Immunosuppressive Treatment Regimens Research Articles

#1365 Clinical efficacy of tonsillectomy combined with steroid pulse therapy in IgA nephropathy

Abstract Background and Aims IgA nephropathy is the most common primary glomerulonephritis in the Asia–Pacific region, including Japan, and often leads to dialysis initiation. The etiology of IgA nephropathy remains unclear; however, focal infections such as chronic tonsillitis are proposed. Although tonsillectomy should not be performed for Caucasian IgA nephropathy patients, some Japanese studies reported that the combination of steroid pulse therapy with tonsillectomy (TSP) was more effective than steroid pulse therapy alone for the remission of urinary findings. However, the immunosuppressive treatment regimens vary among studies, and treatment effect of combination therapy in preventing renal functional decline is unclear. This study aimed to compare the efficacy of steroid pulse therapy alone versus TSP in improving the remission rate of urinary findings and preventing renal functional decline. Method This retrospective observational study included 116 patients diagnosed with IgA nephropathy based on renal biopsy and treated between January 1, 2010 and December 31, 2020 in Gifu University Hospital. TSP group underwent tonsillectomy received 0.5 g/day of methylprednisolone intravenously for 3 consecutive days at 1-3 weeks. TSP and steroid pulse therapy alone group had 83 and 33 patients, respectively. Of these, 25 patients per group were matched using propensity score matching based on clinicopathologic factors including age, urinary protein level, estimated glomerular filtration rate (eGFR), and the risk classification for progression to end-stage renal disease. The remission rate of urinary findings and the change in eGFR one year after treatment initiation were compared between the two groups. Remission of urinary findings was defined as a urinary protein level of <150 mg/day and <5 erythrocytes/high-power field in the urine sediment. Results The TSP and steroid pulse therapy alone groups did not significantly differ in baseline characteristics including median age (interquartile range) (58 [47–63] and 56 [49–68] years, respectively), female sex (9 and 7, respectively), mean eGFR (60 ± 20 and 63 ± 21 mL/min/1.73 m2, respectively), median urinary protein level (764 [440–1,472] and 990 [425–1,872] mg/day, respectively) (p > 0.05 for all). The remission rate of urinary findings was significantly higher in the TSP group than in the steroid pulse therapy alone group (72% vs. 20%; p < 0.001, χ2 test). Albeit statistically nonsignificant, the decline in eGFR was smaller in the TSP group than that in the steroid pulse therapy alone group (−1.5 ± 8.1 vs −3.7 ± 10.5 mL/min/1.73 m2, p = 0.416; t test). No severe side effect was observed in both treatment groups. Conclusion The higher remission rate of urinary findings observed in the TSP group compared to the steroid pulse alone group suggested that the addition of tonsillectomy to steroid pulse therapy was a clinically effective treatment for IgA nephropathy. Albeit not significant, the TSP group tended to have a smaller decline in eGFR reduction at one-year follow-up, indicating the need for further studies with long-term observation.

The Effects of Chronic Immunosuppressive Treatment on Morphological Changes in Cardiac Tissue and the Balance between Matrix Metalloproteinases (MMP-2 and MMP-9) and Their Inhibitors in the Rat Heart.

Using different three-drug immunosuppressive treatment regimens in a rat model, we aimed to determine the effects of long-term therapy on metalloproteinase-2 and metalloproteinase-9 activity and the expression of their inhibitors, as well as to assess the morphology of the animals' cardiac tissue. Our results suggest that chronic use of immunosuppressive drugs disrupts the balance between the activity of MMPs and TIMPs. Depending on the type of drug regimen used, this leads to abnormalities in the cardiac structure, collagen fiber accumulation, or cardiomyocyte hypertrophy. The information obtained in the present study allows us to conclude that the chronic treatment of rats with the most common clinical immunosuppressive regimens may contribute to abnormalities in the myocardial structure and function. The results presented in this study may serve as a prelude to more in-depth analyses and additional research into the optimal selection of an immunosuppressive treatment with the lowest possible risk of cardiovascular complications for patients receiving organ transplants.

The balance between memory and regulatory cell populations in kidney transplant recipients with operational tolerance.

Donor-reactive memory cells represent a barrier to long-term kidney graft survival. A better understanding of regulatory mechanisms that counterbalance alloreactive memory responses may help to identify patients with operational tolerance. This prospective study investigated the equilibrium between memory T-cell subsets and regulatory T or B cells (Tregs, Bregs) in peripheral blood of kidney transplant recipients with operational tolerance (N = 8), chronic rejection (N = 8), and different immunosuppressive treatment regimens (N = 81). Patients on hemodialysis and healthy individuals served as controls (N = 50). In addition, the expression of Treg- and Breg-associated molecule genes was analyzed. Patients with chronic rejection showed a disrupted memory T-cell composition with a significantly higher frequency of circulating CD8+ terminally differentiated effector memory (TEMRA) T cells than patients with operational tolerance, patients on hemodialysis, or healthy controls (P < 0.001). Low frequency of CD8+ TEMRA and high frequency of Tregs and transitional Bregs were found in operationally tolerant patients. Consequently, operationally tolerant patients showed, as compared to all other transplant recipients with different immunosuppressive regiments, the lowest ratios between CD8+ TEMRA T cells and Tregs or Bregs (for both P < 0.001). Moreover, a specific peripheral blood transcription pattern was found in operationally tolerant patients with an increased expression of Breg- and Treg-associated genes CD22 and FoxP3 and a decreased FcγRIIA/FcγRIIB transcript ratio (for all P < 0.001). In conclusion, monitoring the balance between circulating CD8+ TEMRA T cells and regulatory cell subsets and their transcripts may help to distinguish transplant recipients with operational tolerance from recipients at risk of graft loss.

