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SLE is marked by immune dysregulation linked to varied clinical disease activity. Using a unique longitudinal cohort of SLE patients, this study seeks to identify optimal immune mediators informing an empirically refined Flare Risk Index (FRI) reflecting altered immunity prior to clinical disease flare.SLE-associated plasma mediators (n=37) were evaluated by microfluidic immunoassay in 46 Pre-Flare and 53 Pre-Nonflare samples selected from a unique longitudinal cohort of 106 patients with classified SLE (meeting ACR and SLICC criteria). Autoantibody specificities, hybrid SLEDAI (hSLEDAI) scores, clinical features, and medication usage were also compared at Pre-Flare (111±47 days prior to Flare) vs. Pre-Nonflare (99±21 days prior to Nonflare) time points. Variable importance was determined by random forest with logistic regression subsequently applied to determine the optimal number and type of analytes informing a refined FRI.Pre-Flare vs. 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 drew up to 17 candidates differentiating Pre-Flare from Pre-Nonflare. A final combination of 11 mediators best informed a newly refined FRI, achieving a maximum of 97% sensitivity and 98% specificity after applying decision curve analysis to define low, medium, and high FRI scores.We verified altered immune mediators associated with imminent disease flare; a subset 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.

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.

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

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.

This chapter focuses on patients with a preexisting inflammatory arthritis subsequently treated by immune checkpoint inhibitor (ICI) therapy for malignancy. We summarize the available epidemiologic and pathologic studies involving this subgroup of patients. An illustrative case of a patient with preexisting rheumatoid arthritis exposed to ICI for melanoma and followed longitudinally is presented in detail to highlight the clinical course and management challenges faced when caring for these patients.

The immune checkpoint inhibition therapy induces various immune related adverse events (irAEs). The immunological basis of irAEs remains unclear. We recruited a cohort of patients with inflammatory arthritis irAE (IA-irAE), the most common form of rheumatic irAEs, together with matched patients with conventional rheumatoid arthritis (RA) and cancer patients without irAEs. Comprehensive clinical and immunological investigations reveal an imbalance of T cell exhaustion and senescence in IA-irAE patients, and immunological similarities between IA-irAE patients and seronegative RA patients. These data suggest that IA-irAE and seronegative RA may have shared immunological mechanisms. Thus, our study identifies potential immunological underpinnings of IA-irAE and the relationship between IA-irAE and conventional RA. The results may have implications for managing irAE and seronegative RA patients. Supported byR01AR0077518 Arthritis National Research Foundation

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.

To determine the clinical and serologic similarities and differences between inflammatory arthritis induced by immune checkpoint inhibitors (IA-irAE) and rheumatoid arthritis (RA).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.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%).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.

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), Sjogren'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.

BackgroundManaging immune-related adverse events (irAEs) has become a critical challenge with the increasing implementation of immune-checkpoint inhibitors (ICIs) in cancer treatment. IrAEs may cause treatment interruption or discontinuation, the rate of which is higher with multi-agent ICI regimen needed to overcome resistant tumor microenvironment. Herein, we describe our clinical experience using interleukin-6 receptor antagonists (IL-6RA) to manage irAEs in cancer patients receiving ICIs.MethodsWe conducted a retrospective, multi-center study to evaluate the safety and efficacy of IL-6RA for irAE management. Eligible patients were identified from the institutional databases (pharmacy records, tumor registries, oncology and specialty clinic records for diagnosis and management of irAEs). The primary objective was assessing changes in irAE symptoms. The secondary objective was assessing overall response rate (ORR) before and after IL-6RA treatment.ResultsA total of 81 patients received an IL-6RA (tocilizumab or sarilumab); median age was 66 years, 41% were females, 70% received single-agent anti-PD-1 and 23% received nivolumab plus ipilimumab. Cancer types were primarily melanoma (44%), genitourinary cancer (37%), and lung cancer (8.6%). Indications for using IL-6RA were inflammatory arthritis (74%), polymyalgia rheumatica (6%), myositis/myocarditis/myasthenia gravis (5%) encephalitis (5%), and 1% each with pneumonitis, colitis, hepatitis, central nervous system vasculitis, oral mucositis, and flare of pre-existing myasthenia gravis, psoriasis, and Crohn's disease. Notably, 83 % of patients received corticosteroids as first-line therapy, and 29% received disease-modifying antirheumatic drugs, without improvement. After initiation of IL-6RA, improvement of irAEs was observed in 78% after a median of 2.1 months. Of evaluable patients with inflammatory arthritis, the median clinical disease activity index (CDAI) at IL-6RA initiation was 28, indicating high disease activity, and dropped to 6 after treatment, indicating low disease activity. The median CRP level at IL-6RA initiation was 59.5 mg/L and dropped to 1.5 mg/L within 10 weeks of treatment. Seventy-two patients tolerated IL-6RA, and nine stopped treatment due to side effects. Thirty-eight patients were evaluated for tumor response by RECIST 1.1 criteria; the ORR was 58% prior to IL-6RA and 66% after treatment. Of 21 evaluable melanoma patients, the ORR was 62% prior to IL-6RA compared to 71% after treatment (figure 1).ConclusionsOur study demonstrated that targeting IL-6R could be an effective approach to mitigate autoimmunity while maintaining and possibly boosting tumor immunity. Clinical trials are currently evaluating the safety and efficacy of tocilizumab in combination with ICIs in patients with melanoma, non-small cell lung cancer, and urothelial carcinoma (NCT04940299, NCT03999749).Ethics ApprovalThe study was approved by The University of Texas MD Anderson Cancer Center intuition's Ethics Board, approval number PA19-0089Abstract 816 Figure 1A patient with sinonasal malignant melanoma involving the ethmoid air cells. (A) Baseline maximum intensity projection (MIP) PET image at 1 month before initiation of ICI (ipilimumab and nivolumab) shows avid FDG uptake of the tumor at the ethmoid air cells (arrow). (B) MIP PET image at 7 months after ICI initiation shows resolution of the FDG uptake at the site of the tumor, consistent with complete response. (C) Concurrent MIP PET and corresponding fused PET-CT images 7 months after initiation of ICI show avid radiotracer uptake at the knee joints, suggestive of arthritis. (D) MIP PET image at 10 months after concomitant therapy with IL6R antagonist and nivolumab shows persistent absence of hypermetabolic radiotracer activity at the paranasal sinuses, consistent with complete response. (E) Concurrent MIP PET and corresponding fused PET-CT images show physiologic radiotracer uptake at the knee joints, consistent with resolving arthritis.

