI)-induced psoriasis remains poorly understood despite having been described 15 years ago. As TNFIs often provide life-changing patient benefits, understanding effective treatments for TNFI-induced psoriasis is important. OBJECTIVE: We characterized a cohort of patients with TNFI-induced psoriasis whose psoriasis was specifically diagnosed and managed or comanaged by dermatologists at a single tertiary care institution over a 10-year period. METHODS: Retrospective review of patients in whom TNFI-induced psoriasis was diagnosed between 2003 and 2013. RESULTS: A total of 102 patients with TNFI-induced psoriasis were identified. The mean age of onset was 40 years, and there was a female predominance (73.5%). Crohn's disease (in 48% of cases) and rheumatoid arthritis (in 24.5% of cases) were the most common primary conditions. Infliximab (in 52% of cases) was the most common inciting agent. The most common TNFI-induced psoriasis subtypes were plaque-type psoriasis (49.5%), scalp psoriasis (47.5%), and palmoplantar pustulosis (41%). Topical medications alone improved or resolved TNFI-induced psoriasis in 63.5% of patients, and cyclosporine and methotrexate (>10 mg weekly) were often effective if topicals failed. Discontinuation of the inciting TNFI with or without other interventions improved or resolved TNFI-induced psoriasis in 67% of refractory cases, whereas switching TNFIs resulted in persistence or recurrence in 64%. LIMITATIONS: Retrospective nature of the study and the fact that some patients may have developed typical psoriasis unresponsive to TNFIs. CONCLUSION: Our study cohort represents the largest single-institution cohort of patients with TNFI-induced psoriasis diagnosed and managed or comanaged by dermatologists to date. On the basis of our findings, we propose a treatment algorithm for TNFI-induced psoriasis.

Family history of psoriasis, psychological stressors, and tobacco use are associated with the development of tumor necrosis factor-α inhibitor-induced psoriasis: A case-control study.

BACKGROUND: Tumor necrosis factor-α inhibitor-induced psoriasis (TNFI psoriasis) is a paradoxical reaction characterized by development of a psoriasiform rash that mimics psoriasis vulgaris. Temporal onset variability and low incidence rates suggest that underlying risk factors or outside triggers have a role in TNFI psoriasis initiation. OBJECTIVES: We aimed to identify underlying risk factors and outside triggers associated with TNFI psoriasis onset. METHODS: This case-control study included 97 patients at a tertiary care center between 2003 and 2013 who developed TNFI psoriasis. Ninety-seven control patients were matched to age, sex, disease, TNF-α inhibitor, and length of time on treatment before TNFI psoriasis onset. Patient medical records were reviewed ≥6 months immediately preceding TNFI psoriasis onset (similar equivalent time point for matched controls) for information about potential risk factors and outside factors categorized as: (1) serologic abnormalities, (2) acute events, and (3) social factors. RESULTS: Compared with those of matched controls, odds ratios (ORs) were significantly higher in the TNFI psoriasis group for psoriasis family history (OR, 16.0) and acute psychological stressors (OR, 3.14) and marginally associated with tobacco use (OR, 1.76). CONCLUSIONS: Our results suggest that psoriasis family history, psychological stressors, and tobacco use might be risk factors for developing TNFI psoriasis. Performing detailed patient histories when considering TNFI therapy may be useful in identifying patients at risk for TNFI-psoriasis.

Diagnoses of hospitalized patients with skin abnormalities prompting biopsy by consulting dermatologists: A 3-year review from a tertiary care center.

BACKGROUND: Dermatologists play an important role in diagnosing and managing hospitalized patients with cutaneous abnormalities. Skin biopsies remain an indispensable tool for aiding dermatologists in accurate diagnosis and treatment. We aimed to determine the range of conditions, and the most common conditions, prompting skin biopsy by dermatology hospital consultation (HCON) services to aid in evaluation of hospitalized patients. METHODS: All hospitalized patients seen by a single tertiary care center dermatology HCON service between 2015 and 2018 who had associated skin biopsies were identified. Histologic features and clinical diagnoses of each patient were classified into 13 histologic reaction pattern categories. RESULTS: Eight hundred and thirty one inpatients evaluated by our dermatology HCON service had 914 skin biopsies. The most frequent diagnostic categories prompting biopsy were vasculopathic (17.6%), interface dermatitis (16.5%), infectious (12.6%), and spongiotic dermatitis (10.9%). The most frequent diagnostic categories included drug reaction (13.2%), leukocytoclastic vasculitis (8.5%), skin cancer (5.4%), graft-vs-host disease (3.5%), connective tissue disease (3.3%), and calciphylaxis (3.0%). CONCLUSION: Our study suggests a variety of serious diseases affecting inpatients prompts biopsy by dermatology consultation services. Educational curricula for dermatology and pathology residents, fellows, and staff designed with these data may enhance knowledge that improves the quality of inpatient dermatology care.

