Immune Suppressive Medications Research Articles

Computational Analysis of Boerhavia diffusa Plant Extracts Targeting Alpha actinin4 against Focal Segmental Glomerulosclerosis

The most common protein lost in urine (proteinuria) is albumin, which is a symptom of the kidney illness focal segmental glomerulosclerosis (FSGS). It causes damage to podocyte foot processes, resulting in effacement of foot processes, and injury to foot processes leads to the leaking of plasma proteins into the urine, resulting in nephrotic syndrome. Alpha actinin (ACTN4) is extensively produced in glomerular podocytes, has a function in non-muscle cytoskeletal activity, and is enhanced early in the course of nephrotic illness in various types. Mutations in ACTN4 induce autosomal and sporadic steroid-resistance nephritic syndrome, which causes disturbance in podocyte foot process and function. All of the FSGS-causing mutations are situated on actin actin-binding domain of the ACTN4 protein. FSGS is typically treated by decreasing dietary salt and using immune-suppressing medications such as glucocorticoids. There is a risk associated with these drugs for cancer patients. Several studies have found that up to 80% of individuals with primary FSGS are resistant to steroid therapy, even though all other therapeutic options have been exhausted. Patients with steroid-resistant FSGS have a higher incidence of end-stage renal failure. Therefore, several new treatment strategies were put forward to cure the disease form of which use of phytochemicals is one such sustainable modality. In addition to this, our study intended to predict the stability of mutant protein’s structure as compared to wild type structure through molecular dynamic simulation analysis. With this, we extend our study to predict the potency of phytochemicals of Boerhaviadiffusa against FSGS by using molecular docking analysis. From our study, we conclude that the actin-binding domain of ACTN4 protein becomes more unstable or loses its stability after the mutation at position W59R among all the studied mutation positions. The boeravinone F phytochemical of the Boerhaviadiffusa plant shows the best inhibitory effect on the mutant actin-binding domain of ACTN4 protein and it confirms a stable binding confirmation at minimum energy of -7.5 kcal/mol. Hence it may be taken into consideration for future research work.

Peri-Operative Optimization of Patients with Crohn's Disease.

The management of patients with Crohn's disease (CD) undergoing surgery is complex and optimization of modifiable factors perioperatively can improve outcomes. This review focuses on the perioperative management of CD patients undergoing surgery, emphasizing the need for a multi-disciplinary approach. Research highlights the benefits of a comprehensive strategy, involving nutritional optimization, psychological assessment, and addressing septic complications before surgery. Despite many CD patients being on immune-suppressing medications, studies indicate that most of these medications are safe to use and should not delay surgery. However, a personalized approach for each case is needed. This review underscores the importance of multi-disciplinary team led peri-operative management of CD patients. We suggest that this can be done at a dedicated perioperative clinic for prehabilitation, with the potential to enhance outcomes for CD patients undergoing surgery.

Utility of green chemistry for sustainable fluorescence derivatization approach for quantification of fingolimod as antineoplastic drug in pharmaceutical formulation and spiked human plasma

Fingolimod is the immune-suppressive medication, that largely used for multiple sclerosis treatment, thought to be the most prevalent inflammatory condition affecting the central nervous system (CNS). Here in, a second spectrofluorimetric method was advanced for quantifying of fingolimod in pharmaceutical formulation and spiked human plasma. That method depends on fluorescence derivatization of fingolimod with 4‑chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) at 75°C in a (pH 9) of borate buffer to produce a fluorescent derivative which can be detected at 540 nm afterwards excitation at 475 nm. The method has been validated using international conference of harmonization (ICH criteria), and it demonstrated linearity in a range of 1–100 ngmL−1. The proposed method was applied precisely and accurately for quantifying fingolimod within pharmaceutical formulation and spiking human plasma without any interferences. The proposed method was more sensitive, about six folds of intensity of the reported spectrofluorometric method and greenness comparison was done only on the proposed method . Moreover, the method's sustainability was evaluated and compared to the published method using two greenness assessment tools termed analytical eco-scale and Analytical GREENness (AGREE). That findings suggest that the method is more sustainable than the published method.