Indolent Lymphoma Care Delivery and Outcomes during the COVID-19 Pandemic in Ontario, Canada

Background At the outset of the coronavirus infectious disease 2019 (COVID-19) pandemic, hematological malignancy was recognized as a risk factor for severe COVID-19 disease, particularly patients with lymphoma, presenting a unique challenge for optimal management of indolent non-Hodgkin lymphoma (iNHL). To this end, professional societies including ASH favoured less immunosuppressive treatment regimens and omission of rituximab maintenance therapy. However, the implications of these recommendations on the care delivery and outcomes of patients with iNHL are unclear. Accordingly, we examined treatment selection, healthcare utilization, and COVID-19 outcomes of patients with iNHL receiving front line systemic treatment during pre-pandemic vs. pandemic period. Methods We performed a retrospective cohort study using administrative databases in Ontario, Canada, comparing outcomes in patients with iNHL who initiated first-line (1L) treatment with rituximab (R) monotherapy, or with bendamustine (B) or cyclophosphamide, vincristine, prednisone (CVP) from Jan 1, 2015 - Dec 31, 2018 (pre-pandemic cohort) and from Sept 1, 2019 - Aug 1, 2020 (pandemic cohort), with end of follow-up Mar, 31 2022. The primary outcome was comparison of treatment pattern before and during the COVID-19 pandemic which includes the following: 1L regimen received (R-CVP vs. B-R vs. R monotherapy), number of cycles received, dose delays, use of rituximab maintenance, and time-to-completion of full rituximab maintenance course (funded in Ontario every 3 months for 8 doses). Secondary outcomes were death, toxicities, healthcare utilization (emergency department [ED] visit, hospitalization, and ICU admission), and COVID-19 outcomes (SARS-CoV-2 PCR-confirmed infection, ED visit, hospitalization, and death). Adjusted odds ratios (aOR) and hazard ratios (aHR) with 95% confidence intervals (CI) from logistic regression and cause-specific proportional hazards models, respectively, were used to estimate associations between covariates (age, sex, comorbidity burden as measured by Aggregated Disease groups) and outcomes. Results We identified 4,143 patients (1,079 pandemic, 3,064 pre-pandemic), median age 69 (interquartile range 60-76) years, 44% female. In both pre- and pandemic periods, B-R was the most frequent prescribed regimen, with no difference in number of cycles given or in treatment delays (Table). During the pandemic, fewer patients received rituximab maintenance (69.6% vs 75.9%; aOR 0.72, 95% CI 0.60-0.88, p=0.0012). Older age was associated with lower odds of rituximab maintenance initiation (age 75+ vs. age &amp;lt; 60 aOR 0.44, 95% CI 0.35-0.56, p&amp;lt;0.0001). Moreover, patients who initiated maintenance during the pandemic period were less likely to complete the full maintenance course (48.7% vs 56.3%) (aHR 0.81, 95% confidence interval [CI] 0.71-0.92, p=0.0010) (Table) (Figure). Patients treated during the pandemic had less healthcare utilization (ED visit aHR 0.77, 95% CI 0.68, 0.88, p&amp;lt;0.0001; hospitalization aHR 0.81, 95% CI 0.70-0.94, p=0.0067) and treatment-related complications (infection aHR 0.69, 95% CI 0.57-0.82, p&amp;lt;0.0001; febrile neutropenia aHR 0.66, 95% CI 0.47-0.94, p=0.020), with no difference in death (aHR 0.79, 95% CI 0.58-1.08, p=0.14, Table). For COVID-19 outcomes, there were 131 SARS-CoV-2 infections from the beginning of the pandemic until December 31, 2021; with follow-up until March 31, 2022, there were 30 ED visits, 56 hospital admissions, and 23 ICU admissions, and 45 deaths related to COVID-19. Rituximab use (first dose to 1-year post-last dose) was associated with higher risk of COVID-19 infection (aHR 1.56, 95% CI 1.09-2.24, p=0.015) and COVID-19 complications (ED visit aHR 4.28, 95% CI 1.79-10.26, p=0.001; hospitalization/death 1.81, 95% CI 1.11-2.93, p=0.016). Primary vaccination series was associated with lower risk of infection and severe outcomes (infection aHR 0.52, 95% CI 0.28-0.97, p=0.04; hospitalization/death aHR 0.36, 95% CI 0.14-0.94, p=0.036; death aHR 0.26, 95% CI 0.07-0.89, p=0.033). Conclusion During the pandemic, B-R remained the preferred regimen for iNHL treatment, while rituximab maintenance use was less. Despite similar 1L regimen use, healthcare utilization and infectious complications were less in the pandemic cohort. Rituximab use was associated with nearly 2-fold risk of COVID-19 hospitalization/death.

Clinical effect of different immunosuppressive treatment regimens in children with ocular myasthenia gravis: a retrospective analysis

To investigate the clinical effect of different immunosuppressive treatment regimens in children with ocular myasthenia gravis (OMG). A retrospective analysis was conducted on 130 children with OMG who were treated in the Department of Neurology, Jiangxi Children's Hospital, from February 2018 to February 2023. According to the treatment regimen, they were divided into four groups: glucocorticoid (GC) group (n=29), mycophenolate mofetil (MMF) group (GC+MMF; n=33), methotrexate (MTX) group (GC+MTX; n=30), and tacrolimus (FK506) group (GC+FK506; n=38). Treatment outcomes and adverse reactions were compared among the groups. After 3 months of treatment, the FK506 group had significantly lower scores of Myasthenia Gravis Quantitative Scale and Myasthenia Gravis-Specific Activities of Daily Living than the other three groups (P<0.05). After 3 months of treatment, the FK506 group had a significantly lower dose of prednisone than the GC group, and after 6 and 9 months of treatment, the MMF, MTX, and FK506 groups had a significantly lower dose of prednisone than the GC group (P<0.05). After 12 months of treatment, the MMF, MTX, and FK506 groups had a significantly lower incidence rate of GC-related adverse reactions than the GC group (P<0.05). For children with OMG, the addition of various immunosuppressants can reduce the dosage of GC and adverse reactions. Among them, FK506 shows superior efficacy compared to other immunosuppressants in the early treatment of OMG.