Embodiment and Objectification in Illness and Health Care: Taking Phenomenology from Theory to Practice.

AIMS AND OBJECTIVES: To demonstrate a conceptual approach to applied phenomenology using the concept of embodiment. BACKGROUND: Traditionally, qualitative researchers and healthcare professionals have been taught phenomenological methods, such as the epoché, reduction or bracketing. These methods are typically construed as a way of avoiding biases so that one may attend to the phenomena in an open and unprejudiced way. However, it has also been argued that qualitative researchers and healthcare professionals can benefit from phenomenology's well-articulated theoretical framework, which consists of core concepts, such as selfhood, empathy, temporality, spatiality, affectivity and embodiment. DESIGN: This is a discursive article that demonstrates a conceptual approach to applied phenomenology. METHOD: To outline and explain this approach to applied phenomenology, the Discussion section walks the reader through four stages of phenomenology, which progress incrementally from the most theoretical to the most practical. DISCUSSION: Part one introduces the philosophical concept of embodiment, which can be applied broadly to any human subject. Part two shows how philosophically trained phenomenologists use the concept of embodiment to describe general features of illness and disability. Part three illustrates how the phenomenological concept of embodiment can inform empirical qualitative studies and reflects on the challenges of integrating philosophy and qualitative research. Part four turns to phenomenology's application in clinical practice and outlines a workshop model that guides clinicians through the process of using phenomenological concepts to better understand patient experience. CONCLUSION AND RELEVANCE TO CLINICAL PRACTICE: A conceptual approach to applied phenomenology provides a valuable alternative to traditional methodological approaches. Phenomenological concepts provide a foundation for better understanding patient experience in both qualitative health research and clinical practice, and therefore provide resources for enhancing patient care.

Cerebral Microhemorrhage and Purpuric Rash in COVID-19: The Case for a Secondary Microangiopathy.

INTRODUCTION: Since the emergence of Coronavirus Disease 19 (COVID-19) pandemic, multiple neurologic complications in infected patients have been reported. Despite these reports, the mechanism of COVID-19 nervous system injury is not well understood. We report the case of a COVID-19 patient with diffuse microhemorrhages on brain MRI, positive anticardiolipin antibodies, and purpuric rash with biopsy showing a thrombotic vasculopathy, all features suggestive of secondary microangiopathy. CASE REPORT: A 69-year-old male with history of hypertension, chronic kidney disease, and hypothyroidism presented with one week of dyspnea, cough, diarrhea, and fevers. Chest x-ray demonstrated bibasilar consolidations and nasopharyngeal reverse transcriptase polymerase chain reaction confirmed SARS-CoV-2 infection. He had subsequent respiratory decline requiring intubation the day after admission. He developed a truncal morbilliform rash and diffuse purpura, a biopsy of which showed small dermal blood vessels with intraluminal microthrombi consistent with thrombotic vasculopathy. He was found to have elevated aCL IgM and IgG and equivocal lupus anticoagulant study. Brain MRI obtained for persistent encephalopathy showed innumerable areas of susceptibility weighted imaging changes throughout the bilateral juxtacortical white matter, corpus callosum, basal ganglia, and brainstem, as well as multiple small areas of FLAIR hyperintensities, consistent with microhemorrhage DISCUSSION: While there have been several reported cases of neurologic manifestations of COVID-19, the pathophysiology may not be related to neurotropism of the virus itself. The new development of antiphospholipid antibodies and thrombotic vasculopathy in dermal blood vessels in this patient suggest a secondary microangiopathy potentially related to a virally-induced inflammatory state.

Cases from the irAE Tumor Board: A Multidisciplinary Approach to a Patient Treated with Immune Checkpoint Blockade Who Presented with a New Rash.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigms for a broad spectrum of malignancies. Because immune checkpoint inhibitors rely on immune reactivation to eliminate cancer cells, they can also lead to the loss of immune tolerance and result in a wide range of phenomena called immune-related adverse events (irAEs). At our institution, the management of irAEs is based on multidisciplinary input obtained at an irAE tumor board that facilitates expedited opinions from various specialties and allows for a more uniform approach to these patients. In this article, we describe a case of a patient with metastatic urothelial carcinoma who developed a maculopapular rash while being treated with a programmed death-ligand 1 inhibitor. We then describe the approach to management of dermatologic toxicities with ICIs based on the discussion at our irAE Tumor Board. KEY POINTS: Innocuous symptoms such as pruritis or a maculopapular rash may herald potentially fatal severe cutaneous adverse reactions (SCARs); therefore, close attention must be paid to the symptoms, history, and physical examination of all patients.Consultation with dermatology should be sought for patients with grade 3 or 4 toxicity or SCARs and prior to resumption of immune checkpoint inhibitors for patients with grade 3 or higher toxicity.A multidisciplinary immune-related adverse events (irAE) tumor board can facilitate timely input and expertise from various specialties, thereby ensuring a streamlined approach to management of irAEs.