Liver abnormalities are frequent and persistent in patients with Fanconi anemia

AbstractLiver disease has not been well described in patients with Fanconi anemia (FA). Improvements in outcomes of transplant mean that more individuals with FA are reaching adulthood and new features of the FA phenotype are being discovered. We performed a retrospective review of liver function in a cohort of 97 patients with FA followed-up for at least 10 years at a single center. We identified a high frequency of transaminitis (n = 31, 32%) without elevation of bilirubin and with no evidence of structural hepatic abnormality in patients with FA. Transaminitis was persistent in many cases, sometimes lasting more than a decade without clinical manifestation, although 2 patients with prolonged transaminitis are deceased from liver failure, indicating important long-term clinical consequences. Transaminitis was found in patients who had and had not received transplant but was more frequent in recipients of transplant. Exposure to total body irradiation increased risk (odds ratio, 15.5 [95% confidence interval, 2.44-304.54]; P = .01), whereas treatment with androgens did not. Review of limited numbers of liver biopsies and autopsy material showed a cholestatic pattern of liver injury, with progressive fibrosis, in the majority of patients. Occurrence in cases without transplant as well as cases with transplant argues against a potential diagnosis of atypical liver graft-versus-host disease. Limited data regarding therapy suggest no benefit from treatment with steroids or other immune suppressive medications or ursodeoxycholic acid. Our data show that liver disease is common in patients with FA, and because most children with FA now reach adulthood, end-stage liver disease in young adulthood means systematic testing of potential therapies is urgently needed.

Abstract B017: Adverse events following immune checkpoint inhibitors by pre-existing comorbidities and polypharmacy among patients with lung cancer: A population-based study

Abstract Introduction: Pre-existing comorbidities and polypharmacy (PP) are significant issues among older lung cancer patients leading to complex treatment decisions. Immune check inhibitors (ICIs) have significantly improved lung cancer outcomes; however, most patients with comorbidities are excluded from ICI trials. Moreover, medication management in older adults with cancer is complex due to the volume of medications used and existing comorbidities requiring a high degree of coordination among multiple specialists. This study aims to understand the impact of pre-existing comorbidities and PP among older lung cancer patients using ICI. Methods: We used Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked data to identify patients aged ≥66 diagnosed with lung cancer (1999-2017) having continuous Medicare coverage for up to 2 years or until death. Immune-related adverse events (irAEs) grade 3/4 were defined as immune-suppressive medication claims during inpatient hospitalization 2 years after ICI, excluding the 14 days before the hospitalization. Comorbidities were calculated using a modified Charlson comorbidity index (CCI) and stratified into 3 groups: 0, 1, and more than 2 conditions. PP was stratified into 3 groups: No PP (<5 medications), PP (5-9 medications), and excessive PP (>10 medications). Incidence rates (IRs) and adjusted IR ratios (IRRs) were determined using negative binomial regression. The IRR model was adjusted for age, race, marital status, SEER region, state buy-in, education, and income. Results: We identified 2,461 lung cancer patients treated with ICIs. The IR for grade 3/4 irAEs was 27.59 per 100 person-years (PY) for CCI³2, 20.25 per 100 PY among 1 CCI, and 14.99 per 100 PY among no CCI. Overall IR of grade 3/4 irAEs was 29.29 per 100 PY among patients with excessive PP vs. 19.25 per 100 PY among PP and 13.99 per 100 PY among no PP. Patients with CCI more than 2 are 1.53 times more likely to develop a grade 3/4 irAE than those without CCI (IRR: 1.53; 95% CI: 1.09-2.14). Patients with excessive PP were 1.92 times more likely to develop a grade 3/4 irAE than those using <5 medications (IRR: 1.92; 95% CI: 1.31-2.83). Conclusion: Older adults with lung cancer usually have pre-existing comorbidities and, on average, use at least 11 concurrent medications. Multi-morbidity and polypharmacy are associated with a higher rate of irAEs among these patients; therefore, it’s critical to pay close attention to this population while on ICIs. Further studies are warranted to confirm these findings. Citation Format: Nikita Nikita, Swapnil Sharma, Amy Shaver, Krupa Gandhi, Scott Keith, Christopher Yang, Sarah Gordon, Grace Lu-Yao. Adverse events following immune checkpoint inhibitors by pre-existing comorbidities and polypharmacy among patients with lung cancer: A population-based study [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B017.