Introduction Immune-mediated hematologic disorders are relatively rare but potentially life-threatening immune-related adverse events (irAE) with immune checkpoint inhibitor (ICI) therapy (Shiuan, Beckermann et al 2017). The management strategy often relies on systemic corticosteroids and other immunosuppressant agents in steroid-refractory cases (Brahmer, Lacchetti et al 2018). We hereby describe our institution's experience in diagnosing and managing immune-related hematologic adverse events (ir-h-AE). Methods We retrospectively searched the electronic health record for all ir-h-AE diagnosed by treating providers and confirmed by study authors between 2015 and 2020. The search included patients on ICI and the following conditions: immune-related neutropenia (IRN), autoimmune hemolytic anemia (AIHA), cold agglutinin disease (CAD), immune thrombocytopenia (ITP), immune-related pancytopenia, aplastic anemia (AA), and pure red cell aplasia (PRCA). For AIHA, PRCA, and CAD, partial response (PR) was defined as hemoglobin greater than 10 g/dL but < 12 g/dL and 2 g/dL above the nadir without blood product transfusion. Complete response (CR) was defined as hemoglobin of ≥ 12 g/dL and 2 g/dL above the nadir without blood product transfusion (Peñalver, Alvarez-Larrán et al. 2010). For ITP, CR was defined as platelet count ≥ 100 × 109/L and absence of bleeding. PR was defined as platelet count ≥ 30 × 109/L and ≥ two-fold increase from the baseline count and absence of bleeding (Gómez-Almaguer, Tarín-Arzaga et al. 2013). For IRN, CR was defined as absolute neutrophil count (ANC) ≥ 1500/ mm3 on 2 consecutive measurements separated by 7 days; PR was defined as ANC ≥ 500/ mm3 sustained over 7 days. JMP® 14.1 was used for data analysis. Results Seventeen patients were identified, 9 (52.9%) of whom were female (table 1). Median age was 68 years (range 26-78). The most common pre-existing malignancies were melanoma (6 patients, 35.3%), non-small cell lung cancer (4 patients, 23.5%), and gastrointestinal cancer (3 patients, 17.6%). The ir-h-AE included 7 patients (41.2%) with warm AIHA, 4 (23.5%) with ITP (1 had immune-related pancytopenia that resolved with ITP persisting), 3 (17.6%) with IRN, 1 with AA, 1 with CAD, and 1 with PRCA and mild ITP. All patients had received an ICI dose within 60 days of diagnosis (range 3-52 days, median 18 days). Only 1 patient had a concomitant chronic autoimmune disorder (antinuclear antibody-positive arthritis). Four patients (23.5%) were receiving chemotherapy. Sixteen patients (94.1%) required treatment and received corticosteroids. Eight out of 15 evaluable patients (53.3%) responded to corticosteroids only. Another 4 responders (26.7%) required additional therapies including intravenous immunoglobulins (IVIG) (4, 23.5%) and/or rituximab (4, 23.5%). Overall response rate was 71.4% for AIHA and 100% for IRN. ITP was likely underrepresented in our cohort, and the response rate of 66.7% is likely lower than the response rate in clinical practice. This could be related to the fact that many mild thrombocytopenia cases are not further evaluated in clinical practice. None of our patients died from the sequelae of an ir-h-AE. Two patients (11.8%) died within 30 days of ir-h-AE diagnosis (disseminated intravascular coagulation likely due to the underlying malignancy and sepsis from bacterial pneumonia). At the time of ir-h-AE diagnosis, the malignancy was showing evidence of response in 9 patients (52.9%), progression in 6 patients (35.3%), and stability in 2 patients (11.8%). ICI therapy was permanently discontinued in 9 patients (52.9%) and temporarily held in 6 patients (35.3%). Three of the 5 patients (60%), who were rechallenged with ICI therapy, had recurrence of the same ir-h-AE (AIHA) with adequate response to therapy. Non-hematologic irAE (7 patients, 41.2%) included 3 patients with hepatitis, 2 with thyroiditis, 2 with pneumonitis, 1 with colitis, and 1 with dermatitis. Conclusion Our clinical experience with ir-h-AE highlights the importance of exercising vigilance in assessing the hematologic parameters of patients receiving ICI therapy. While relatively rare, ir-h-AE may impact the clinical course of patients with cancer and their eligibility for therapies that have the potential of offering durable control of the underlying malignancy. ir-h-AE respond to classical therapies including corticosteroids, IVIG, and rituximab. Disclosures Block: Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Marker Therapeutics: Research Funding; Transgene: Research Funding; Immune Design: Research Funding. Kottschade:Bristol-Myers Squibb: Consultancy, Research Funding.

