Regional european genetic ancestry predicts type I interferon level and risk of severe viral infection.

BACKGROUND: Viral infection outcomes vary widely between individuals, ranging from mild symptoms to severe organ failure and death, and it is clear that host genetic factors play a role in this variability. Type I interferon (IFN) is a critical anti-viral cytokine, and we have previously noted differences in type I IFN levels between world populations. METHODS: In this study, we investigate the interrelationship between regional European genetic ancestry, type I IFN levels, and severe viral infection outcomes. RESULTS: In cohorts of European ancestry lupus patients living in Europe, we noted higher IFN in the Northwestern populations as compared to Southeastern populations. In an independent cohort of European ancestry lupus patients from the United States with varying proportional regional European genetic admixture, we observed the same Northwest vs. Southeast European ancestry IFN gradient. We developed a model to predict type I IFN level based on regional European ancestry (AUC = 0.73, p = 6.1e-6). Examining large databases containing serious viral outcomes data, we found that lower predicted IFN in the corresponding European country was significantly correlated with increased viral infection fatality rate, including COVID-19, viral hepatitis, and HIV [Correlation coefficients: -0.79 (p = 4e-2), -0.94 (p = 6e-3), and -0.96 (p = 8e-2) respectively]. CONCLUSIONS: This association between predicted type I IFN level and viral outcome severity suggests a potential causal relationship, as greater intrinsic type I IFN is beneficial in host defense against viruses. Genetic testing could provide insight into individual and population level risk of fatality due to viruses prior to infection, across a wide range of viral pathogens.

Multimorbidity in systemic lupus erythematosus in a population-based cohort: the lupus Midwest network.

OBJECTIVES: To assess the prevalence and incidence of multimorbidity and the association with the SLICC/ACR damage index (SDI) among patients with systemic lupus erythematosus (SLE). METHODS: Using prevalent and incident population-based cohorts of patients with SLE and their matched comparators, we assessed 57 chronic conditions. Chronic conditions were categorized as SDI-related or SDI-unrelated. Multimorbidity was defined as the presence of 2+ chronic conditions. Multimorbidity at prevalence and incidence/index was compared between cohorts using logistic regression. Cox models were used to examine development of multimorbidity after SLE incidence. RESULTS: The prevalent cohort included 449 patients with established SLE on January 1, 2015. They were three times more likely to have multimorbidity compared with non-SLE comparators (OR 2.98, 95% CI 2.18-4.11). The incident cohort included 270 patients with new-onset SLE. At SLE incidence, patients with SLE were more likely to have multimorbidity than comparators (OR 2.27, 95% CI 1.59-3.27). After incidence, the risk of developing multimorbidity was 2-fold higher among patients with SLE than comparators (hazard ratio (HR) 2.11, 95% CI 1.59-2.80). Development of multimorbidity was higher in patients with SLE based on SDI-related (HR 2.91, 95% CI 2.17-3.88) and SDI-unrelated conditions (HR 1.73, 95% CI, 1.32-2.26). CONCLUSION: Patients with SLE have a higher burden of multimorbidity, even before the onset of the disease. The risk disparity continues after SLE classification and is also seen in a prevalent SLE cohort. Multimorbidity is driven both by SDI-related and unrelated conditions.

Immune responses and disease biomarker long-term changes following COVID-19 mRNA vaccination in a cohort of rheumatic disease patients.

Introduction: The longitudinal responses towards multiple doses of COVID-19 mRNA vaccines in patients with systemic autoimmune diseases remain incompletely understood. While observational studies suggested the safety of COVID-19 mRNA vaccines in rheumatic disease patients, laboratory evidence is lacking. Methods: Here we evaluated seroreactivity, clinical manifestions, and multiple disease biomarkers after 2 or 3 doses of COVID-19 mRNA vaccines in a cohort of patients with rheumatic diseases. Results: Most patients generated high SARS-CoV-2 spike-specific neutralizing antibodies comparable to those in healthy controls after 2 doses of mRNA vaccines. The antibody level declined over time but recovered after the third dose of the vaccine. Patients with systemic lupus erythematosus (SLE) or psoriatic arthritis (PsA) remained without significant flares post-vaccination. The changes in anti-dsDNA antibody concentration and expression of type I interferon (IFN) signature genes were highly variable but did not show consistent or significant increases. Frequency of double negative 2 (DN2) B cells remained largely stable. Discussion: Our data provide experimental evidences indicating the efficacy and safety of repeated COVID-19 mRNA vaccination in rheumatic disease patients.