1937. Use of Paxlovid for Treatment of Acute COVID-19 and Occurrence of Post-COVID Conditions among Children and Adults at High-Risk for Severe COVID-19, April 1 - December 31, 2022

Abstract Background Data have suggested that treatment with Paxlovid for acute COVID-19 decreases the incidence of Post-COVID Conditions (PCC); however, results are limited to specific age groups and populations. This analysis assessed the occurrence of PCC following receipt of Paxlovid among children and adults at risk for severe COVID-19. Methods Patients aged ≥ 12 years with COVID-19 (defined by ICD-10 code, positive SARS-CoV-2 test, or Paxlovid prescription) and at increased risk for severe COVID-19 due to age, underlying conditions, or immune-suppressing medications, were identified in HealthVerity claims data. Eligible persons had an outpatient, telehealth, or emergency department encounter for COVID-19 between April 1 – August 31, 2022. Exclusions included liver disease, end-stage renal disease, a prescription for contraindicated medications, pregnancy in the previous year, or death within 60 days. Case patients received a Paxlovid prescription within ±5 days of the index date; control patients matched on age, sex, month, and region did not receive Paxlovid within ±5 days. Cases and controls were matched 1:2. Analysis was conducted separately for 3 age groups: 12-17 years, 18-49 years, and ≥50 years. PCC was defined as new conditions > 60 days after index date and prior to December 31, 2022. We calculated the relative risk (RR) of two overall PCC indicators (≥ 1 or ≥ 2 conditions) and 45 individual conditions. Results Among adults aged ≥ 50 years, the risks of overall and individual PCCs were generally lower among case- than control patients (RR for ≥1 condition=0.92, 95% CI=0.91-0.93; Figure 1). There was no overall difference in risk among adults 18-49; the RR of individual conditions varied (Figure 2). Among adolescents, the risks of overall and individual PCCs were higher among case than control patients (RR for ≥1 condition=1.07, 95% CI=1.02-1.12; Figure 3).Figure 1.Relative Risk of Post-COVID Conditions among Patients who Received Paxlovid, Ages ≥50 (N=564,303)Figure 2.Relative Risk of Post-COVID Conditions among Patients who Received Paxlovid, Ages 18-49 (N=292,818)Figure 3.Relative Risk of Post-COVID Conditions among Patients who Received Paxlovid, Ages 12-17 (N=17,178) Conclusion The results suggest that Paxlovid helps reduce occurrence of PCC in adults aged ≥ 50 years. Among younger adults and adolescents, associations were observed for only certain conditions. This may be due to a difference in baseline health in these age groups. Further investigation may help clarify whether Paxlovid provides benefits in reducing PCC in addition to severity of acute COVID-19. Disclosures Priti Patel, MD, MPH, Pfizer: Stocks/Bonds

Association of Inflammatory Cytokine Levels with Extra Glandular Manifestations, Fatigue, and Disease Activity in Primary Sjögren's Syndrome in Saudi Patients: A Cross-Sectional Study.

Primary Sjögren's syndrome (pSS) is an autoimmune disease that can cause fatigue and extraglandular manifestations (EGMs). pSS is associated with cytokine network dysregulation, which may be related to the immune-mediated destruction of exocrine glands. We determined cytokine levels and their relationship to EGMs, the European League Against Rheumatism (EULAR) Sjögren's syndrome disease activity index (ESSDAI), and fatigue in Saudi patients with pSS. This study was a cross-sectional, single-center study. We included forty-one patients and 71 controls. Serum samples were collected from random healthy people and pSS patients who were followed in the rheumatology and pulmonary clinics of King Saud University Medical City in Riyadh, Saudi Arabia. Levels of the frequently studied cytokines were measured using Luminex xMAP technology. Each ESSDAI score and EGM were recorded, and the Arabic version of the fatigue severity scale (FSS) was applied to assess fatigue. The main outcome measures were cytokine levels in pSS Saudi patients using/not using immune-suppressive medications (ISMs). Thirty-six (87.8%) patients had one or more EGMs, and the mean ESSDAI score was 9.95 ± 7.73. There was a significant decrease in TNFα and IL-21 levels in the pSS group compared to those in the control group (p = 0.034 and p < 0.001, respectively), whereas IL-12 levels were significantly elevated in the pSS group (p = 0.002). Cytokine levels in patients who used ISMs were the same as those in patients who did not use medications. Decreased IL-1β (p = 0.014), IL-2 (p = 0.035), IL-6 (p = 0.014), and IL-35 (p = 0.010) levels were observed in patients who had EGMs. Patients who had low disease activity exhibited low IL-10 (p = 0.018) and high IFN-α (p = 0.049), IFN-β (p = 0.049), IL-1β (p = 0.006), and IL-35 (p = 0.032) levels compared to patients with high disease activity. A negative association between a positive fatigue score and IL-1β (p = 0.010), IL-2 (p = 0.037), IFN-α (p = 0.025), TNFα (p = 0.030), IL-17 (p = 0.029), IL-12 (p = 0.046), and IL-21 (p = 0.005) levels was found. Cytokine profiles correlate with EGMs, ESSDAI, and fatigue. Patients with controlled disease activity have a normal cytokine profile that is similar to that of controls.