Differential Fibrinolysis Profile in COVID-19 Patients Dependent on Immunosuppressive Treatment Regimen: A Nested Case-Control Study

Introduction: Severe coronavirus disease 2019 (COVID-19) is associated with thrombotic complications, despite prophylactic and therapeutic anticoagulation. The disease course of critically ill COVID-19 patients has been characterized by severe hypercoagulability and hypofibrinolysis leading to an increased risk of venous thromboembolism. In COVID-19 (low molecular weight) heparins do not provide sufficient protection against venous thromboembolism. Since the start of the COVID-19 pandemic, several immune modulatory interventions have been introduced to improve outcome, including dexamethasone and tocilizumab. Whether dexamethasone and tocilizumab would alter the course of hypercoagulability by modifying inflammation, is unknown. Tocilizumab, that reduces IL-6 binding to its cellular receptors, has been shown to reduce the plasma plasminogen activator inhibitor-1 (PAI-1). On the other hand, dexamethasone can induce PAI-1 release. Data on the net impact of dexamethasone and tocilizumab on fibrinolysis in critically ill COVID-19 patients is lacking. Therefore, we aimed to characterize the fibrinolytic profile of severe COVID-19 patients on different treatment regimens and to unravel underlying mechanisms of the hypofibrinolytic state of these patients. Methods: A nested case-control study within the Maastricht Intensive Care COVID (MaastrICCht) cohort on mechanically ventilated COVID-19 patients was conducted. Patients receiving tocilizumab and dexamethasone (toci group) were age- and sex-matched with patients receiving only dexamethasone (dexa group) and patients receiving neither tocilizumab nor dexamethasone (control group). Whole blood was collected from these patients at three different time points after intubation (week 1, 2, and 3). The dexa and toci group received dexamethasone treatment before intubation and the toci group received one bolus of tocilizumab before or on the day of intubation. All blood samples were collected thereafter. Whole blood tissue plasminogen activator rotational thromboelastometry (tPA-ROTEM) was performed and subsequently inflammatory markers (c-reactive protein (CRP), ferritin, IL-6, fibrinogen), fibrinolysis parameters (tPA, PAI-1, thrombin activatable fibrinolysis inhibitor (TAFI), plasmin-alpha-2-antiplasmin complex (PAP)) and coagulation biomarkers (D-dimer, prothrombin fragment 1.2 (F1.2)) were measured in plasma samples. All markers were analyzed with linear mixed-effects regression models to estimate the differences between treatment groups over time. Results: Matching showed similar groups (Table 1.) for the baseline characteristics. At week 1 the dexagroup's IL-6 level was significantly lower, whereas the toci group's IL-6 level was significantly higher compared to the control group (difference[95%CI]: -198.37 [-350.86- -45.88], p=0.017 and 269.59 [113.91-425.27], p=0.002, respectively). CRP levels were significantly lower at week 1 in both dexa and toci groups compared to the control group (median [IQR] 60.50 [30.75 - 131.25] and 18.50 [6.00 - 60.00] vs. 296.00 [223.75 - 347.00]) suggesting effective immune suppression. Divergent fibrinolysis was seen at week 1 by tPA-ROTEM showing lower lysis time (LT) in the toci group compared to the control group (difference[95%CI]: -1,759.21 [-2752.05 - -766.34; p=0.002), whereas the dexa group did not differ. Interestingly, LT decreased over time in the control group, while an increase was seen in the toci group (Figure 1.). PAI-1 levels were lower in week 1 in the toci group compared to the control group (difference [95%CI] -7.32 [-14.95 - 0.30], p=0.071) and the tocigroup showed an overall increase in PAI-1 levels, while the control and dexa group showed a decrease over time. High TAFI and tPA levels were observed in all groups at week 1 and over time regardless of the treatment regimens. Coagulation biomarkers D-dimer and prothrombin fragment 1.2 were elevated but did not differ or change over time between groups. Conclusions: The differences and changes over time revealed by tPA-ROTEM and the fibrinolysis markers between the three different treatment regimens show the direct interaction between inflammation and fibrinolysis in these patients. The lower LT and PAI-1 levels upon tocilizumab treatment could be indicative for better fibrinolytic activity in these patients. This study was supported by the Dutch Covid and Thrombosis Coalition (DCTC). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Infliximab and Tofacitinib Attenuate Neutralizing Antibody Responses Against SARS-CoV-2 Ancestral and Omicron Variants in Inflammatory Bowel Disease Patients After 3 Doses of COVID-19 Vaccine

Infliximab and Tofacitinib Attenuate Neutralizing Antibody Responses Against SARS-CoV-2 Ancestral and Omicron Variants in Inflammatory Bowel Disease Patients After 3 Doses of COVID-19 Vaccine

AB1122 HAVE TREATMENTS FOR AUTOIMMUNE DISEASES WORSENED THE PROGNOSIS OF COVID-19 INFECTION?