Selective immune suppression using interleukin-6 receptor inhibitors for management of immune-related adverse events.

BACKGROUND: Management of immune-related adverse events (irAEs) is important as they cause treatment interruption or discontinuation, more often seen with combination immune checkpoint inhibitor (ICI) therapy. Here, we retrospectively evaluated the safety and effectiveness of anti-interleukin-6 receptor (anti-IL-6R) as therapy for irAEs. METHODS: We performed a retrospective multicenter study evaluating patients diagnosed with de novo irAEs or flare of pre-existing autoimmune disease following ICI and were treated with anti-IL-6R. Our objectives were to assess the improvement of irAEs as well as the overall tumor response rate (ORR) before and after anti-IL-6R treatment. RESULTS: We identified a total of 92 patients who received therapeutic anti-IL-6R antibodies (tocilizumab or sarilumab). Median age was 61 years, 63% were men, 69% received anti-programmed cell death protein-1 (PD-1) antibodies alone, and 26% patients were treated with the combination of anti-cytotoxic T lymphocyte antigen-4 and anti-PD-1 antibodies. Cancer types were primarily melanoma (46%), genitourinary cancer (35%), and lung cancer (8%). Indications for using anti-IL-6R antibodies included inflammatory arthritis (73%), hepatitis/cholangitis (7%), myositis/myocarditis/myasthenia gravis (5%), polymyalgia rheumatica (4%), and one patient each with autoimmune scleroderma, nephritis, colitis, pneumonitis and central nervous system vasculitis. Notably, 88% of patients had received corticosteroids, and 36% received other disease-modifying antirheumatic drugs (DMARDs) as first-line therapies, but without adequate improvement. After initiation of anti-IL-6R (as first-line or post-corticosteroids and DMARDs), 73% of patients showed resolution or change to ≤grade 1 of irAEs after a median of 2.0 months from initiation of anti-IL-6R therapy. Six patients (7%) stopped anti-IL-6R due to adverse events. Of 70 evaluable patients by RECIST (Response Evaluation Criteria in Solid Tumors) V.1.1 criteria; the ORR was 66% prior versus 66% after anti-IL-6R (95% CI, 54% to 77%), with 8% higher complete response rate. Of 34 evaluable patients with melanoma, the ORR was 56% prior and increased to 68% after anti-IL-6R (p=0.04). CONCLUSION: Targeting IL-6R could be an effective approach to treat several irAE types without hindering antitumor immunity. This study supports ongoing clinical trials evaluating the safety and efficacy of tocilizumab (anti-IL-6R antibody) in combination with ICIs (NCT04940299, NCT03999749).

Immune responses and disease biomarker long-term changes following COVID-19 mRNA vaccination in a cohort of rheumatic disease patients.

Objective: To evaluate seroreactivity and disease biomarkers after 2 or 3 doses of COVID-19 mRNA vaccines in a cohort of patients with rheumatic diseases. Methods: We collected biological samples longitudinally before and after 2-3 doses of COVID-19 mRNA vaccines from a cohort of patients with systemic lupus erythematosus (SLE), psoriatic arthritis, Sjogren's syndrome, ankylosing spondylitis, and inflammatory myositis. Anti-SARS-CoV-2 spike IgG and IgA and anti-dsDNA concentration were measured by ELISA. A surrogate neutralization assay was utilized to measure antibody neutralization ability. Lupus disease activity was measured by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Expression of type I interferon signature was measured by real-time PCR. The frequency of extrafollicular double negative 2 (DN2) B cells was measured by flow cytometry. Results: Most of the patients generated high SARS-CoV-2 spike-specific neutralizing antibodies comparable to those in healthy controls after 2 doses of mRNA vaccines. The antibody level declined over time but recovered after the third dose of the vaccine. Rituximab treatment substantially reduced antibody level and neutralization ability. Among SLE patients, no consistent increase in SLEDAI scores was observed post-vaccination. The changes in anti-dsDNA antibody concentration and expression of type I IFN signature genes were highly variable but did not show consistent or significant increases. Frequency of DN2 B cells remained largely stable. Conclusion: Rheumatic disease patients without rituximab treatment have robust antibody responses toward COVID-19 mRNA vaccination. Disease activity and disease-associated biomarkers remain largely stable over 3 doses of vaccines, suggesting that COVID-19 mRNA vaccines may not exacerbate rheumatic diseases. KEY MESSAGES: Patients with rheumatic diseases mount robust humoral immunity towards 3 doses of COVID-19 mRNA vaccines.Disease activity and biomarkers remain stable following 3 doses of COVID-19 mRNA vaccines.