Paediatric-onset Evans syndrome: Breaking away from refractory immune thrombocytopenia.

Since its first description by Evans in 1951, this syndrome has been linked to chronic immune thrombocytopenia with the concurrent or delayed onset of autoimmune haemolytic anaemia or neutropenia. For decades, the evolution of Evans syndrome (ES) has carried a poor prognosis and often resulted in chronic steroid exposure, multiple immune suppressing medications directed against T or B lymphocytes, and splenectomy. This paper presents a new view of ES based on recent advances in genomics which begin to classify patients based on their underlying molecular variants in previously described primary immune disorders. This has opened up new avenues of targeted therapy or bone marrow transplant at rather than broad long-term immune suppression or splenectomy. Importantly, recent studies of the full lifespan of ES suggest that at least 80% of those paediatric patients will progress to various clinical or biological immunopathological manifestations with age despite the resolution of their cytopenias. Those patients merit long-term follow-up and monitoring in dedicated transition programs to improve outcome at the adult age.

Rheumatoid arthritis and older age are associated with lower humoral and cellular immune response to primary series COVID-19 mRNA vaccine

ObjectivePeople with autoimmune disease have worse COVID-19 infection-related outcomes, lower antibody responses to COVID-19 vaccine, and higher rates of breakthrough infection. Immunosuppressive medications used to treat rheumatoid arthritis (RA) are associated with lower COVID-19 vaccine responses, though independent contributions of comorbidities, T-cell immunity, and age are less clear. We sought to test the hypothesis that RA, immunosuppressive medications used to treat RA, and older age, contribute to reduced B and T cell response to COVID-19 vaccine. MethodsWe evaluated serum samples, taken the day of 1st vaccine dose, the day of 2nd dose, 2–6 weeks after 2nd dose, 7–12 weeks after 2nd dose, 13–24 weeks after 2nd dose, and 2–6 weeks after the 3rd dose, for anti-spike IgG and neutralizing antibody levels to Wuhan and Omicron BA.1 and peripheral blood mononuclear cells (PBMC) for spike-specific IFN-γ and IL-2 production by ELISPOT assay in 46 RA and 101 non-autoimmune control participants before and after the primary series COVID-19 mRNA vaccination. ResultsRA participants had lower spike-specific IgG and Wuhan-strain neutralizing antibody levels 2–6 weeks compared to controls after the second dose of primary vaccine series. Neutralizing antibody levels against Omicron BA.1 were low in both groups. IFN-γ production correlated with Wuhan neutralizing antibody levels, while older age negatively correlated with spike-specific IL-2, IFN-γ and IgG. Lower antibody levels were associated with older age, RA status, and medication usage, while lower T cell responses were associated primarily with older age. ConclusionsThese data indicate lower COVID-19 mRNA vaccine-induced antibody levels in persons with RA compared to individuals without RA, likely partially attributable to immune suppressive medications. At the same time, older age is associated with lower antibody and cellular immune response to COVID-19 vaccines.

Lowering maintenance immune suppression in elderly kidney transplant recipients; connecting the immunological and clinical dots.

The management of long-term immune suppressive medication in kidney transplant recipients is a poorly explored field in the area of transplant medicine. In particular, older recipients are at an increased risk for side effects and have an exponentially increased risk of infection-related death. In contrast, an aged immune system decreases the risk of acute T-cell-mediated rejection in older recipients. Recent advances in alloimmunity research have shown a rapid and substantial decline in polyfunctional, high-risk CD4+ T cells post-transplantation. This lowers the direct alloreactivity responsible for T-cell-mediated rejection, also known as donor-specific hyporesponsiveness. Chronic antibody-mediated rejection (c-aABMR) is the most frequent cause of kidney graft loss in the long term. However, in older adults, c-aABMR as a cause of graft loss is outnumbered by death with a functioning graft. In addition, DSA development and a diagnosis of c-aABMR plateau ~10 years after transplantation, resulting in a very low risk for rejection thereafter. The intensity of immune suppression regimes could likely be reduced accordingly, but trials in this area are scarce. Tacrolimus monotherapy for 1 year after transplantation seems feasible in older kidney transplant recipients with standard immunological risk, showing the expected benefits of fewer infections and better vaccination responses.