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.

95 Background: The incidence of immune-related adverse events (irAEs) in patients (pts) with Hodgkin lymphoma (HL) treated with PD-1 antibodies (ICI) is reported at 28 - 36%. However, clinically relevant information on irAE onset, duration, or impact on ability to continue therapy in HL is lacking. Additionally, these incidence rates reflect CTCAE definition and grading, and not ASCO Clinical Practice Guidelines irAE-specific criteria (Brahmer et al, JCO 2018). The objectives of this study were to evaluate the rate and severity of irAEs in HL pts using ASCO criteria, to characterize irAE time profile and to assess their impact on continued therapy. Methods: HL pts who received a PD-1 inhibitor for the treatment of HL at Mayo Clinic Rochester between January 1, 2011 and March 1, 2018 were identified. We conducted a detailed, longitudinal retrospective chart review with definition and grading of irAEs in accordance with ASCO guidelines. Results: Fifty-one pts were identified (35% women, median age at ICI initiation 35 years [range: 19-87]). Median duration of follow up from ICI start was 30 months (range: 1-70). Thirty-one pts (61%) had any irAE. Most common irAEs were inflammatory/bullous dermatoses (23.5%/5.9% any grade/grade3-4; median onset/duration of 81/57 days[d]), followed by thyroiditis (22%/0%; 86/84 d), colitis (14%/8%; 82/106 d), pneumonitis (14%/10%; 241/182 d), and hepatitis (14%/4%; 71/35 d). Fifteen pts (29%) required treatment with steroids. Among the total cohort, ICI was held for an irAE 28 times (50% of 56 total irAEs). Median treatment cycles held was 2.5 and ICI was permanently discontinued due to irAE in 18%. The most common irAE leading to treatment discontinuation was pneumonitis, followed by neuritis (5.9%/3.9%; 179/374 d), colitis, and rash. Conclusions: The rate of irAEs of 61% in this cohort as defined by ASCO consensus criteria was higher than reported in trials. Most irAEs were characterized by delayed onset of several months and prolonged duration, particularly pneumonitis and neuritis. Treatment discontinuation due to irAEs was infrequent overall. Further studies are needed to determine whether the development or duration of irAEs is predictive of treatment outcomes in HL.

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.

