A scoping review of vasculitis as an immune-related adverse event from checkpoint inhibitor therapy of cancer: Unraveling the complexities at the intersection of immunology and vascular pathology.

BACKGROUND/PURPOSE: Vasculitis as an immune-related adverse event (irAE) from checkpoint inhibitor therapy (ICI) to treat cancer is a rare clinical event, and little is known regarding its nosology, clinical manifestations, or response to treatment and outcomes. METHODS: To address these gaps, we used the Preferred Reporting Items for Systemic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) framework to further define this complication. Two independent PUBMED searches in September and November of 2022 revealed 127 publications with 37 excluded from title by relevance, 43 excluded by article type, and 23 excluded due to lack of biopsy results, or biopsy negative for vasculitis. Twenty-nine documented cases from 24 publications were included for final analysis. Basic demographics, ICI details, timing of onset of vasculitis symptoms, irAE treatment and outcomes were collected. The vasculitides were classified using 2022 ACR/EULAR Vasculitis Classification Criteria as well as 2012 Revised Chapel-Hill Nomenclature. Adaptations from Naidoo et al. 2023 [1] consensus definitions for irAEs were used and efforts were made to classify steroid-responsive versus unresponsive irAEs. RESULTS: Of the 29 cases reviewed, the average age of patients was 62.1 ± 11.0, composed of 58.6 % (n = 17) male and 41.3 % (n = 12) female. Prominent cancer types were lung cancer (41.4 %; n = 12), melanoma (41.4 %; n = 12), and renal cancer (10.3 %; n = 3), with majority being stage 4 (75.9 %, n = 22) and stage 3 (10.3 %, n = 3). Only 8 cases met the ACR/EULAR criteria, and by Chapel-Hill Nomenclature, approximately a third were small-vessel vasculitis (31.0 %; n = 9) with n = 4 positive for ANCA. Most biopsies were taken from the skin (37.9 %, n = 11) and kidney (24.1 %, n = 7). Patients were either treated with single (65.5 %, n = 19), dual (17.2 %; n = 5), or sequential (17.2 %; n = 5) ICI regimen which included anti-PD-1 therapy in all but one case, with mean of 8.7 ± 10.5 cycles received. Mean time to onset of symptoms from start of ICI was 7.2 ± 7.8 months, with 55.2 % occurring >3 months since the initial immunotherapy. Vasculitis treatment included glucocorticoids in 96 % of cases and immunotherapy was often discontinued (44.8 %; n = 13). Clinical improvement of irAE was documented in 86.2 % (n = 25). Data were missing in terms of fate of ICI (34.5 %; n = 10) and tumor outcomes (41.4 %; n = 12). Cancer progressed in 20.7 % (n = 6), stable in 34.5 % (n = 10) cases, and 6 patients died of all-causes. CONCLUSION: Vasculitis as an irAE appears clinically heterogeneous and rare. Among reported cases with adequate documentation, vasculitis is of delayed onset following the initiation of immunotherapy. Outcomes of ICI-vasculitis were generally favorable, responding to glucocorticoids and immunotherapy withdrawal. There is an urgent need for more standardized reporting of rare irAEs such as vasculitis to clarify clinical risks, classification, relationship to immunotherapy and outcomes.

Improving the nosology of Long COVID: it is not so simple.

Long COVID is a diagnostic label currently given to those suffering from a poorly understood state of incomplete recovery or who have development of a myriad of medically unexplained symptoms occurring in the wake of infection with SARS CoV-2 that is both poorly understood and controversial. Many of the features of one of the most common clinical endotypes of Long COVID are shared by a condition well familiar to all rheumatologists and one with a large body of epidemiologic, clinical and basic research accrued over many decades namely the syndrome of fibromyalgia. Some have recently suggested that Long COVID may merely be a new name for fibromyalgia and that this diagnosis is indeed the condition that many or most may be suffering from as a post infectious sequela. In this Viewpoint we argue that while the parallels between the clinical syndrome experienced by many of those currently labeled as Long COVID and fibromyalgia are strong we should be not too quick to rename the disorder. We further argue that relabeling Long COVID as fibromyalgia is clinically reductionistic and any such relabeling may be attended by harm in both the design and execution of a future research agenda as well to patients who may be inadvertently and unfortunately pejoritised by such labeling. We further explore the parallels and differences between Long COVID and fibromyalgia and outline areas of needed future research and care.