Attitudes and beliefs towards COVID-19 and COVID-19 vaccination among rheumatology patients in a Los Angeles County safety net clinic

BackgroundThe novel Coronavirus disease (COVID-19) pandemic has represented an evolving global threat with high morbidity and mortality. Patients with autoimmune rheumatic diseases and on immune-suppressing medications may be at increased risk to more severe disease, hospitalization, and death. Vaccines are essential to combat the COVID-19 pandemic and curb the spread of infection. Rheumatology patients may be more fearful to receive the vaccine compared to the general population. The Los Angeles County rheumatology patients are primarily Hispanic and represent a unique and possibly particularly vulnerable cohort warranting further exploration into barriers to receive the COVID-19 vaccine. We aimed to explore the willingness of COVID-19 vaccine acceptance among patients with rheumatic disease.MethodsWe conducted a cross-sectional survey to assess the perceptions and barriers to COVID-19 vaccine acceptance in our Los Angeles County rheumatology clinics between July 2021 to September 2021 and received responses from 116 patients.ResultsThe majority of respondents were female (83.9%), 41–60 years of age (59.8%), Hispanic (89.2%), with high school or lower level of education (68.7%), and had Rheumatoid Arthritis (56.9%). We found most (88.4%) patients received at least one dose of the COVID-19 vaccine. We identified no differences in vaccine acceptance related to age, education, race, and ethnicity. Most respondents agreed that their health condition puts them at high risk of COVID-19 complications. In addition, individuals reported that they valued being engaged by their rheumatologists in discussions of the risk and benefits of the vaccine prior to receiving it.ConclusionWe found that the majority of patients were already vaccinated or willing to be vaccinated, at higher levels than general United States population and that a conversation initiated by a rheumatologist can have positive effect on patients’ health behaviors related to COVID-19.

Undifferentiated Connective Tissue Disease: Comprehensive Review.

Undifferentiated connective tissue disease (UCTD) is characterized by the presence of clinical symptoms of a systemic autoimmune disease in addition to laboratory evidence of autoimmunity with the patients not fulfilling any of the widely used classification criteria for classic autoimmune diseases. The presence of UCTD as a separate entity versus an early stage of such diseases as systemic lupus erythematosus (SLE) or scleroderma has long been debated. Given the uncertainty regarding this condition, we performed a systematic review on the topic. UCTD can be subcategorized as evolving (eUCTD) or stable UCTD (sUCTD) based on its evolution towards a definable autoimmune syndrome. Analyzing the data from six UCTD cohorts published in the literature, we found that 28% of patients have an evolving course with the majority developing SLE or rheumatoid arthritis within 5-6years of the UCTD diagnosis. From the remaining patients, 18% do achieve remission. Published treatment regimens were similar to other mild autoimmune diseases with low-dose prednisone, hydroxychloroquine, and NSAID. One-third of patients did need immune suppressive medications. Importantly, the reported outcomes were excellent with survival rates of more than 90% over 10years. It has to be noted though that as data on patient related outcomes are not available to date, the exact impact of this condition on quality of life is unclear. UCTD is a mild autoimmune condition with generally good outcomes. There is still great uncertainty though regarding diagnosis and management. Going forward, consistent classification criteria are needed to advance UCTD research and eventually provide authoritative guidance on the management of the condition.

OA03 Impact of the COVID-19 pandemic on rheumatology training: results of the regional survey from the North West of England