BackgroundAccording to the literature patients with autoimmune diseases (AID) have a high risk of develop serious infections due to the use of immunosuppressive treatment. In published clinical trials neither the risk nor the severity of COVID-19 infection in patients with AID seem to be higher than in the general population.ObjectivesThe objective of our study is to analyse the clinical course in patients with AID undergoing immunosuppressive treatments and infected by COVID-19.MethodsPatients were included after reviewing four rheumatology outpatient clinics from Ciudad Real University General Hospital between November 2020 and February 2021. The inclusion criteria were being older than 18 years and being positive for COVID-19 by epidemiological (positive molecular and/or antigen test) or clinical criteria (symptoms compatible between March and May 2020). We collected demographic data, cardiovascular comorbidities, AID, treatment with synthetic or biological DMARDs, immunomodulators or glucocorticoids; and progression of infection COVID-19.ResultsWe found a total of 210 patients that had suffered from SARS-COV2 of which 95 patients were affected by AID. The most prevalent pathology in our sample was spondylarthritis followed by arthritis rheumatoid and systemic lupus erythematosus of which 81.82%, 100% and one 92.86% respectively were receiving treatment to control the disease. Among the 95 patients suffering from COVID and AID a small number of patients did not follow any immunosuppressive treatment regimen (n=25) but most of our patients were undergoing immunosuppressors (n=70); the most used drugs were prednisone and methotrexate. No statistically significant differences were found between the treated versus untreated group in the studied variables, being similar the results relative to mean age, sex, presence of cardiovascular risk factors, absence of symptoms, number of admissions to hospital ward or in Intensive Care Unit, or complications during COVID-19 infection (Table 1).Table 1.Baseline characteristics of patient with AID undergoing or not immunosuppressors.TreatedUntreatedpn=70 (73,68%)n=25 (26,32%)Medium age (SD)51,74 (+/- 2,18)55,74 (+/-3,36)0,467Female sex, n (%)49 (70%)17 (68%)0,852HTA, n (%)22 (31,4%)5 (20%)0,277DM, n (%)8 (11,4%)2 (8%)0,632DL, n (%)13 (18,6%)1 (4%)0,078Tobacco, n (%)7 (10%)3 (12%)0,78Asymptomatic, n (%)13 (18,6%)4 (16%)0,773Admitted, n (%)11 (15,7%)5 (20%)0,623ICU, n (%)2 (2,9%)0 (0%)0,393ARDS, n (%)7 (10%)2 (8%)0,769Overinfection, n (%)4 (5,7%)0 (0%)0,222Thrombosis, n (%)1 (1,4%)0(0%)0,548Death, n (%)6 (8,6%)2 (8%)0,930SD, standard deviation; n, absolute numbers; %, percentages; p, p-value; AID, autoimmune diseases; HTA, arterial hypertension; DM, diabetes mellitus; DL, dyslipidaemia; ICU: intensive care unit; ARDS: Acute respiratory distress syndromeConclusionPatients treated with synthetic or biologicals DMARDs, immunomodulators or glucocorticoids do not seem have a higher rate of death or hospital admission respect to patients diagnosed of AID without such treatments.

Rationale and design of the CORE (COrticosteroids REvised) study: protocol

IntroductionCorticosteroids are an important pillar in many anti-inflammatory and immunosuppressive treatment regimens and are available in natural and synthetic forms, which are considered equipotent if clinical bioequivalence data are used....

Interventions for focal segmental glomerulosclerosis in adults.

Focal segmental glomerulosclerosis (FSGS) can be separated into primary, genetic or secondary causes. Primary disease results in nephrotic syndrome while genetic and secondary forms may be associated with asymptomatic proteinuria or with nephrotic syndrome. Overall only about 20% of patients with FSGS experience a partial or complete remission of nephrotic syndrome with treatment. FSGS progresses to kidney failure in about half of the cases. This is an update of a review first published in 2008. To assess the benefits and harms of immunosuppressive and non-immunosuppressive treatment regimens in adults with FSGS. We searched the Cochrane Kidney and Transplant Register of Studies to 21 June 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Randomised controlled trials (RCTs) and quasi-RCTs of any intervention for FSGS in adults were included. Studies comparing different types, routes, frequencies, and duration of immunosuppressive agents and non-immunosuppressive agents were assessed. At least two authors independently assessed study quality and extracted data. Statistical analyses were performed using the random-effects model and results were expressed as a risk ratio (RR) for dichotomous outcomes, or mean difference (MD) for continuous data with 95% confidence intervals (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Fifteen studies (560 participants) were included. No studies specifically evaluating corticosteroids compared with placebo or supportive therapy were identified. Studies evaluated participants with steroid-resistant FSGS. Five studies (240 participants) compared cyclosporin with or without prednisone with different comparators (no specific treatment, prednisone, methylprednisolone, mycophenolate mofetil (MMF), dexamethasone). Three small studies compared monoclonal antibodies (adalimumab, fresolimumab) with other agents or placebo. Six single small studies compared rituximab with tacrolimus, cyclosporin plus valsartan with cyclosporin alone, MMF with prednisone, chlorambucil plus methylprednisolone and prednisone with no specific treatment, different regimens of dexamethasone and CCX140-B (an antagonist of the chemokine receptor CCR2) with placebo. The final study (109 participants) compared sparsentan, a dual inhibitor of endothelin Type A receptor and of the angiotensin II Type 1 receptor, with irbesartan. In the risk of bias assessment, seven and five studies were at low risk of bias for sequence generation and allocation concealment, respectively. Four studies were at low risk of performance bias and 14 studies were at low risk of detection bias. Thirteen, six and five studies were at low risk of attrition bias, reporting bias and other bias, respectively. Of five studies evaluating cyclosporin, four could be included in our meta-analyses (231 participants). Cyclosporin with or without prednisone compared with different comparators may increase the likelihood of complete remission (RR 2.31, 95% CI 1.13 to 4.73; I² = 1%; low certainty evidence) and of complete or partial remission (RR 1.64, 95% CI 1.10 to 2.44; I² = 19%) but not of partial remission (RR 1.36, 95% CI 0.78 to 2.39, I² = 22%). In Individual studies, cyclosporin with prednisone versus prednisone may increase the likelihood of partial (49 participants: RR 7.96, 95% CI 1.09 to 58.15) or complete or partial remission (49 participants: RR 8.85, 95% CI 1.22 to 63.92) but not of complete remission. The remaining individual comparisons may make little or no difference to the likelihood of complete remission, partial remission or complete or partial remission compared with no treatment, methylprednisolone, MMF, or dexamethasone. Individual study data and combined data showed that cyclosporin may make little or no difference to the outcomes of chronic kidney disease or kidney failure. It is uncertain whether cyclosporin compared with these comparators in individual or combined analyses makes any difference to the outcomes of hypertension or infection. MMF compared with prednisone may make little or no difference to the likelihood of complete remission (33 participants: RR 1.05, 95% CI 0.58 to 1.88; low certainty evidence), partial remission, complete or partial remission, glomerular filtration rate, or infection. It is uncertain whether other interventions make any difference to outcomes as the certainty of the evidence is very low. It is uncertain whether sparsentan reduces proteinuria to a greater extent than irbesartan. No RCTs, which evaluated corticosteroids, were identified although the KDIGO guidelines recommend corticosteroids as the first treatment for adults with FSGS. The studies identified included participants with steroid-resistant FSGS. Treatment with cyclosporin for at least six months was more likely to achieve complete remission of proteinuria compared with other treatments but there was considerable imprecision due to few studies and small participant numbers. In future studies of existing or new interventions, the investigators must clearly define the populations included in the study to provide appropriate recommendations for patients with primary, genetic or secondary FSGS.