Rheumatology and Long COVID: lessons from the study of fibromyalgia.

Rheumatology, such as other subspecialties, has both a unique perspective to offer as well as an evolving role to play in the global COVID-19 pandemic. Our field has already contributed meaningfully to the development and repurposing of many of the immune-based therapeutics which are now standard treatments for severe forms of the disease as well as to the understanding of the epidemiology, risk factors and natural history of COVID-19 in immune-mediated inflammatory diseases. Still in evolution is our potential to contribute to burgeoning research efforts in the next phase of the pandemic: the syndrome of postacute sequelae of COVID-19 or Long COVID. While our field brings many assets to the study of Long COVID including our expertise in the investigation of chronic inflammation and autoimmunity, our Viewpoint focuses on the strong similarities between fibromyalgia (FM) and Long COVID. While one can speculate on how embracing and confident practising rheumatologists already are regarding these interrelationships, we assert that in the emerging field of Long COVID the potential lessons from the field of fibromyalgia care and research have been underappreciated and marginalised and most importantly now deserve a critical appraisal.

Clinical characteristics, brain magnetic resonance imaging findings and diagnostic approach of the primary central nervous system vasculitis according to angiographic classification.

OBJECTIVES: To determine the diagnostic accuracy for high-resolution vessel wall image (HR-VWI) and brain biopsy according to angiographical classification in patients with primary central nervous system vasculitis (PCNSV). METHODS: We extracted the patients with PCNSV who underwent the complete brain MRI protocol and cerebral vascular image from Cleveland Clinic prospective CNS vasculopathy Bioregistry. The large-medium vessel variant (LMVV) was defined as patients with cerebral vasculature indicating vasculitis in proximal or middle arterial segments, whereas vessel involvements in smaller distal branches or normal angiography were considered as the small vessel variant (SVV). We compared clinical demographics, magnetic resonance imaging (MRI) findings, and diagnostic approaches between two variants. RESULTS: In this case-control study that included 34 PCNSV patients, the LMVV group comprised a total of 11 patients (32.4%), and 23 patients (67.6%) were classified as the SVV group. The LMVV had more strong/concentric vessel wall enhancement on HR-VWI (LMVV: 90% (9/10) vs. SVV: 7.1% (1/14), p<0.001). By contrast, meningeal/parenchymal contrast enhancement lesion was more frequently observed in the SVV group (p=0.006). The majority of SVV was diagnosed by brain biopsy (SVV: 78.3% vs. LMVV: 30.8%, p=0.022). The diagnostic accuracy of the brain biopsy was 100% (18/18) in SVV and 57.1% (4/7) in LMVV, respectively (p=0.015). CONCLUSIONS: Diagnostic approach for PCNSV differs concerning the affected vessel size. HR-VWI is a useful imaging modality for the diagnosis of LMVV. Brain biopsy remains the gold standard for proving PCNSV with SVV but is still positive in almost one-third of LMVV.

Interleukin 6 Blockade With Tocilizumab Diminishes Indices of Inflammation That Are Linked to Mortality in Treated Human Immunodeficiency Virus Infection.