A Flare Risk Index Informed by Select Immune Mediators in Systemic Lupus Erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) is marked by immune dysregulation linked to varied clinical disease activity. Using a unique longitudinal cohort of SLE patients, this study sought to identify optimal immune mediators informing an empirically refined flare risk index (FRI) reflecting altered immunity prior to clinical disease flare. METHODS: Thirty-seven SLE-associated plasma mediators were evaluated by microfluidic immunoassay in 46 samples obtained in SLE patients with an imminent clinical disease flare (preflare) and 53 samples obtained in SLE patients without a flare over a corresponding period (pre-nonflare). SLE patients were selected from a unique longitudinal cohort of 106 patients with classified SLE (meeting the American College of Rheumatology 1997 revised criteria for SLE or the Systemic Lupus International Collaborating Clinics 2012 revised criteria for SLE). Autoantibody specificities, hybrid SLE Disease Activity Index (hSLEDAI) scores, clinical features, and medication usage were also compared at preflare (mean ± SD 111 ± 47 days prior to flare) versus pre-nonflare (99 ± 21 days prior to nonflare) time points. Variable importance was determined by random forest analysis with logistic regression subsequently applied to determine the optimal number and type of analytes informing a refined FRI. RESULTS: Preflare versus pre-nonflare differences were not associated with demographics, autoantibody specificities, hSLEDAI scores, clinical features, nor medication usage. Forward selection and backward elimination of mediators ranked by variable importance resulted in 17 plasma mediator candidates differentiating preflare from pre-nonflare visits. A final combination of 11 mediators best informed a newly refined FRI, which achieved a maximum sensitivity of 97% and maximum specificity of 98% after applying decision curve analysis to define low, medium, and high FRI scores. CONCLUSION: We verified altered immune mediators associated with imminent disease flare, and a subset of these mediators improved the FRI to identify SLE patients at risk of imminent flare. This molecularly informed, proactive management approach could be critical in prospective clinical trials and the clinical management of lupus.

Extensive scarring alopecia and widespread rash.

This patient's nonadherence to treatment and lack of precautionary steps exacerbated this condition.

Clinical Presentations and Outcomes of Patients Receiving Immune Checkpoint Inhibitors Presenting to the Emergency Department.

Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of cancer. Immune checkpoint inhibitors may cause a wide-range of autoimmune toxicities referred to as immune-related adverse events (irAEs). There is a paucity of data regarding the presentations and outcomes of patients receiving ICIs who seek care in an emergency department (ED). We performed a retrospective review of patients receiving an ICI who presented to a tertiary care ED between May 1, 2017, and April 30, 2018. Data including ED chief complaint, diagnosis, treatment, and disposition were collected along with baseline characteristics and diagnosis at the time of outpatient oncology follow-up. We report descriptive statistics summarizing the characteristics of the cohort. There were 98 ED visits identified among 67 unique patients. Immune-related adverse events were diagnosed in 16 (16.3%) cases. The most common chief complaints within the irAE group were gastrointestinal symptoms 10 (62.5%). Among the 16 confirmed irAE cases, the most common irAE diagnosed was colitis 9 (56.3%). Two (12.5%) patients with irAEs received corticosteroids during their stay in the ED, and 10 (62.5%) patients with irAEs required hospital admission. Emergency medicine providers documented consideration of an irAE in the differential diagnosis in 14.3% of all ED visits and in 43.8% of visits in which an irAE was ultimately diagnosed. Emergency providers should be familiar with ICIs given their expanding use and potential adverse effects to improve early recognition and patient outcomes in ED settings.

Exploring the Role of Antinuclear Antibody Positivity in the Diagnosis, Treatment, and Health Outcomes of Patients With Rheumatoid Arthritis.