Background Immune checkpoint inhibitors for advanced malignancy are associated with a wide range of autoimmune phenomena known as immune-related adverse effects (irAEs).1 Knowledge of irAEs resembling rheumatologic diseases is limited to case reports and small case series, and there are currently no specific guidelines on how to diagnose or manage these patients. Objectives To describe the prevalence, clinical presentation, and management of patients with rheumatologic irAEs from checkpoint inhibitor therapy. Methods We retrospectively studied all patients who received a checkpoint inhibitor for any malignancy at Mayo Clinic Rochester, Minnesota between January 1 st, 2011 and November 1 st, 2017. From these patients we identified those with possible rheumatologic irAEs using diagnostic codes, search terms, and the presence of specific laboratory testing. Results Of the 1216 patients who received any checkpoint inhibitor, we identified 29 who were clinically diagnosed with a rheumatologic irAE. The diagnosis was confirmed by a rheumatologist in all but 3 cases. Mean follow up time from irAE diagnosis was 1.5 years (±1.1). Seven patients had a pre-existing autoimmune disease with one of these being a rheumatologic disease (Giant-cell arteritis). irAEs included inflammatory arthritis,15 sicca syndrome,3 systemic sclerosis,3 myositis,3 vasculitis,3 spondylitis,1 and polymyalgia rheumatica.1 Only one irAE represented a disease flare. Mean time from initiation of checkpoint inhibitor therapy to onset of irAE symptoms was 15.0 weeks (±10.8). 24 patients (83%) were treated with corticosteroids and 8 patients (28%) received additional therapy with disease modifying drugs. Mean treatment duration for these 24 patients was 19.5 weeks (±21.7), and 8 patients (33%) had complete symptom resolution within the study period. Rheumatologic irAEs resulted in discontinuation of checkpoint inhibitor therapy in 7 patients (24%). Conclusions Our study represents one of the largest cohorts of rheumatologic irAEs to date. Most patients required long courses of treatment with only a minority achieving complete symptom resolution. Prospective, multicenter studies are necessary to determine the optimal management of these emerging disorders. Reference [1] Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. European journal of cancer2016;54:139–48. Disclosure of Interest None declared

Background Immune checkpoint inhibitors (specifically the anti-CTLA-4 antibody ipilimumab, and the anti-PD-1 antibodies nivolumab and pembrolizumab, have revolutionized the treatment of advanced malignancies. However, by virtue of their mechanism of action – that is, loss of T-cell inhibition and impaired self-tolerance, patients with underlying autoimmune and rheumatologic diseases were typically excluded from the clinical trials leading to the approval of these agents. Limited data, typically of single checkpoint inhibitors, exist for their safety in patients with autoimmune diseases. However, the risk for rheumatologic disease flare in patients exposed to checkpoint inhibitors is unknown. Objectives To determine the risk of rheumatologic disease flare in patients receiving checkpoint inhibitor therapy. Methods We retrospectively studied all patients who had received a checkpoint inhibitor (i.e. ipilimumab, nivolumab, pembrolizumab, or any combination thereof) for any malignancy on the Mayo Clinic Rochester, Minnesota campus between January 1st, 2011 and May 16th, 2016 (approximately 5,200 patients.) Of these patients, we identified those with preexisting rheumatologic disease according to specific diagnostic codes. Results Of the 16 patients identified (13 [81%] female; median [range] age, 68.5 [34–86]y), 6 had inflammatory arthritis, 3 had polymyalgia rheumatica, 2 had lupus, 2 had Sjogren9s syndrome, 1 had temporal arteritis, 1 had IBD-associated spondyloarthropathy and 1 had gout. Patients were treated for the following metastatic/advanced malignancies: melanoma (9 [56%]), lung (5 [31%]) and lymphoma (2 [12%]) with; ipilimumab (4 [25%]), nivolumab (7 [44%]), pembrolizumab (5 [31.2%]) and ipilimumab/nivolumab (1 [6%]). Notably, in all cases, checkpoint inhibitor therapy was offered after failure of numerous other chemotherapies. Ten (62.5%) patients were on immunosuppressive therapy (mainly low dose prednisone and methotrexate) at the time of cancer diagnosis, and the majority (10 [62.5%]) were well-controlled/in remission from the standpoint of their rheumatologic disease. Three (19%) patients had flares of their rheumatologic disease after treatment for the following cancers as noted: Patient 1 - temporal arteritis – nivolumab - non-small cell lung cancer, Patient 2 - Sjogren9s (severe sicca)– pembrolizumab - melanoma, and Patient 3 - spondylitis-ipilimumab/pembrolizumab combination –melanoma. All flares responded to steroids or supportive therapy. Checkpoint inhibitor therapy was discontinued in all three patients for the following reasons: Patient 1 – flare of temporal arteritis, Patients 2 & 3 – cancer progression. Conclusions To our knowledge, we have identified the largest cohort (16) of patients from a single academic with preexisting rheumatologic disease who had been exposed to checkpoint inhibitor therapy for advanced malignancy. Of these patients, only a minority experienced a flare of their disease during cancer treatment, and responded to standard therapies. With close monitoring and in the appropriate clinical context, checkpoint inhibitor therapies should be considered and made available to patients with preexisting rheumatologic disease who develop advanced malignancies. Disclosure of Interest None declared

Objective We describe a 38-year-old woman presenting with a history of inflammatory arthritis, rash and daily fevers. She was noted to have chronic parvoviral 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 described in forms of hereditary neutropenia. However, our patient was never neutropenic. 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 studied by flow cytometry and fluorescent substrate based functional assay, respectively. Multiplex assay was used to quantitate neutrophil inflammatory cytokine production. PYMOL software was used to generate three-dimensional models of mutant elastase. Results The patient's activated neutrophils demonstrated significantly decreased ability to form NETs by scanning electron microscopy, as well as quantitative defects in neutrophil activation and neutrophil elastase activity. The patient's neutrophils demonstrated altered levels of IL-12 and IL-8 - 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 impact neutrophil function by decreasing NETosis, and altering key antiviral activities of neutrophils. Conclusions This is the first report of a human pathogenic ELANE mutation associated with a defect in NET-osis and a distinct syndrome of recurrent viral infection and chronic inflammation. This article is protected by copyright. All rights reserved.