BACKGROUND: People with human immunodeficiency virus (PWH) are at increased risk for comorbidities, and plasma interleukin 6 (IL-6) levels are among the most robust predictors of these outcomes. Tocilizumab (TCZ) blocks the receptor for IL-6, inhibiting functions of this cytokine. METHODS: This was a 40-week, placebo-controlled, crossover trial (NCT02049437) where PWH on stable antiretroviral therapy (ART) were randomized to receive 3 monthly doses of TCZ or matching placebo intravenously. Following a 10-week treatment period and a 12-week washout, participants were switched to the opposite treatment. The primary endpoints were safety and posttreatment levels of C-reactive protein (CRP) and CD4+ T-cell cycling. Secondary endpoints included changes in inflammatory indices and lipid levels. RESULTS: There were 9 treatment-related toxicities of grade 2 or greater during TCZ administration (mostly neutropenia) and 2 during placebo administration. Thirty-one of 34 participants completed the study and were included in a modified intent-to-treat analysis. TCZ reduced levels of CRP (median decrease, 1819.9 ng/mL, P < .0001; effect size, 0.87) and reduced inflammatory markers in PWH, including D-dimer, soluble CD14, and tumor necrosis factor receptors. T-cell cycling tended to decrease in all maturation subsets after TCZ administration, but was only significant among naive CD4 T cells. Lipid levels, including lipid classes that have been related to cardiovascular disease risk, increased during TCZ treatment. CONCLUSIONS: TCZ is safe and decreases inflammation in PWH; IL-6 is a key driver of the inflammatory environment that predicts morbidity and mortality in ART-treated PWH. The clinical significance of lipid elevations during TCZ treatment requires further study. Clinical Trials Registration. NCT02049437.

Online, low-volume meditation does not alter immune-related biomarkers.

Objectives: Prior studies of mindfulness meditation have demonstrated anti-inflammatory and immunoregulatory effects but whether meditation courses delivered online can exert similar effects is poorly understood. Barriers to large scale implementation of traditional mindfulness meditation programs has created an increased interest in the effect of less time- and resource-intensive online meditation courses. The purpose of this study was to determine whether a 6-week online mindfulness program with low time demands on nurses would lead to changes in gene expression, cytokine profiles, telomerase activity, and cortisol profiles. Methods: This was a randomized, parallel pilot study comparing an online mindfulness-based stress management program to an active control group from December 2018 to May 2019. Healthy nurses with above average levels of perceived stress were randomized to receive a 6-week online mindfulness-based stress management program including ≥5 min daily meditation practice or listen to relaxing music for ≥5 min daily as the control arm. Blood samples were collected at baseline and after 6 weeks, and various self-reported measures of stress, physical and emotional health were collected at baseline, after 6 weeks, and after 12 weeks. Whole transcriptome mRNA sequencing of whole blood at baseline and after 6 weeks was performed along with measurement of plasma IL-6, IL-8, IL-10, TNF-α, and IFN-γ. Peripheral blood mononuclear cells were isolated, and telomerase activity was measured. Diurnal salivary cortisol profiles were assessed at baseline and after 6 weeks. The primary outcome was change over time in a pre-determined set of 53 genes representative of the immune-related changes seen with stress, which was analyzed using a mixed linear model. Secondary outcomes included all other self-reported measures and biomarkers mentioned above. Results: A total of 61 nurses were randomized, with 52 having sufficient data to include in the final analysis. After 6 weeks, nurses in the control group reported significant reductions in stress as measured by the Perceived Stress Scale while those in the mindfulness group did not. However, after 12 weeks, the mindfulness group also showed a significant reduction in stress. When compared to the control group, no significant changes in RNA gene expression or any other biomarkers were observed in the nurses who participated in the mindfulness program. Conclusions: Our study found that this brief online mindfulness-based intervention was effective in reducing stress in nurses, albeit with a delayed effect compared to listening to relaxing music. Regarding immunoregulatory effects, there were no significant differences between treatment and control groups in transcriptomic or other tested biomarkers of immune function. This study provides evidence for a floor effect of mindfulness on transcriptional and circulating biomarkers of immune function.

Serial vessel wall enhancement pattern on high-resolution vessel wall magnetic resonance imaging and clinical implications in patients with central nervous system vasculitis.