OBJECTIVE: The objective of this study was to describe differences in the clinical course of patients with rheumatoid arthritis (RA) who are antinuclear antibody (ANA)-positive compared with those who are ANA-negative. METHODS: This was a retrospective population-based cohort study of residents in Olmsted County, Minnesota, who first fulfilled 1987 American College of Rheumatology criteria for RA in 2009-2014. Data were collected on first documentation of joint swelling. Data on rheumatoid factor or anti-cyclic citrullinated peptide antibody testing and the ANA level were also collected. Comparisons between groups were performed by using χ2 and rank sum tests. RESULTS: In this cohort, 64% of patients were tested for ANA within ±90 days of RA criteria fulfillment. In the161 patients with ANA testing, 25% were ANA-positive. Patients who were ANA-positive were younger, female, and less likely to be current smokers. ANA positivity did not differ between patients with RA who were seropositive and seronegative. In seropositive patients who were ANA-positive, there was an increased time to fulfillment of RA criteria, increased time to treatment with disease-modifying antirheumatic drugs (DMARDs), and increased likelihood of being treated with hydroxychloroquine as opposed to methotrexate. Other outcomes, including disease activity and mortality, did not differ significantly between groups. CONCLUSION: In patients with RA, important differences exist between those who are ANA-positive and ANA-negative in terms of time to fulfillment of RA criteria and time to DMARD initiation as well as choice of initial pharmacotherapy. These findings could indicate a difference in clinical presentation or perception of patients with RA who are ANA-positive. Further research is needed to study the long-term outcomes of patients with RA who are ANA-positive.

Immune Checkpoint Inhibition-Does It Cause Rheumatic Diseases? Mechanisms of Cancer-Associated Loss of Tolerance and Pathogenesis of Autoimmunity.

Mechanisms of immune checkpoints and their role in autoimmunity are discussed in the context of immune checkpoint inhibitor (ICI) therapy for cancer. The updated clinical spectrum of immune-related adverse events (irAEs), with an in-depth discussion of rheumatic irAEs, is presented. The relationship between ICI-induced loss of self-tolerance in cancer and the implications for understanding of irAEs, rheumatic irAEs in particular, is overviewed.

Immune checkpoint inhibitor-induced inflammatory arthritis: a novel clinical entity with striking similarities to seronegative rheumatoid arthritis.

OBJECTIVE: To determine the clinical and serologic similarities and differences between inflammatory arthritis induced by immune checkpoint inhibitors (IA-irAE) and rheumatoid arthritis (RA). METHODS: In this retrospective cross-sectional comparative study, 20 patients with IA-irAE were age and sex matched to 40 seropositive and 40 seronegative RA patients. Electronic medical records were reviewed from diagnosis of inflammatory arthritis through May 2019. Arthritis characteristics, treatment, and relevant laboratory and serologic studies were captured. RESULTS: Clinically, IA-irAE differed from seropositive and seronegative RA with respect to disease duration (4.18 versus 11.59 and 13.3 months, respectively, p = 0.005 (IA-irAE vs seropositive RA), p = 0.002 (IA-irAE vs seronegative RA)), polyarticular joint involvement at presentation (75% versus 97.5% and 100%, p = 0.013, p = 0.003), absence of erosive changes (5.9% vs 43.6% and 53.8%, p = 0.005, p = 0.001), mean prednisone dose (24.7 mg versus 16.53 mg and 15.68 mg, p = 0.008, p = 0.005), and use of methotrexate (5.0% versus 85.0% and 70.0%, p < 0.0001, p < 0.0001). Serologically, IA-irAE closely resembled seronegative RA. ANA positivity was seen in a minority of patients and did not differ significantly between all groups; however, the ANA staining pattern (speckled) was similar between IA-irAE and seronegative RA (100% versus 75%, respectively) and was not commonly observed in seropositive RA (18.2%). CONCLUSION: IA-irAE is a new subset of IA that resembles seronegative RA immunologically. Our findings suggest that further study of IA-irAE might provide a window into underlying pathogenic mechanisms of early-stage seronegative RA. Key Points • Comprehensive comparison of clinical features between inflammatory arthritis irAE (IA-irAE) and regular rheumatoid arthritis indicates IA-irAE as a new subset of inflammatory arthritis. • IA-irAE resembles seronegative RA immunologically, suggesting that study of IA-irAE may provide a window into underlying pathogenic mechanisms of early-stage seronegative RA.

MOG-IgG myelitis coexisting with systemic lupus erythematosus in the post-partum setting.