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.

Background Evidence-based practice in education requires high-quality evidence, and many in the medical education community have called for an improvement in the methodological quality of education research. Objective Our aim was to use a valid measure of medical education research quality to highlight the methodological quality of research publications and provide an overview of the recent internal medicine (IM) residency literature. Methods We searched MEDLINE and PreMEDLINE to identify English-language articles published in the United States and Canada between January 1, 2010, and December 31, 2011, focusing on IM residency education. Study quality was assessed using the Medical Education Research Study Quality Instrument (MERSQI), which has demonstrated reliability and validity. Qualitative articles were excluded. Articles were ranked by quality score, and the top 25% were examined for common themes, and 2 articles within each theme were selected for in-depth presentation. Results The search identified 731 abstracts of which 223 articles met our inclusion criteria. The mean (±SD) MERSQI score of the 223 studies included in the review was 11.07 (±2.48). Quality scores were highest for data analysis (2.70) and lowest for study design (1.41) and validity (1.29). The themes identified included resident well-being, duty hours and resident workload, career decisions and gender, simulation medicine, and patient-centered outcomes. Conclusions Our review provides an overview of the IM medical education literature for 2010–2011, highlighting 5 themes of interest to the medical education community. Study design and validity are 2 areas where improvements in methodological quality are needed, and authors should consider these when designing research protocols.

The patient was admitted to a local hospital 2 weeks priorfor a 3-month duration of weight loss, generalized weak-ness, and progressive lower extremity pain. The symptomsstarted gradually, without any notable antecedent event.He felt weak, lost appetite, and developed intermittent drycough and pain in the lower extremities, initially in thethighs, and progressed to bilateral legs. In a matter ofmonths, his health deteriorated from being physically ac-tive and independent to mostly bedridden.Evaluation at the local hospital revealed low-grade fever(37.9°C), mild hypertension (140–150/90 mm Hg), multi-ple new lung nodules on a contrast-enhanced chest andabdominal computed tomography (CT) scan, and an ele-vated serum creatinine concentration of 2.6 mg/dl (fromhis baseline of 0.9 mg/dl approximately 6 months ago)with microscopic hematuria. Screening for hepatitis B andC, antinuclear antibodies, complements, and antineutro-phil cytoplasmic antibody (ANCA) panel (myeloperoxi-dase [MPO] and proteinase 3) was negative. His erythro-cyte sedimentation rate (ESR) was 49 mm/hour (referencerange 0–25). A transbronchial biopsy sample of severallung nodules showed no evidence of malignancy or activeinfection and was interpreted as nondiagnostic. For hislower extremity pain, he was empirically treated withintravenous (IV) immunoglobulin for possible Guillain-Barre´ syndrome. The treatment was discontinued 4 dayslater after an electromyogram sample revealed primaryaxonal sensory motor peripheral neuropathy. His kidneydysfunction worsened following intravenous contrast ex-posure for the CT scan; his serum creatinine level rose to3.4 mg/dl. He underwent a left kidney percutaneous bi-opsythatwasreadaspossiblecrescenticglomerulonephri-tis. IV methylprednisolone, 500 mg once daily, was initi-ated. During his hospital stay, the patient developedepisodic confusion. A spinal tap was performed andshowed no abnormality, nor evidence of syphilis or WestNile virus infection. Two days following the initiation ofIV methylprednisolone, his condition further deterioratedwith worsening extremity weakness to the point that hecould not ambulate with assistance and mental confusion.He was then transferred to our institution.