OBJECTIVES: High-resolution vessel wall imaging (HR-VWI) often demonstrates strong and concentric vessel wall enhancement (VWE) in patients with central nervous system vasculitis (CNS-V). However, little is known about follow-up VWE characteristics and monitoring the response to treatments. The aim of this study was to investigate serial VWE patterns and its clinical practice through the management of CNS-V. METHODS: We extracted 9 patients with diagnosed of CNS-V who underwent serial HR-VWI (baseline, 1st follow-up, and 2nd follow-up) from Cleveland Clinic CNS vasculopathy registry. VWE were analysed in 17 intracranial artery segments. VWE was graded on a 3-point scale (0; none, 1; mild/eccentric, and 2; strong/concentric). VWE grade for each arterial segment was summed to create a total VWE score. We investigated the relationship between serial VWE patterns and clinical course. RESULTS: In unique 153 intracranial arterial segments, 39 arteries (25.5%) had strong/concentric VWE on baseline HR-VWI. The positive rates of concentric VWE have decreased to 12.4% (19/153) at 1st follow-up and (10/153) 6.5% at 2nd follow-up, respectively (p<0.001). Mean total VWE scores have significantly decreased over time courses (p=0.034). Two patients had relapse at 1st follow-up image. In relapse cases, mean total VWE scores have worsened at 1st follow-up (baseline:2.0 to 1st follow-up: 6.0). After intensive immunosuppressive treatment, mean VWE scores have improved at 2nd follow-up (1st follow-up: 6.0 to 2nd follow-up: 2.0). CONCLUSIONS: Decreasing contrast VWE at follow-up images may indicate good response to treatment in CNS-V. By contrast, relapse patients might have temporal VWE worsening during the clinical course.

Transient elastography score is elevated during rheumatoid factor-positive chronic hepatitis C virus infection and rheumatoid factor decline is highly variable over the course of direct-acting antiviral therapy.

BACKGROUND: Elevated rheumatoid factor (RF) levels and systemic immune activation are highly prevalent during chronic hepatitis C virus (HCV) infection. Direct-acting antiviral (DAA) therapy has been associated with normalization of various soluble immune activation parameters. Whether the RF levels relate to soluble immune activation markers during chronic HCV infection, and over what time frame RF levels normalize during and after DAA treatment is unknown and was investigated here. METHODS: In a longitudinal study, plasma and serum was obtained from HCV infected RF positive (RF+) and RF negative (RF-) participants. The levels of RF, HCV RNA and soluble markers of inflammation were determined before (week 0), during (weeks 4, 8 and 12) and after (week 24) treatment with HCV DAA therapy. In a subset of RF+ participants, the analysis was extended to over 70 weeks after therapy initiation. Hepatic and other clinical parameters were determined at baseline (week 0) in all participants. RESULTS: Before therapy, transient elastography (TE) score was greater in RF+ compared to RF- HCV infected participants, while the systemic levels of soluble inflammatory markers were comparable. Following DAA therapy initiation, HCV RNA levels became undetectable within 4 weeks in both the RF+ and RF- groups. RF levels declined in the first 6 months in most RF+ persons but most commonly remained positive. The levels of some soluble inflammatory markers declined, mainly within 4 weeks of DAA therapy start, in both the RF+ and RF- groups. The baseline (week 0) TE score correlated with RF levels before, during and after DAA therapy, while plasma IL-18 levels correlated with RF level after DAA therapy. CONCLUSION: During chronic HCV infection, TE score is elevated in RF+ HCV infected individuals and factors other than HCV viremia (including liver stiffness or fibrosis and select markers of inflammation) likely contribute to persistence of RF after treatment of HCV with DAA.

Immune-Mediated Disease Flares or New-Onset Disease in 27 Subjects Following mRNA/DNA SARS-CoV-2 Vaccination.