Abstract Background/Aims The COVID-19 pandemic has disrupted healthcare delivery and provision of medical education and training worldwide. We assessed the impact of the COVID-19 pandemic on rheumatology training experience in the Northwest and Merseyside deaneries of England. Methods Rheumatology trainees from the Northwest and Merseyside deaneries were issued links to an anonymous web-based survey on their training experience between August 2020 to April 2021, during the 2nd wave of the Covid-19 pandemic. Results 34 of 42 trainees completed the survey. 31 were in clinical training: 13 (42%) in a pure rheumatology post and 18 (58%) in a dual post with general medicine. Most trainees attended 3-4 clinics per week (58%), with 23% attending ≤2 clinics and 19% attending 5 clinics. The proportion of face-to-face clinics ranged from 20% to 100% (median 60%). The reduced face-to-face clinical experience was not due to trainees’ needs to shield. The range of proportion of phone consultations was 0% to 80% (median 40%). Remote consultations were conducted by telephone only for 26 (84%) trainees and by video or phone for 3 (10%). The durations for both face-to-face and virtual consultations were ranged similarly at 15 to 45 minutes (median 30minutes) for new cases and 15 to 30 minutes (median 20 minutes) for follow-ups. Only 5 (16%) trainees felt confident with assessing new patients by remote consultation. 8 (26%) trainees had some form of formal training in a virtual consultation. However, only 4 (13%) reported being “aware” of how to guide a patient through self-examination of the joints, 17 (55%) trainees were “somewhat aware”, and 10 (32%) were “not aware”. 20 (65%) trainees reported reliance on radiological and serological investigations rather than clinical skills during remote consultations. Development of skills for patient communication, joint injections, time management, and prescribing immune-suppressive medications were mainly hampered. The majority of trainees agreed that virtual educational programs had improved opportunities for attendance at structured deanery teaching sessions. Conclusion The impact of the COVID-19 pandemic on rheumatology training has been significant both in terms of current rheumatology education programme delivery and training requirements. Our regional survey shows less than a third of trainees had formal training in conducting remote consultations resulting in low levels of confidence in assessing patients remotely. Less face-to-face patient contact negatively impacted clinical and procedural skills development. Restructuring the rheumatology curricula to include training in rheumatology-specific remote consultations and ensuring clinical and procedural competencies by including novel support modalities like simulation sessions may be options for consideration going forwards. Delivery of some structured teaching sessions through the virtual platform is here to stay. Disclosure E.P. Chua: None. Y. Tan: None. L.K. Mercer: None. S. Wig: None.

Therapeutic Hyperthermia Is Associated With Improved Survival in Afebrile Critically Ill Patients With Sepsis: A Pilot Randomized Trial.

To test the hypothesis that forced-air warming of critically ill afebrile sepsis patients improves immune function compared to standard temperature management. Single-center, prospective, open-label, randomized controlled trial. One thousand two hundred-bed academic medical center. Eligible patients were mechanically ventilated septic adults with: 1) a diagnosis of sepsis within 48 hours of enrollment; 2) anticipated need for mechanical ventilation of greater than 48 hours; and 3) a maximum temperature less than 38.3°C within the 24 hours prior to enrollment. Primary exclusion criteria included: immunologic diseases, immune-suppressing medications, and any existing condition sensitive to therapeutic hyperthermia (e.g., brain injury). The primary outcome was monocyte human leukocyte antigen (HLA)-DR expression, with secondary outcomes of CD3/CD28-induced interferon gamma (IFN-γ) production, mortality, and 28-day hospital-free days. External warming using a forced-air warming blanket for 48 hours, with a goal temperature 1.5°C above the lowest temperature documented in the previous 24 hours. We enrolled 56 participants in the study. No differences were observed between the groups in HLA-DR expression (692 vs 2,002; p = 0.396) or IFN-γ production (31 vs 69; p = 0.678). Participants allocated to external warming had lower 28-day mortality (18% vs 43%; absolute risk reduction, 25%; 95% CI, 2-48%) and more 28-day hospital-free days (difference, 2.6 d; 95% CI, 0-11.6). Participants randomized to external forced-air warming did not have a difference in HLA-DR expression or IFN-γ production. In this pilot study, however, 28-day mortality was lower in the intervention group. Future research should seek to better elucidate the impact of temperature modulation on immune and nonimmune organ failure pathways in sepsis.

COVID-19 in Recent Lung Transplant Recipients: Clinical Outcomes and Management Strategies

BackgroundCOVID-19 causes a wide range of symptoms, with particularly high risk of severe respiratory failure and death in patients with predisposing risk factors such as advanced age or obesity. Recipients of solid organ transplants, and in particular lung transplantation, are more susceptible to viral infection owing to immune suppressive medication. As little is known about the SARS-CoV-2 infection in these patients, this study was undertaken to describe outcomes and potential management strategies in early COVID-19 infection early after lung transplantation.MethodsWe describe the incidence and outcome of COVID-19 in a cohort of recent lung transplant recipients in Munich. Six of 186 patients who underwent lung transplantation in the period between March 2019 and March 2021 developed COVID-19 within the first year after transplantation. We documented the clinical course and laboratory changes for all patients showing differences in the severity of the infection with COVID-19 and their outcomes.ResultsThree of 6 SARS-CoV-2 infections were hospital-acquired and the patients were still in inpatient treatment after lung transplantation. All patients suffered from symptoms. One patient did not receive antiviral therapy. Remdesivir was prescribed in 4 patients and the remaining patient received remdesivir, bamlanivimab and convalescent plasma.ConclusionsCOVID-19 does not appear to cause milder disease in lung transplant recipients compared with the general population. Immunosuppression is potentially responsible for the delayed formation of antibodies and their premature loss. Several comorbidities and a general poor preoperative condition showed an extended hospital stay.