Current Status of Malignant Tumors after Organ Transplantation.

Objective To analyze the diagnosis and treatment of patients with concomitant malignant tumors after organ transplantation by compiling data from organ transplantation patients. Methods By searching CNKI and PubMed databases, we made a systematic analysis of the studies of postorgan transplantation complicating malignant tumors in the last decade. Results There were 10 articles on malignant tumors after renal transplantation, 8 articles on liver transplantation, 2 articles on heart transplantation, and 1 article on lung transplantation. The incidence of malignant tumors complicating renal transplantation is 10.4% in Europe, with skin cancer and Kaposi's sarcoma being common; the incidence in the United States is 3.4%, with PTLD having the highest incidence; the incidence of malignant tumors is relatively lowest in Asia, with gastrointestinal malignancies being the main ones. The mean time to complication of malignancy after renal transplantation is 3.83 years. The incidence of concurrent malignancies after liver transplantation is 8.8% in Europe, where skin cancer and Kaposi's sarcoma are common; 5.6% in Asia, where gastrointestinal tract tumors are prevalent; and 4.5% in the United States, where gastrointestinal tract tumors, PTLD, and hematologic diseases are predominant. The mean time to complication of malignancy after liver transplantation is 4.79 years. The incidence of malignancy after heart transplantation is 6.8-10.7%. The incidence of malignancy after lung transplantation is about 10.1%. Minimization of immunosuppression or modification of immunosuppression regimens may be a key component of cancer prevention. mTOR inhibitors and phenolate (MMF) reduce the incidence of de novo malignancies in patients after solid organ transplantation. Surgical treatment improves survival in patients with early malignancies. The use of external beam radiation therapy in the treatment of hepatocellular carcinoma is limited due to the risk of radiation liver disease. Conclusions The risk of concomitant malignancy needs to be guarded for 5 years of immunosuppressive therapy after organ transplantation surgery. Adjusting the immunosuppressive treatment regimen is an effective way to reduce concurrent malignancies. Systemic chemotherapy or radiotherapy requires vigilance against the toxic effects of drug metabolism kinetics on the transplanted organ.

COVID-19 vaccine acceptance over time in patients with immune-mediated inflammatory rheumatic diseases

Before the global distribution of COVID-19 vaccines, we observed substantial concerns among non-immunocompromised people about the lack of long-term research or the occurrence of adverse events after vaccination, and concerns among patients with immune-mediated inflammatory rheumatic diseases about interactions with their underlying autoimmune disease or immunosuppressive treatment regimens.1 Our findings have since been replicated,2,3 but there is as yet no data on how patients' thoughts and behaviour have evolved as vaccines were distributed, or data that compare COVID-19 vaccine coverage between patients with rheumatic immune-mediated inflammatory diseases and healthy controls.

COVID-19 vaccine-induced antibody responses in immunosuppressed patients with inflammatory bowel disease (VIP): a multicentre, prospective, case-control study