BACKGROUND: Infectious diseases and vaccines can occasionally cause new-onset or flare of immune-mediated diseases (IMDs). The adjuvanticity of the available SARS-CoV-2 vaccines is based on either TLR-7/8 or TLR-9 agonism, which is distinct from previous vaccines and is a common pathogenic mechanism in IMDs. METHODS: We evaluated IMD flares or new disease onset within 28-days of SARS-CoV-2 vaccination at five large tertiary centres in countries with early vaccination adoption, three in Israel, one in UK, and one in USA. We assessed the pattern of disease expression in terms of autoimmune, autoinflammatory, or mixed disease phenotype and organ system affected. We also evaluated outcomes. FINDINGS: 27 cases included 17 flares and 10 new onset IMDs. 23/27 received the BNT - 162b2 vaccine, 2/27 the mRNA-1273 and 2/27 the ChAdOx1 vaccines. The mean age was 54.4 ± 19.2 years and 55% of cases were female. Among the 27 cases, 21 (78%) had at least one underlying autoimmune/rheumatic disease prior the vaccination. Among those patients with a flare or activation, four episodes occurred after receiving the second-dose and in one patient they occurred both after the first and the second-dose. In those patients with a new onset disease, two occurred after the second-dose and in one patient occurred both after the first (new onset) and second-dose (flare). For either dose, IMDs occurred on average 4 days later. Of the cases, 20/27 (75%) were mild to moderate in severity. Over 80% of cases had excellent resolution of inflammatory features, mostly with the use of corticosteroid therapy. Other immune-mediated conditions included idiopathic pericarditis (n = 2), neurosarcoidosis with small fiber neuropathy (n = 1), demyelination (n = 1), and myasthenia gravis (n = 2). In 22 cases (81.5%), the insurgence of Adverse event following immunization (AEFI)/IMD could not be explained based on the drug received by the patient. In 23 cases (85.2%), AEFI development could not be explained based on the underlying disease/co-morbidities. Only in one case (3.7%), the timing window of the insurgence of the side effect was considered not compatible with the time from vaccine to flare. INTERPRETATION: Despite the high population exposure in the regions served by these centers, IMDs flares or onset temporally-associated with SARS-CoV-2 vaccination appear rare. Most are moderate in severity and responsive to therapy although some severe flares occurred. FUNDING: none.

EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors.

BACKGROUND: Rheumatic and musculoskeletal immune-related adverse events (irAEs) are observed in about 10% of patients with cancer receiving checkpoint inhibitors (CPIs). Given the recent emergence of these events and the lack of guidance for rheumatologists addressing them, a European League Against Rheumatism task force was convened to harmonise expert opinion regarding their identification and management. METHODS: First, the group formulated research questions for a systematic literature review. Then, based on literature and using a consensus procedure, 4 overarching principles and 10 points to consider were developed. RESULTS: The overarching principles defined the role of rheumatologists in the management of irAEs, highlighting the shared decision-making process between patients, oncologists and rheumatologists. The points to consider inform rheumatologists on the wide spectrum of musculoskeletal irAEs, not fulfilling usual classification criteria of rheumatic diseases, and their differential diagnoses. Early referral and facilitated access to rheumatologist are recommended, to document the target organ inflammation. Regarding therapeutic, three treatment escalations were defined: (1) local/systemic glucocorticoids if symptoms are not controlled by symptomatic treatment, then tapered to the lowest efficient dose, (2) conventional synthetic disease-modifying antirheumatic drugs, in case of inadequate response to glucocorticoids or for steroid sparing and (3) biological disease-modifying antirheumatic drugs, for severe or refractory irAEs. A warning has been made on severe myositis, a life-threatening situation, requiring high dose of glucocorticoids and close monitoring. For patients with pre-existing rheumatic disease, baseline immunosuppressive regimen should be kept at the lowest efficient dose before starting immunotherapies. CONCLUSION: These statements provide guidance on diagnosis and management of rheumatic irAEs and aim to support future international collaborations.

Vasculitis as a Major Morbidity Factor in Patients With Partial RAG Deficiency.

Vasculitis can be a life-threatening complication associated with high mortality and morbidity among patients with primary immunodeficiencies (PIDs), including variants of severe and combined immunodeficiencies ((S)CID). Our understanding of vasculitis in partial defects in recombination activating gene (RAG) deficiency, a prototype of (S)CIDs, is limited with no published systematic evaluation of diagnostic and therapeutic modalities. In this report, we sought to establish the clinical, laboratory features, and treatment outcome of patients with vasculitis due to partial RAG deficiency. Vasculitis was a major complication in eight (13%) of 62 patients in our cohort with partial RAG deficiency with features of infections and immune dysregulation. Vasculitis occurred early in life, often as first sign of disease (50%) and was complicated by significant end organ damage. Viral infections often preceded the onset of predominately non-granulomatous-small vessel vasculitis. Autoantibodies against cytokines (IFN-α, -ω, and IL-12) were detected in a large fraction of the cases tested (80%), whereas the majority of patients were anti-neutrophil cytoplasmic antibodies (ANCA) negative (>80%). Genetic diagnosis of RAG deficiency was delayed up to 2 years from the onset of vasculitis. Clinical cases with sole skin manifestation responded well to first-line steroid treatment, whereas systemic vasculitis with severe end-organ complications required second-line immunosuppression and/or hematopoietic stem cell transplantation (HSCT) for definitive management. In conclusion, our data suggest that vasculitis in partial RAG deficiency is prevalent among patients with partial RAG deficiency and is associated with high morbidity. Therefore, partial RAG deficiency should be included in the differential diagnosis of patients with early-onset systemic vasculitis. Diagnostic serology may be misleading with ANCA negative findings, and search for conventional autoantibodies should be extended to include those targeting cytokines.