Oncolytic virotherapy can be achieved in two ways: (1) by exploiting an innate ability of certain viruses to selectively replicate in tumor tissues, and (2) by using viruses to deliver toxic or immunostimulatory genes to tumors. Vesicular stomatitis virus (VSV) selectively replicates in tumors lacking adequate type I interferon response. The efficacy of oncolytic virotherapy using VSV against B16 melanomas in C57BL/6 mice is dependent on CD8(+) T and natural killer cells. Because immunotherapies that prime specific CD8(+) T cells against melanocyte/melanoma antigens can generate significant therapeutic responses, we hypothesized that engineering VSV to express the potent T cell costimulatory molecule CD40 ligand (VSV-CD40L) would enhance virotherapy with concomitant priming of melanoma-specific T cells. However, we observed no difference in antitumor efficacy between the parental VSV-GFP and VSV-CD40L. In contrast, intratumoral injection of a replication-defective adenovirus expressing CD40L (Ad-CD40L) consistently produced significantly greater therapy than either replication-competent VSV-GFP or VSV-CD40L. The Ad-CD40L-mediated tumor regressions were associated with specific T cell responses against tumor-associated antigens (TAAs), which took several days to develop, whereas VSV-CD40L rapidly induced high levels of T cell activation without specificity for TAAs. These data suggest that the high levels of VSV-associated immunogenicity distracted immune responses away from priming of tumor-specific T cells, even in the presence of potent costimulatory signals. In contrast, a replication-defective Ad-CD40L allowed significant priming of T cells directed against TAAs. These observations suggest that an efficiently primed antitumor T cell response can produce similar, if not better, therapy against an established melanoma compared with intratumoral injection of a replication-competent oncolytic virus.

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.

Summary Diverse immunotherapy approaches have achieved success in controlling individual aspects of immune responses in animal models. Transfer of such immunotherapies to clinical trials has obtained some success in patients, with clinical responses observed or effective antigen specific immune responses achieved, but has had limited impact on patient survival. Key elements required to generate de novo cell-mediated antitumour immune responses in vivo include recruitment of antigen-presenting cells to the tumour site, loading these cells with antigen, and their migration and maturation to full antigen-presenting function. In addition, it is essential for antigen-specific T cells to locate the tumour to mediate cytotoxicity, emphasizing the need for local inflammation to target effector cell recruitment. We review those therapies that involve the tumour site as a target and source of antigen for the initiation of immune responses, and discuss strategies to generate and co-ordinate an optimal cell-mediated immune response to control tumours locally.

Relapsing polychondritis (RP) is an inflammatory disease of the cartilaginous tissue primarily affecting the cartilaginous structures of the ear, nose, joints, and the respiratory system. Cardiovascular complications of RP are associated with high morbidity and mortality and occur most commonly as valvular disease. Pericarditis is a less common complication, occurring in 4% of patients with RP and has not previously been described at presentation. We describe a case of relapsing polychondritis with acute pericarditis at presentation.

Allelic loss of the chromosome 19q arm is a frequent event in human diffuse gliomas, suggesting that it contains a tumor suppressor gene. Recent deletion mapping studies have broadly implicated a 1.6-Mb interval between D19S241E and D19S596, with a limited subset of tumors, suggesting that the region may be as narrow as 150 kb. Focusing on this smaller interval, we have used cDNA selection, exon amplification, and genomic sequencing to identify three novel transcripts (EHD2, GLTSCR1, and GLTSCR2) and to map two known genes (SEPW1 and CRX). A partial transcript map of 19 transcripts and two EST markers has been constructed for the 1.6-Mb interval D19S241E-D19S596. Ten of these transcripts, including the 5 mapped to the 150-kb deletion interval, have been examined for alterations in a panel of gliomas with allelic loss of 19q. Tumor-specific alterations have not been identified in the transcripts examined thus far. Collectively, these data should facilitate subsequent efforts to identify and characterize the remaining transcripts in the 1.6-Mb interval.

In situ tumor cell killing by the herpes simplex virus thymidine kinase (HSVtk) gene can effectively prime antitumor T-cell responses, at least in part through local induction of a pro-inflammatory environment. Therefore, we reasoned that tumor-associated HSVtk expression would significantly enhance the efficacy of adoptive T-cell transfer (ACT) of (tumor) antigen-specific T cells into tumor-bearing hosts. When B16ovaHSVtk tumors were treated with ganciclovir (GCV), along with suboptimal numbers of activated OT-1T cells, complete tumor regressions were observed where GCV, or ACT, alone was completely ineffective. To our surprise, analysis of regressing tumors showed no increases in intratumoral OT-1T cell trafficking. However, the intratumoral percentages of both OT-1 and endogenous natural killer (NK) cells were substantially increased over controls. Depletion of endogenous NK cells abrogated the efficacy of the combination therapy and reduced the percentages of interferon-gamma(IFNgamma)-secreting OT-1T cells in mice that received combined therapy to levels similar to those of control mice. These data suggest that even relatively low levels of gene transfer of suicide genes into tumors may have therapeutic value as an adjuvant for other T-cell therapies, by providing immunological signals that support T-cell activation and expansion in vivo.