BackgroundThe effects that therapies for inflammatory bowel disease (IBD) have on immune responses to SARS-CoV-2 vaccination are not yet fully known. Therefore, we sought to determine whether COVID-19 vaccine-induced antibody responses were altered in patients with IBD on commonly used immunosuppressive drugs.MethodsIn this multicentre, prospective, case-control study (VIP), we recruited adults with IBD treated with one of six different immunosuppressive treatment regimens (thiopurines, infliximab, a thiopurine plus infliximab, ustekinumab, vedolizumab, or tofacitinib) and healthy control participants from nine centres in the UK. Eligible participants were aged 18 years or older and had received two doses of COVID-19 vaccines (either ChAdOx1 nCoV-19 [Oxford–AstraZeneca], BNT162b2 [Pfizer–BioNTech], or mRNA1273 [Moderna]) 6–12 weeks apart (according to scheduling adopted in the UK). We measured antibody responses 53–92 days after a second vaccine dose using the Roche Elecsys Anti-SARS-CoV-2 spike electrochemiluminescence immunoassay. The primary outcome was anti-SARS-CoV-2 spike protein antibody concentrations in participants without previous SARS-CoV-2 infection, adjusted by age and vaccine type, and was analysed by use of multivariable linear regression models. This study is registered in the ISRCTN Registry, ISRCTN13495664, and is ongoing.FindingsBetween May 31 and Nov 24, 2021, we recruited 483 participants, including patients with IBD being treated with thiopurines (n=78), infliximab (n=63), a thiopurine plus infliximab (n=72), ustekinumab (n=57), vedolizumab (n=62), or tofacitinib (n=30), and 121 healthy controls. We included 370 participants without evidence of previous infection in our primary analysis. Geometric mean anti-SARS-CoV-2 spike protein antibody concentrations were significantly lower in patients treated with infliximab (156·8 U/mL [geometric SD 5·7]; p<0·0001), infliximab plus thiopurine (111·1 U/mL [5·7]; p<0·0001), or tofacitinib (429·5 U/mL [3·1]; p=0·0012) compared with controls (1578·3 U/mL [3·7]). There were no significant differences in antibody concentrations between patients treated with thiopurine monotherapy (1019·8 U/mL [4·3]; p=0·74), ustekinumab (582·4 U/mL [4·6]; p=0·11), or vedolizumab (954·0 U/mL [4·1]; p=0·50) and healthy controls. In multivariable modelling, lower anti-SARS-CoV-2 spike protein antibody concentrations were independently associated with infliximab (geometric mean ratio 0·12, 95% CI 0·08–0·17; p<0·0001) and tofacitinib (0·43, 0·23–0·81; p=0·0095), but not with ustekinumab (0·69, 0·41–1·19; p=0·18), thiopurines (0·89, 0·64–1·24; p=0·50), or vedolizumab (1·16, 0·74–1·83; p=0·51). mRNA vaccines (3·68, 2·80–4·84; p<0·0001; vs adenovirus vector vaccines) were independently associated with higher antibody concentrations and older age per decade (0·79, 0·72–0·87; p<0·0001) with lower antibody concentrations.InterpretationFor patients with IBD, the immunogenicity of COVID-19 vaccines varies according to immunosuppressive drug exposure, and is attenuated in recipients of infliximab, infliximab plus thiopurines, and tofacitinib. Scheduling of third primary, or booster, doses could be personalised on the basis of an individual's treatment, and patients taking anti-tumour necrosis factor and tofacitinib should be prioritised.FundingPfizer.

Two severe cases of disseminated cutaneous nontuberculous mycobacteriosis due to Mycobacterium haemophilum

Mycobacterium haemophilum is arare pathogen belonging to the group of slowly growing nontuberculous mycobacteria (NTM) that can cause infections, especially in immunocompromised patients. Detection by culturing is difficult because M.haemophilum only grows under special cultivation conditions. Therefore, it is believed that the pathogen is too rarely identified as acause of disease overall. In addition to patients with severe immunodeficiency, e.g. due to acquired immunodeficiency syndrome (AIDS), chemotherapy or immunosuppression after transplantation, patients with underlying rheumatic diseases are increasingly described in the literature, who are at risk due to the immunosuppressive treatment regimen. Clinically, ulcerative skin alterations, lymphadenopathy and arthropathy are in the foreground. In immunosuppressed patients with unclear skin lesions, infections due to M.haemophilum should be considered and specific microbiological diagnostics should be initiated.

Intrathecal methotrexate – Another tool for the treatment of refractory autoimmune encephalitis - Single institution cohort and literature review

BackgroundAutoimmune encephalitis (AIE) encompasses a range of inflammatory disorders manifesting with some combination of encephalopathy, seizures, behavioral changes, movement disorders, dysautonomia or other neurologic symptoms. Anti-N-methyl-d-aspartate receptor encephalitis (NMDARE) is the most common AIE and is an autoantibody mediated disorder, often paraneoplastic. Untreated or undertreated AIE has a high degree of morbidity and mortality. Immunosuppressive treatment regimens including glucocorticoids, plasma exchange (PLEX), intravenous immunoglobulin (IVIG) and rituximab used alone or in combination for such patients. Patients' refractory to such treatments requires more aggressive and potentially toxic therapies. We report favorable outcomes in patients with refractory AIE who received intrathecal methotrexate (IT-MTX) as part of treatment. MethodsCases at our institution seen between 2010 and 2020 were reviewed. We identified 5 patients in our clinical practice whose clinical presentation was compatible with NMDARE. Three patients met criteria for definite NMDARE. An additional two patients met criteria for probable NMDARE in the acute setting but were ultimately seronegative autoimmune encephalitis. All patients received at least one dose of IT-MTX after failing conventional therapies. At the time of IT-MTX administration patients were catatonic, comatose, or severely encephalopathic despite initial treatments. ResultsAll patients were treated with methylprednisolone; 3 received a course of IVIG, 4 underwent PLEX, and 4 received rituximab. At the time IT-MTX was given, three patients required mechanical ventilation and 1 had a pacemaker placed for autonomic failure. Two patients were under consideration for transition to palliative care. All patients improved and were at or near their premorbid baseline at last follow-up. All patients tolerated IT-MTX well. ConclusionsThis retrospective review demonstrates the efficacy of intrathecal methotrexate in the treatment of severe AIE who had failed other immunosuppressive regimens.

Factors affecting relapse in patients with Granulomatosis Polyangiitis: a single-center retrospective cohort study

Background and aimThis study aimed to determine the frequency of relapse, the risk factors for relapse, and the correlation of relapse with immunosuppressive regimens in patients with granulomatosis polyangiitis (GPA).Materials and methodsThe demographic characteristics, the clinical, laboratory, and radiological findings, the immunosuppressive treatment regimens, and the remission and relapse rates of 50 patients with GPA were obtained retrospectively from medical records.Results: The mean relapse-free survival rates at years 1, 3, and 5 were 82%, 60%, and 50%, respectively. Increased relapse rates were observed in patients who had cavitary lung lesions (52.2% vs. 22.2%, p = 0.04) and in those who had elevated serum creatinine levels (1.8 vs. 0.9, p = 0.00). The patients received two different types of remission induction therapies; 36% of them received the combination therapy involving cyclophosphamide (CYC) and rituximab (RTX), and 62% received CYC alone. Relapse was observed in 22.3% of the patients who received the combination remission induction therapy and in 61.3% of the patients who received CYC alone (P = 0.003). ConclusionAn increased risk of relapse was observed in patients who had cavitary lung lesions and in those who had elevated serum creatinine levels. The combined use of RTX and CYC for the remission therapy in GPA reduced the relapse rates compared with the use of CYC alone