BACKGROUND: Longitudinally extensive transverse myelitis (LETM) accompanying systemic lupus erythematosus (SLE) is often due to coexisting aquaporin-4-IgG seropositive neuromyelitis optica spectrum disorder but has not been associated with myelin oligodendrocyte glycoprotein-IgG (MOG-IgG). OBJECTIVE AND METHODS: Case report at an academic medical center. RESULTS: A 32-year-old woman developed severe transverse myelitis (paraplegia) shortly after SLE onset in the post-partum period. Magnetic resonance imaging (MRI) revealed an LETM, cerebrospinal fluid showed marked inflammation, and testing for infections was negative. Serum live-cell-based assay for MOG-IgG was positive but aquaporin-4-IgG was negative. CONCLUSION: In patients with SLE and LETM, MOG-IgG testing should be considered, in addition to AQP4-IgG.

Type I Interferon Predicts an Alternate Immune System Phenotype in Systemic Lupus Erythematosus.

OBJECTIVE: Type I interferon (IFN) is important to systemic lupus erythematosus (SLE) pathogenesis, but it is not clear how chronic elevations in IFN alter immune function. We compared cytokine responses after whole blood stimulation with Toll-like receptor (TLR) agonists in high- and low-IFN SLE patient subgroups. METHODS: SLE patients and nonautoimmune controls were recruited, and SLE patients were categorized as either high or low IFN. Whole blood was dispensed into tubes coated with lipopolysaccharide (LPS), oligonucleotides with cytosine-guanine repeats, Resiquimod, IFN-α, and IFN-α + LPS. Cytokine production in patient sera and after whole blood TLR stimulation was measured by multiplex assay, and type I IFN was assessed using a functional assay. RESULTS: Circulating plasmacytoid dendritic cell numbers were specifically reduced in high-IFN SLE patients and not in low-IFN SLE patients. In serum, we observed that the correlations between cytokines in serum differed to a much greater degree between the high- and low-IFN groups (P < 0.0001) than the absolute cytokine levels differed between these same groups. In stimulated conditions, the high-IFN patients had less cytokine production in response to TLR ligation than the low-IFN SLE patients. LPS produced the most diverse response, and a number of interactions between type I IFN and LPS were observed. CONCLUSION: We find striking differences in resting and stimulated cytokine patterns in high- vs. low-IFN SLE patients, which supports the biological importance of these patient subsets. These data could inform personalized treatment approaches and the pathogenesis of SLE flare following infection.

Rheumatic Syndromes Associated With Immune Checkpoint Inhibitors: A Single-Center Cohort of Sixty-One Patients.

OBJECTIVE: To describe the prevalence, clinical presentation, and management of rheumatic immune-related adverse effects (Rh-irAEs) from immune checkpoint inhibitor (ICI) therapy. METHODS: From a database of all patients who received any ICI at the Mayo Clinic Rochester, Minnesota campus between January 1, 2011 and March 1, 2018, we retrospectively identified those with Rh-irAEs, using diagnostic codes, search terms, and manual chart review. RESULTS: Of the 1,293 patients who received any ICI, Rh-irAEs were clinically diagnosed in 43. Eighteen patients with Rh-irAEs who received ICI therapy elsewhere were also analyzed. Clinical syndromes included inflammatory arthritis (n = 34 [prevalence 2%]), myopathy (n = 10), and other rheumatic syndromes (n = 17). Inflammatory arthritis was most commonly polyarticular, and glucocorticoid treatment was required in 26 patients (76%). The mean ± SD duration of treatment was 18 ± 18 weeks. Five patients (15%) also received disease-modifying antirheumatic drugs, and ICI therapy had to be discontinued in 3 patients (9%). Myopathy was treated with glucocorticoids in all cases (mean ± SD treatment duration 15 ± 17 weeks) and led to 2 deaths and permanent ICI discontinuation in 9 patients (90%). Other syndromes included connective tissue diseases, vasculitis, polymyalgia rheumatica-like syndrome, and flare of preexisting rheumatic disease. Most (71%) were treated with immunosuppression, with 12% requiring ICI discontinuation. CONCLUSION: This study represents the largest cohort of patients with Rh-irAEs reported to date. Most patients received long courses of immunosuppressive treatment, although discontinuation of ICI therapy was required in only a minority.

Brief Report: Cancer Immunotherapy in Patients With Preexisting Rheumatic Disease: The Mayo Clinic Experience.