Modulating the wayward T cell: New horizons with immune checkpoint inhibitor treatments in autoimmunity, transplant, and cancer.

The T-cell response is regulated by the balance between costimulatory and coinhibitory signals. Immune checkpoints are essential for efficient T-cell activation, but also for maintaining self-tolerance and protecting tissues from damage caused by the immune system, and for providing protective immunity. Modulating immune checkpoints can serve diametric goals, such that blocking a coinhibitory molecule can unleash anti-cancer immunity whereas stimulating the same molecule can reduce an over-reaction in autoimmune disease. The purpose of this review is to examine the regulation of T-cell costimulation and coinhibition, which is central to the processes underpinning autoimmunity, transplant rejection and immune evasion in cancer. We will focus on the immunomodulation agents that regulate these unwanted over- and under-reactions. The use of such agents has led to control of symptoms and slowing of progression in patients with rheumatoid arthritis, reduced rejection rates in transplant patients, and prolonged survival in patients with cancer. The management of immune checkpoint inhibitor treatment in certain challenging patient populations, including patients with pre-existing autoimmune conditions or transplant patients who develop cancer, as well as the management of immune-related adverse events in patients receiving antitumor therapy, is examined. Finally, the future of immune checkpoint inhibitors, including examples of emerging targets that are currently in development, as well as recent insights gained using new molecular techniques, is discussed. T-cell costimulation and coinhibition play vital roles in these diverse therapeutic areas. Targeting immune checkpoints continues to be a powerful avenue for the development of agents suitable for treating autoimmune diseases and cancers and for improving transplant outcomes. Enhanced collaboration between therapy area specialists to share learnings across disciplines will improve our understanding of the opposing effects of treatments for autoimmune disease/transplant rejection versus cancer on immune checkpoints, which has the potential to lead to improved patient outcomes.

Moving towards personalized treatments of immune-related adverse events.

The enhancement of immune responses upon treatment with immune checkpoint inhibitors can have the desired outcome of reinvigorating antitumour immune surveillance, but often at the expense of immune-related adverse events (irAEs). This novel disease entity often prompts comparisons with, and extrapolation of treatment approaches from, primary autoimmune disorders. Accordingly, current treatment guidelines for irAEs make generic recommendations adapted from the literature describing primary autoimmune diseases, without taking into consideration the substantial disparity of the immunohistopathological findings within each organ affected by an irAE. The treatment modalities themselves are complex and have many potential drawbacks, such as serious and rarely fatal infections, drug toxicities overlapping with irAEs and the risk of compromising cancer immune surveillance. Herein, we provide an overview of key cellular and soluble immunological factors mediating irAEs and propose a model integrating this knowledge with the immunohistopathological findings of the affected organs for a personalized decision-making process for each patient.

Differentiation between neurosarcoidosis and primary central nervous system vasculitis based on demographic, cerebrospinal and imaging features.