Kolonda nadir bir darlık ve ülser nedeni: Kronik graft versus host hastalığı

Dear Editor;&#x0D; Often during routine gastroenterology examinations, ulcers and strictures in the colon and small intestine are encountered in patients. Differential diagnosis of ulcers in these patients may not always be easy. Graft-versus-host disease (GVHD) is a serious complication that can be life-threatening after allogeneic bone marrow transplantation (1). Since the introduction of modern immunosuppressive treatment regimens, clinical symptoms, radiographic and histological findings are rarely seen in chronic graft-versus-host disease (CGVHD) (2). However, CGVHD patients often present with various gastrointestinal symptoms such as esophageal reflux, dysphagia, bloating, weight loss, and diarrhea (2). Edema, erythema, diffuse polypoid lesions, multiple ulcers, and strictures in the mucosa can be observed in the endoscopic examination of intestinal GVHD (3). &#x0D; We present a patient who was diagnosed with CGVHD in a colonoscopic examination performed for iron deficiency anemia. &#x0D; A 52-year-old female patient was referred to our gastroenterology outpatient clinic for endoscopic examination after the laboratory tests revealed iron deficiency anemia. The patient's medical history revealed that she had undergone autologous stem cell transplantation in 2012 and allogeneic stem cell transplantation in 2016 with a diagnosis of Non-Hodgkin lymphoma. A hysterectomy had been performed due to myoma. &#x0D; When the patient's complaints were questioned, there were no gastrointestinal complaints such as bloating, constipation, diarrhea, or abdominal pain. Physical examination revealed multiple psoriasis colored rashes on the skin on the neck and nape (Figure 1). White blood cell count in laboratory tests: 8920 x103/μL, platelet: 470 x103/μL, Hgb: 10.9 g/dl, aspartate aminotransferase: 47 U/L, alanine transaminase: 39 U/L, alkaline phosphatase: 99 U/L, total bilirubin: 0.56 mg/dl, albumin: 4.2 g/dL, serum iron: 115 u/dl, total iron-binding capacity: 274 u/dl, ferritin: 12 u/L, vitamin B12: 353 ng/L were detected.&#x0D; The colonoscopic examination showed that, in the ascending colon, the lumen was narrowed fibrotically, not allowing the endoscope to pass proximally (Figure 2). In addition, multiple ulcerated lesions extending perpendicular to the lumen, covered with white exudate, causing shrinkage in the mucosa, and approximately 5-6 mm diameter were observed in the ascending colon, transverse colon, and descending colon (Figure 3). In the pathological examination of the biopsies taken from the lesions, the patient was diagnosed with CGVHD after intense inflammation in the lamina propria. Apoptosis in the crypts was observed, and cytomegalovirus (CMV) was excluded (Figure 4).&#x0D; Endoscopic images of GVHD-induced gastrointestinal involvement vary, and the involvement of lesions may be focal or diffuse (4,5). Various lesions such as mild mucosal erythema, edema, prominent ulcers, lytic mucosal lesions can be seen in the upper and lower gastrointestinal tract (GIS) in endoscopic evaluation. The demonstration of apoptosis is very supportive for diagnosis. The diagnosis of gastrointestinal GVHD is made by endoscopic examination and mucosal biopsy, in the endoscopic biopsy (3). Other causes of apoptotic colopathy, especially CMV, should be considered in the differential diagnosis. Thus, chronic GVHD should be considered in the differential diagnosis of strictures and ulcers in a colonoscopic examination.

T Cell Responses to Tumor Associated Antigens in Multiple Myeloma Patients Treated with MV-NIS, an Oncolytic Measles Virus

Introduction: Oncolytic virus therapy leads to immunogenic death of virus infected tumor cells. Evidence from mouse studies shows that this mode of tumor cell killing can boost the cytotoxic T lymphocyte response against tumor associated antigens (TAA), leading to ‘bystander’ killing of uninfected tumor cells.Methods: To investigate whether oncolytic virotherapy can boost immune responses to tumor antigens in human subjects we studied T cell responses to 10 different TAA reported to have high expression in patients with multiple myeloma (n=10) before and after intravenous administration of an oncolytic measles virus (MV-NIS). Baseline and 6 week post-therapy PBMC samples were frozen at the time of collection from each enrolled patient throughout the course of the clinical trial. After thawing, 2 x 105 PBMC were stimulated with peptide pools specific to each of the selected TAA and their responses to this antigenic stimulation were measured using IFNγ ELISPOT. Spots more than 50 were counted as positive response.Results: Despite their prior exposure to multiple immunosuppressive anti-myeloma treatment regimens, some of the tested patients had higher T cell responses to some of the TAA even prior to Measles virotherapy. Measurable baseline T cell responses against MAGEc1 were present in 50% of the patients, and against hTERT and NYESO-1 in 30% of the patients for each target. Furthermore, MV-NIS treatment significantly boosted T cell responses against NYESO-1, MAGEc1, MAGEA1 and MUC1 in 40% of the patients. Interestingly, in one outlier patient who achieved a stringent and durable complete disease remission after MV-NIS therapy, strong baseline T cell responses were present against 8 of the 10 tested TAA but did not change significantly after virotherapy. Based on the T cell responses to the TAA, three distinct phenotypes can be identified. Phenotype 1 was characterized by positive T cell responses to TAA prior and post therapy, Phenotype 2 was characterized by positive T cell responses to TAA only post therapy and phenotype 3 was characterized by negative T cell responses to TAA prior and post therapy (Figure 1). Additionally, these observed phenotypes in T cell responses correlated with anti-tumor response.Conclusion: Our data suggests oncolytic measles virotherapy boosted the cytotoxic T lymphocyte response against tumor associated antigens in some of the patients. Identifying patient's phenotype based on responsiveness to the TAA could be useful marker for identifying the immune responsive state in multiple myeloma patients and identify patients who can be most responsive to oncolytic measles virotherapy. Additionally, the boosted T cell responses against TAA post measles virotherapy provide a good rationale for combining oncolytic virotherapy with checkpoint antibody therapy to increase the efficacy of the oncolytic measles virotherapy.Figure 1: T cell response phenotypes against 10 different TAAs. Representative IFNγ ELISPOT data shown below. PRE: T cell responses prior to virotherapy; Post 6 wks: T cell responses 6 weeks post virotherapy [Display omitted] DisclosuresDispenzieri:Celgene, Millenium, Pfizer, Janssen: Research Funding. Peng:Imanis Life Sciences: Employment, Equity Ownership; Vyriad: Equity Ownership. Russell:Vyriad: Equity Ownership; Imanis Life Sciences: Equity Ownership.