OBJECTIVE: To determine the risk of rheumatic disease flare and adverse effects in patients with preexisting rheumatic disease who were receiving immune checkpoint inhibitor (ICI) therapy. METHODS: A retrospective medical record review was performed to identify all patients who received ICI therapy at Mayo Clinic in Rochester, Minnesota between 2011 and 2016 (~700 patients). Those with a preexisting rheumatic disease were identified using specific diagnostic codes. RESULTS: Sixteen patients were identified (81% female, median age 68.5 years). The most common rheumatic diseases were rheumatoid arthritis (n = 5), polymyalgia rheumatica (n = 5), Sjögren's syndrome (n = 2), and systemic lupus erythematosus (n = 2). Seven patients were receiving immunosuppressive therapy or glucocorticoids for their rheumatic disease at the time of initiation of the ICI. The primary malignancies were melanoma (n = 10), pulmonary (n = 4), or hematologic (n = 2). In most cases, ICIs were offered only after failure of several other therapies. Immune-related adverse effects (IRAEs) occurred in 6 patients, and all were treated successfully with glucocorticoids and discontinuation of the ICI therapy. There were no significant differences in time from cancer diagnosis to immunotherapy, duration of immunotherapy, age, or sex between the patients with and those without IRAEs. CONCLUSION: To our knowledge, this represents the largest single-center cohort of patients with rheumatic diseases who were exposed to modern cancer immunotherapy. Only a minority of these patients experienced a flare of their preexisting rheumatic disease or any other IRAE.

Brief Report: A Novel ELANE Mutation Associated With Inflammatory Arthritis, Defective NETosis, and Recurrent Parvovirus Infection.

OBJECTIVE: We describe a 38-year-old woman who presented with a history of inflammatory arthritis, rash, and daily fevers. She was noted to have chronic parvovirus infection with persistently detectable viral titers and a novel mutation in the ELANE gene. ELANE encodes neutrophil elastase, a neutrophil serine protease with important antimicrobial effects, and is found as part of neutrophil extracellular trap (NET) complexes. Pathogenic ELANE mutations have been identified in forms of hereditary neutropenia. However, our patient never had neutropenia. Because of the striking clinical scenario, we investigated this mutation functionally. METHODS: NET formation by neutrophils was assessed by scanning electron microscopy. Neutrophil activation and neutrophil elastase production were evaluated by flow cytometry and fluorescent substrate-based functional assay, respectively. A multiplex assay was used to quantitate neutrophil inflammatory cytokine production. PyMOL software was used to generate 3-dimensional models of mutant elastase. RESULTS: Activated neutrophils from the patient demonstrated a significantly decreased ability to form NETs on scanning electron microscopy, as well as quantitative defects in neutrophil activation and neutrophil elastase activity. The patient's neutrophils showed altered levels of interleukin-12 (IL-12) and IL-8, which are key cytokines for antiviral immunity and neutrophil chemotaxis. Three-dimensional mapping revealed that the mutation could alter protein folding and surface charge distribution, potentially perturbing protein trafficking. Thus, the mutation could affect neutrophil function by decreasing NETosis and altering key antiviral activities of neutrophils. CONCLUSION: This is the first report of a human pathogenic ELANE mutation associated with a defect in NETosis and a distinct syndrome of recurrent viral infection and chronic inflammation.

Scleroderma Induced by Pembrolizumab: A Case Series.

Immune checkpoint inhibitors are approved for select cancer treatment and have shown survival benefit in patients with advanced melanoma. Adverse events, including immune-related adverse events, are common and potentially life-threatening. We describe cases of 2 patients with scleroderma (patient 1 had diffuse scleroderma, and patient 2 had limited scleroderma) that developed while they were receiving pembrolizumab therapy for metastatic melanoma. Prompt recognition and treatment of immune-related adverse events may improve tolerance to immune checkpoint inhibitors and contribute to an understanding of the manifesting autoimmune disease.

Immune checkpoint blockade in lymphoid malignancies.

Malignant cells may subvert and escape endogenous host immune surveillance by up-regulation of immune inhibitory signals known as immune checkpoints. These checkpoints are important therapeutic targets, and antibodies that block checkpoint signaling have shown remarkable efficacy in some solid tumors as well as in some refractory hematologic malignancies. In hematologic cancers, the mechanism of these checkpoints is complex, as the tumor and immune system are one and the same. In this review, we evaluate the biology of checkpoint inhibition, review the current data on its efficacy in lymphoid tumors, and explore uncertainties in the field, including those involving the precise mechanisms of action, the appropriate timing of therapy, and the differences in response rate between lymphoid tumor types.