Adoptive T-cell transfer has achieved significant clinical success in advanced melanoma. However, therapeutic efficacy is limited by poor T-cell survival after adoptive transfer and by inefficient trafficking to tumor sites. Here, we report that intratumoral expression of the chemokine CCL21 enhances the efficacy of adoptive T-cell therapy in a mouse model of melanoma. Based on our novel observation that CCL21 is highly chemotactic for activated OT-1 T cells in vitro and down-regulates expression of CD62L, we hypothesized that tumor cell–mediated expression of this chemokine might recruit, and retain, adoptively transferred T cells to the sites of tumor growth. Mice bearing metastatic tumors stably transduced with CCL21 survived significantly longer following adoptive T-cell transfer than mice bearing non–CCL21-expressing tumors. However, although we could not detect increased trafficking of the adoptively transferred T cells to tumors, tumor-expressed CCL21 promoted the survival and cytotoxic activity of the adoptively transferred T cells and led to the priming of antitumor immunity following T-cell transfer. To translate these observations into a protocol of real clinical usefulness, we showed that adsorption of a retrovirus encoding CCL21 to OT-1 T cells before adoptive transfer increased the therapeutic efficacy of a subsequently administered dose of OT-1 T cells, resulting in cure of metastatic disease and the generation of immunologic memory in the majority of treated mice. These studies indicate a promising role for CCL21 in enhancing the therapeutic efficacy of adoptive T-cell therapy. [Cancer Res 2007;67(1):300–8]

Strategies that generate tumor Ag-specific effector cells do not necessarily cure established tumors. We hypothesized that the relative efficiency with which tumor-specific effector cells reach the tumor is critical for therapy. We demonstrate in this study that activated T cells respond to the chemokine CCL3, both in vitro and in vivo, and we further demonstrate that expression of CCL3 within tumors increases the effector T cell infiltrate in those tumors. Importantly, we show that adenoviral gene transfer to cause expression of CCL3 within B16ova tumors in vivo increases the efficacy of adoptive transfer of tumor-specific effector OT1 T cells. We additionally demonstrate that such therapies result in endogenous immune responses to tumor Ags that are capable of protecting animals against subsequent tumor challenge. Strategies that modify the “visibility” of tumors have the potential to significantly enhance the efficacy of both vaccine and adoptive transfer therapies currently in development.

c r t e r A otherwise healthy woman presented with a 3-day history of explosive diarrhea, abdominal cramping, and right red blood per rectum. Rectal examination was notable only or trace bright red blood on the examining glove. Initial laboraory findings included hemoglobin of 10.0 g/dL and a total white lood cell count of 11.4 109/L. Stool studies were negative for Clostridium difficile and enteric pathogens. She underwent further evaluation with colonoscopy (Figure A), which revealed scattered ulcers ranging in size from 5 mm to 2 cm. In total, there were more than 20 ulcers scattered throughout the colon, except for cecal sparing. Ulcer borders were erythematous and edematous with white exudative bases, but without signs of active bleeding. The intervening mucosa between ulceration was normal. Cytomegalovirus immunostain was negative. Biopsies of the lesions showed foci of ulceration and hemorrhage within the lamina propria and scattered foci of cryptitis and crypt abscesses. Three days into her hospital course she developed new hypoxia and had apparently aspirated. A chest x-ray showed extensive infiltrates and consolidation in the left upper lobe, which was new compared with a film taken 10 days prior. She was treated for aspiration pneumonia. She was discharged to home with oxygen and instructions to complete a 10-day course of oral levofloxacin. She was readmitted 6 days later with worsened shortness of breath, intermittent hemoptysis, and acute renal failure (creatinine, 2.0 mg/dL). Unenhanced computed tomography of the chest showed extensive bilateral infiltrates in the upper lobes consistent with diffuse alveolar hemorrhage (Figure B). The patient was found to have a C-reactive protein of 253.9 mg/L and was positive for cytoplasmic anti-neutrophilic cytoplasmic antibody and equivocal for PR3. A renal biopsy demonstrated pauciimmune necrotizing and crescentic glomerulonephritis. A diagnosis of Wegener’s granulomatosis (WG) was made. Our patient underwent treatment with cyclophosphamide and systemic steroids as well as plasma exchange for 14 days. Her respiratory status and renal function improved dramatically. She had no recurrence of gastrointestinal bleeding and was eventually discharged to home. Discrete colonic ulcerations can be seen in Crohn’s disease, nonsteroidal anti-inflammatory drug ingestion, ischemia, or infectious processes (eg, amebiasis, Campylobacter or Yersinia infection.). However, in the context of new pulmonary infiltrates and renal failure, gastrointestinal involvement by vasculitis should be considered. WG, a disseminated, small-vessel necrotizing vasculitis, typically affects the kidneys and respiratory tract. In this rare case, WG initially presented with colonic ulcerations. Colonic ulcerations, typically presenting with lower gastrointestinal bleeding and diarrhea, are unusual manifestations of systemic vasculitides, but they have been described in WG.1,2 At olonoscopy, multiple ulcerations with sharp borders, no surounding inflammation, and in a nonspecific anatomic distribuion are seen.1 Characteristic histologic changes include the presnce of granulomas and vasculitis; however, these are rarely eported in mucosal biopsy material.3 In this case, biopsies of the colonic mucosa were largely nonspecific. This case illustrates that the differential for colonic ulcerations in patients with multisystemic disease should include vasculitis, specifically WG.