P157 Potential benefit of intravenous immunoglobulin in connective tissue disease associated interstitial lung diseases

Abstract Background/Aims Intravenous immunoglobulin (IVIg) confers significant benefit in range of connective tissue diseases (CTD) including inflammatory myopathy (IM) of which interstitial lung diseases (ILD) are a major complication. This study aimed to assess the efficacy of IVIg on pulmonary involvement in refractory active CTD including systemic sclerosis (SSc). Methods All patients with CTD-ILD confirmed on HRCT either with IM or SSc overlap myositis who did not achieve satisfactory clinical response to standard immunosuppressive agents and subsequently received regular IVIg infusions for IM were retrospectively identified. Serial lung function tests and immunosuppressive treatment regimen 9-12 months prior and 9-12 months after repeat courses of IVIg were recorded. Progressive ILD was considered when, despite immunosuppressive treatment, a relative FVC decline≥10% and/or relative DLco decline ≥15% were identified during the 9-12 months preceding IVIg treatment. The significance of median DLco and FVC percentage relative change to IVIg treatment was assessed by Wilcoxon signed-rank test. Results 22 patients (mean age 50.5±13.1 years old) with IM-ILD treated with IVIg were identified. ILD occurred in association with IM in 10 patients, overlap SSc myositis in another 11 patients, while one had mixed connective tissue disease with myositis. Lung function results were available for 19/22 (86%). Eight patients (42.1%) were found to have progressive ILD(four with IM and four with overlap SSc-myositis). The median change in FVC% predicted and DLco% predicted in the 9-12 months before and after IVIg treatment is presented in Table 1. There was a significant difference in the DLco% predicted rate of relative change before and after IVIg treatment (p = 0.035) for the overall cohort. However, no differences in lung function were observed in the rate of relative change between patients with IM and patients with SSc myositis overlap. Significant improvement in DLco% predicted values was identified in the subgroup analysis of patients with progressive ILD(p = 0.012). P157 Table 1:The median change in FVC and DLco% predicted values prior and after the IVIg treatmentPatients with myositis related ILD9-12 months before IVIg treatment (relative change)9-12 months after IVIg treatment (relative change)p-valueAll (n = 19)FVC % predicted-3.8 (-54.4 - 14.6)2.1 (-33 - 33.7)0.145DLco % predicted-9.2 (-60.7 - 9.2)-2.3 (-26 - 41.9)0.035PM/DM (n = 10)FVC % predicted-1.8 (-20.2 - 14.6)0.8 (-33 - 30.9)0.401DLco % predicted-9.6 (-60.7 - 9.2)-2.4 (-26 - 41.9)0.093SSc-PM/DM overlap (n = 11)FVC % predicted-6 (-54.4 - 10.6)3.4 (-19.9 - 33.7)0.139DLco % predicted-10.8 (-47.1 - 2.5)4.2 (-22.7 - 16.8)0.173Progressive ILD (n = 8)FVC % predicted-14.5 (-54.4 - 14.6)5.7 (-11.9 - 33.7)0.123DLco % predicted-25.3 (-60.6 - -14.1)12 (-2.3 - 41.9)0.012 Conclusion IVIg may be an effective rescue therapy in the prevention of further lung function decline in refractory myositis and SSc overlap in particular in subgroups with progressive ILD. Future studies to determine its role in CTD-ILD are warranted. Disclosure V. Kouranos: None. L.V. Host: None. C. Campochiaro: None. A. Wells: None. C.P. Denton: None. V.H. Ong: None. E. Renzoni: None.

Extremely High Cell-free DNA Levels Observed in Renal Allograft Patient With SARS-CoV-2 Infection.

Beyond its widely recognized morbidity and mortality, coronavirus disease 2019 poses an additional health risk to renal allograft recipients. Detection and measurement of donor-derived cell-free DNA (dd-cfDNA), expressed as a fraction of the total cell-free DNA (cfDNA), has emerged as a noninvasive biomarker for allograft rejection. Here, we present a case report of a patient who was infected with severe acute respiratory syndrome coronavirus 2, 11 mo post–kidney transplant. The patient was serially monitored using an analytically and clinically validated massively multiplex PCR-based dd-cfDNA assay to assess allograft injury and risk for rejection. Over the course of infection, low dd-cfDNA fractions were observed (below the 1% cutoff) and were accompanied by unusually highly elevated levels of total cfDNA, which gradually declined as the infection resolved. The case study highlights the variability in total cfDNA levels during and after viral infection, and the need to consider both total and dd-cfDNA levels when clinically interpreting the results for allograft rejection. Furthermore, the study highlights the importance of serial testing, wherein an interplay between total cfDNA and dd-cfDNA can inform the optimization of a patient’s immunosuppressive treatment regimen in response to infection.