Inflammatory Bowel Disease Risk Variants Are Associated with an Increased Risk of Skin Cancer.

Inflammatory bowel disease is associated with an increased risk of skin cancer. The aims of this study were to determine whether IBD susceptibility variants are also associated with skin cancer susceptibility and if such risk is augmented by use of immune-suppressive therapy. The discovery cohort included participants in the UK Biobank. The validation cohort included participants in the Michigan Genomics Initiative. The primary outcome of interest was skin cancer, subgrouped into nonmelanoma skin cancers (NMSC) and melanoma skin cancers (MSC). Multivariable logistic regression with matched controls (3 controls:1 case) was performed to identify genomic predictors of skin malignancy in the discovery cohort. Variants with P <.05 were tested for replication in the validation cohort. Validated Single nucleotide polymorphisms were then evaluated for effect modification by immune-suppressive medications. The discovery cohort included 10,247 cases of NMSC and 1883 cases of MSC. The validation cohort included 7334 cases of NMSC and 3304 cases of MSC. Twenty-nine variants were associated with risk of NMSC in the discovery cohort, of which 5 replicated in the validation cohort (increased risk, rs7773324-A [DUSP22; IRF4], rs2476601-G [PTPN22], rs1847472-C [BACH2], rs72810983-A [CPEB4]; decreased risk, rs6088765-G [PROCR; MMP24]). Twelve variants were associated with risk of MSC in the discovery cohort, of which 4 were replicated in the validation cohort (increased risk, rs61839660-T [IL2RA]; decreased risk, rs17391694-C [GIPC2; MGC27382], rs6088765-G [PROCR; MMP24], and rs1728785-C [ZFP90]). No effect modification was observed. The results of this study highlight shared genetic susceptibility across IBD and skin cancer, with increased risk of NMSC in those who carry risk variants in IRF4, PTPN22, CPEB4, and BACH2 and increased risk of MSC in those who carry a risk variant in IL2RA.

Immunogenicity of SARS-CoV-2 vaccination in rituximab-treated patients: Effect of timing and immunologic parameters

Rituximab (RTX), an important therapeutic option for patients with rheumatic diseases, has been shown to reduce immune responses to various vaccines. We asked whether following SARS-CoV-2 vaccination, response rates in RTX treated patients are reduced and whether specific patient characteristics influence the responses. We recruited patients on chronic RTX therapy undergoing anti-SARS-CoV2 vaccination and measured the post-vaccination anti-spike IgG antibody levels. The median time from pre-vaccination RTX infusion to vaccination and from vaccination to the post-vaccination RTX infusion was 20.5 weeks and 7.2 weeks respectively. Only 36.5% of patients developed measurable titers of IgG anti-SARS-CoV-2 spike antibody after vaccination. Hypogammaglobulinemia (IgG and/or IgM) but not timing of vaccination, B cell numbers, or concomitant immune suppressive medications, correlated with sero-negativity (p = 0.004). Our results underscore the fact that even after B cell reconstitution, RTX induced chronic hypogammaglobulinemia significantly impairs the ability of the immune system to respond to SARS-CoV-2 vaccination.

The association of chronic, enhanced immunosuppression with outcomes of diabetic foot infections.

We investigated if a chronic, enhanced immunosuppressed condition, beyond the immunodeficiency related to diabetes, is associated with clinical failures after combined surgical and medical treatment for diabetic foot infection (DFI). This is a case‐control cohort study in a tertiary centre for diabetic foot problems, using case‐mix adjustments with multivariate Cox regression models. Among 1013 DFI episodes in 586 patients (median age 67 years; 882 with osteomyelitis), we identified a chronic, enhanced immune‐suppression condition in 388 (38%) cases: dialysis (85), solid organ transplantation (25), immune‐suppressive medication (70), cirrhosis (9), cancer chemotherapy (15) and alcohol abuse (243). Overall, 255 treatment episodes failed (25%). By multivariate analysis, the presence (as compared with absence) of chronic, enhanced immune‐suppression was associated with a higher rate of clinical failures in DFI cases (hazard ratio 1.5, 95% confidence interval 1.1–2.0). We conclude that a chronic, enhanced immune‐suppressed state might be an independent risk factor for treatment failure in DFI. Validation of this hypothesis could be useful information for both affected patients and their treating clinicians.