In order to generate antitumor immunity through direct in situ modification of an established primary tumor, it will be necessary to recruit antigen presenting cells to the tumor site, release tumor antigens in an immunostimulatory, rather than tolerogenic form, and then promote the trafficking of effector T cells back to the tumor site. To model the coordinated steps of immune cell recruitment, loading/activation and trafficking, we generated stable cell lines and recombinant adenoviral vectors expressing the chemokines CCL3, CCL20 and CCL21. By in vitro chemotactic assays, CCL21 was the most potent chemoattractant for naive and activated OT-1 T cells, as well as for mature dendritic cells; in contrast, CCL3 was more effective for the migration of macrophages and immature dendritic cells. To investigate the relevance of these findings in vivo, we studied the capacity of the chemokines to (i) recruit immune cells to a tumor site in vivo, and (ii) to enhance the efficacy of adoptively transferred OT-1 T cells as a tumor therapy. Our data show that intratumoral injections of recombinant adenoviral vectors expressing the chemokines CCL3 and CCL20, lead to transient recruitment of a variety of immune cell populations including immature dendritic cells. However, this combination of chemokine-mediated recruitment plus the intrinsic immunogenicity of the adenoviral vector was insufficient to clear established tumors or generate appreciable evidence of anti tumor immunization. However, in a metastatic model of melanoma, stable expression of CCL21 significantly prolonged survival of mice seeded with B16ova-CCL-21 expressing tumors compared to those seeded with B16ova tumors. The combination of CCL21 expression, along with adoptive transfer of a suboptimal dose of activated OT-1 T cells, led to greater survival advantages compared to treatment of B16ova tumors with OT-1 alone, or expression of CCL-21 alone in B16ova. Therefore, although the transient recruitment of antigen presenting cells to a tumor is itself insufficient to induce an effective anti-tumor response in the absence of additional signals such as tumor cell killing, intratumoral expression of chemokines can be effective in the context of recruiting endogenously activated, or adoptively transferred, T cells to tumors. We are now studying the effects of further combinations of immune cell recruitment, along with additional signals such as T cell activating signals, to improve the therapy of local tumors and the concomitant priming of anti tumor immunity through intratumoral immunotherapy.

Top of pageAbstract Many cancer gene therapy strategies rely upon the ability to deliver genes to tumors in vivo leading to the direct killing of tumor cells. We have shown previously, using the B16/HSVtk melanoma model, that in situ tumor cell death can be immunogenic due to recruitment, loading and activation of antigen presenting cells with released tumor antigens. We have now focused upon combining gene therapy with other therapeutic modalities to increase the efficacy of either alone in an attempt to compensate for the poor efficiency of gene delivery. Therefore, we have studied the effects of killing tumors with the HSVtk system to generate an inflammatory environment in vivo to enhance the recruitment of adoptively transferred T cells to the tumor site. B16 melanoma cells expressing the model antigen chicken ovalbumin were engineered to stably express HSVtk by retrovirus infection. In vivo GCV treatment of mice bearing B16ovaHSVtk tumors resulted in intratumoral expression of IL-12, IFN-|[gamma]| and TNF|[alpha]|, amongst other cytokines. Tumors treated with GCV accumulated increased percentages of NK1.1+ and Ly6G+ cells over PBS control. Suboptimal numbers of adoptively transferred ova-specific activated CD8+ T cells, along with GCV therapy, in tumor bearing mice resulted in complete tumor regressions in a dose dependent manner, where neither of the therapies alone was curative. NK cells were necessary for the efficacy of the therapy since NK cell depleted mice did not benefit from GCV treatment plus adoptive transfer. Interestingly, in vitro treatment of B16ovaHSVtk cells with TNF|[alpha]| and IFN-|[gamma]| enhanced GCV mediated cell killing, suggesting that the cytokines induced intratumorally upon in vivo GCV treatment of B16ovaHSVtk tumors play a significant role in tumor regression. These studies indicate that the local inflammatory reaction induced by achieving only limited tumor cell killing by HSVtk gene transfer can be exploited therapeutically by the combination with adoptive transfer of antigen specific T cells. The efficacy of this therapy relies on the dose and timing of the adoptive transfer as well as on host NK cells, and, probably, intratumoral cytokines. These results emphasize the importance of the immune mediated bystander effects of HSVtk-mediated tumor cell killing for the success of suicide gene therapy in vivo, and indicate that adoptive transfer of antigen specific activated T cells, in combination with HSVtk/GCV gene therapy, offers a novel combination approach for cancer therapy.