OBJECTIVES: Neurosarcoidosis (NS) and primary angiitis of central nervous system (PACNS) are inflammatory diseases affecting central nervous system, with overlapping clinical and pathological characteristics. Distinguishing these diseases is important given distinct therapeutic implications. In this study, we aimed to compare demographic, CSF and MRI characteristics between these two conditions. METHODS: All the clinical, CSF and laboratory characteristics at the time of presentation were retrieved from electronic medical records. Brain and/or spinal cord MRI performed near the time of presentation were blindly evaluated by two neuroradiologists. Data regarding involvement of pachy- and leptomeninges, basal meninges, cranial nerves, cerebral grey and white matter, and spinal cord were recorded for each patient. RESULTS: 78 patients with PACNS and 25 patients with NS were included in the study. Mean age of patients was 43.7 (±16.7) and 43.6 (±12.5) in PACNS and NS, respectively. African-American race was found to be associated with the diagnosis of NS rather than PACNS. Patients with PACNS had higher frequency of cerebral involvement, while patients with NS demonstrated more frequent spinal cord, basal meningeal and cranial nerve involvements. CONCLUSIONS: These findings suggest that MRI can be an efficient tool in distinguishing PACNS from NS. A follow-up study with a larger sample size would be required to validate our results.

The immunopathogenesis of rheumatic immune adverse events from checkpoint inhibitors: prospects for targeted therapy.

PURPOSE OF REVIEW: The introduction of checkpoint inhibitors as well as other allied advances in cancer immunology has made immunotherapy a pillar in the treatment of cancer. At the same time, these therapies have been associated with a remarkable array of immune-mediated toxicities observed in virtually every organ system, a portion of which are rheumatic in nature or multisystem in expression making them of particular relevance for rheumatologists. RECENT FINDINGS: Most of our knowledge of these immune-related adverse events (irAEs) stems from clinical descriptive reports; we lack detailed understanding on immunopathogenesis for most complications. Therapeutic approaches are currently empiric and rely heavily on glucocorticoids and inhibitors of tumor necrosis factor. Serious consideration must now be given to advance our understanding of the immunopathogenesis of this emergent field and to exploit the full depth and breadth of the rich armamentarium of targeted therapies currently available to treat autoimmune and autoinflammatory diseases. SUMMARY: irAEs are and will continue to increase in incidence and pose major hurdles to the continuing success and evolution of cancer immunotherapy. Basic and translational research into pathogenesis of irAEs and clinical trials of targeted therapies for these complications is urgently needed. Rheumatologists are well poised to actively contribute to the care and research of these complications.

Central nervous system vasculitis: advances in diagnosis.

PURPOSE OF REVIEW: The main purpose of this review is to present advances in diagnostics of central nervous system vasculitis (CNS-V). RECENT FINDINGS: Progress in molecular technologies and neuroimaging have added formidably to our knowledge of CNS-V. Next-generation sequencing has the promise to enhance our ability to diagnose, interrogate, and track infectious diseases, making this test attractive and capable of avoiding brain biopsy in cases where CNS infections are suspected. Further the continuum of neuroimaging progress has advanced our ability to diagnose CNS-V. Our capability to visualize the vessel wall have added a great value in differentiating inflammatory from noninflammatory vasculopathies. New genetic variations are being exposed with exome and genome sequences which will aid future diagnosis. SUMMARY: We have witnessed tremendous advances in CNS-V mainly by our ability to rule out mimics. Progress in molecular technologies, neuroimaging and genetic studies will continue to enhance the field further.

AMSSM Position Statement Update: Blood-Borne Pathogens in the Context of Sports Participation.

This AMSSM position statement update is directed toward health care providers of patients involved in sport and exercise. There have been significant advances in clinical and scientific research in the understanding of blood-borne pathogens (BBPs), and this update incorporates these advancements. This document is intended as a general guide to clinical practice based on the current state of evidence, while acknowledging the need for modification as new knowledge becomes available. Confirmed transmission of BBPs during sport is exceedingly rare. There are no well-documented reports of HIV, hepatitis C virus, or hepatitis D virus transmission during sport. There is also no evidence for universal testing for BBPs as a specific requirement for participation in sports. Competitive athletes and nonathletes should follow appropriate general public health agency recommendations for screening for BBPs, considering their individual risk factors and exposures. Standard (universal) precautions must be followed by those providing care to athletes. Exercise and athletic participation can help promote a healthy lifestyle for persons living with BBPs. Those with acute symptomatic BBP infection should limit exercise intensity based on their current health status. Education is the key tool for preventing BBP transmission. Research gaps include evaluation of the prevalence of BBP infections in competitive athletes, the effects of long-term, intense training on infected athletes, and the effects of BBP treatment therapies on performance.