S830 Real World Assessment of Factors Influencing Fecal Calprotectin Test Completion Rates

Introduction: Individuals on immunosuppression were excluded from COVID-19 vaccine clinical trials which led to their emergency use authorization (EUA). As a result, patients with inflammatory bowel disease (IBD) who are frequently treated with immune suppressing medications have questions about COVID-19 vaccine effectiveness. Data of vaccine effectiveness and immune response in the IBD population are urgently needed to guide vaccination strategies. This study aimed to assess serologic response after completion of COVID-19 vaccine series in a large IBD population across the US. Methods: Partnership to Report Effectiveness of Vaccination in populations Excluded from iNitial Trials of COVID (PREVENT-COVID) is a prospective observational cohort study of IBD patients who received any COVID-19 vaccine granted EUA in the US. Enrolled participants had the option to provide serum samples to evaluate antibody development 8 weeks following completion of COVID-19 vaccine series. Quantitative analysis of anti-receptor binding domain (RBD) IgG antibodies specific to SARS-CoV-2 was performed using the LabCorp Cov2Quant IgG assay. Qualitative assessment of nucleocapsid antibodies as an indicator of past infection was also completed. This analysis included participants who completed vaccination series and laboratory testing prior to 6/17/ 21. Individuals who reported prior COVID infection and/or had positive nucleocapsid antibody were excluded. Descriptive statistics were performed to characterize the study population and antibody response. Results: A total of 788 participants with IBD (mean age 48 yrs, 73% female) were included, and 752/ 788 [95.4%, 95% confidence interval (CI) 93.7-96.7%] had detectable anti-RBD antibodies. Additional demographic characteristics and distribution of antibody response across medication classes are shown in Table 1. Antibody response was generally similar across age group, vaccine type, and IBD medication class (Figure 1);however, individuals receiving corticosteroids (n=35) had reduced antibody response with 85.7% (95% CI 70.6-93.7) having detectable antibodies vs 95.9% (95% CI 94.2-97.1) in non-steroid users. Conclusion: A vast majority of our IBD cohort including those on immunosuppressive therapies demonstrated humoral immune response after completion of COVID-19 vaccine series. Longer term data are needed to assess durability of antibody response, but this emerging data provides reassurance that most IBD medications do not significantly diminish response to COVID-19 vaccination.

Clinical characteristics of non‐infectious inflammatory myopathy in the boxer dog

To evaluate the clinical characteristics, treatment, outcome and potential association between non-infectious inflammatory myopathy and malignancy in boxer dogs. Boxer dogs histologically diagnosed with non-infectious inflammatory myopathy at the Comparative Neuromuscular Laboratory, University of California San Diego from 2010 to 2018 and with complete medical records were included in this retrospective study. Signalment, history, clinical signs, clinicopathologic findings, treatment and outcome were documented. Twenty-eight boxer dogs with non-infectious inflammatory myopathy, aged 1 to 11 years, were included. Eighteen were male (16 neutered; two entire) and 10 were female (seven spayed; three entire). Clinical signs included generalised weakness (n=17), dysphagia (n=11) and weight loss (n=10). Serum creatine kinase activity was elevated in all 20 cases tested (range 908 to 138,000 IU/L). One dog had undifferentiated round cell neoplastic infiltration within the muscle at the time of inflammatory myopathy diagnosis. Five dogs historically had mast cell tumours and 21 dogs were not diagnosed with neoplasia prior, at the time of or after inflammatory myopathy diagnosis. Treatment included glucocorticoid monotherapy (n=12), cyclosporine monotherapy (n=1) or multiple immune-suppressive medications (n=14). Six dogs neurologically improved, 11 improved but relapsed while on treatment, seven did not improve. Eight dogs were euthanased, one died, four were lost to follow-up. Boxer dogs with non-infectious inflammatory myopathy can present for generalised weakness and dysphagia; long-term successful outcome is uncommon. The relationship between neoplasia and non-infectious inflammatory myopathy in boxer dogs remains unclear; future prospective studies evaluating a larger cohort are warranted.