Start Of Immunosuppressive Therapy Research Articles

#1639 Nephrotic syndrome with anti-nephrin antibodies—case report of minimal change glomerulonephritis

Abstract Background and Aims Minimal change disease (MCD) in adults is one of the causes of nephrotic syndrome. Recently, anti-nephrin antibodies localized in glomerular podocytes have been described in a certain subset of patients with MCD, supporting the autoimmune etiology of the disease. Method A 79-year-old man with arterial hypertension, hypothirosis and mild dementia presented with new-onset nephrotic syndrome. Peripheral and periocular edema, hypoalbuminemia (serum albumin 17 g/l), proteinuria 15 g/day and hypercholesterolemia (serum cholesterol 6.7 mmol/l) were noted. Blood pressure was 133/85 mmHg. Creatinine was 165 mcmol/l on admission and increased to 361 mcmol/l in the following days. Immunologic tests were negative, including antibodies against phospholipase A2-receptor (anti-PLA2R) and thrombospondin-7A (anti-THSD7A). Anti-HBc was positive, HBV DNA was below 15 IU/ml. Liver tests and abdominal ultrasound were normal, with no signs of liver disease. Results Renal biopsy revealed 18 glomeruli with global sclerosis of one glomerulus (1/18) and 5% interstitial fibrosis. Tubular damage was noted, which could be attributed to severe proteinuria. Immunofluorescence showed discrete IgG podocyte deposits with a uniform kappa/lambda distribution and a high probability of idiopathic minimal change disease due to anti-nephrin antibodies. Electron microscopy showed diffuse effacement of the podocyte foot processes without deposits. The serum taken after the biopsy and before the start of immunosuppressive therapy was positive for anti-nephrin antibodies. Due to a possible pharmacokinetic interaction with tenofovir, which the patient was receiving because of his anti-HBc positivity, we decided not to use cyclosporine. In addition to standard therapy with angiotensin convertase inhibitors, calcium channel blockers and furosemide, the patient was treated with low-dose oral glucocorticoids and mycophenolic acid. In addition, he received rituximab. After a few weeks, the oral glucocorticoids and mycophenolic acid were discontinued. The nephrotic syndrome regressed completely and renal function improved. Conclusion Anti-nephrin antibodies have contributed to a subgroup of patients with MCD, they can be found in a renal biopsy and are also detected in the serum of these patients. Targeted anti-B-cell therapy should be introduced to improve the prognosis of patients.

Cytomegalovirus-Specific T Cells in Pediatric Liver Transplant Recipients.

Cytomegalovirus (CMV) infection is a major opportunistic infection after liver transplantation (LT) that necessitates monitoring. Because of the lack of studies in children, we aimed to investigate CMV-specific T cell immune reconstitution among pediatric LT recipients. The recipients were monitored for CMV infection and CMV-specific T cells from the start of immunosuppressive therapy until 48 weeks after LT. Clinically significant CMV viremia (csCMV) requiring preemptive therapy was defined as a CMV load of >2000 IU/mL. Peripheral blood CMV-specific T cells were analyzed by flow cytometry based on IFNγ secretion upon stimulation with CMV antigens including immediate early protein 1 (IE1) Ag, phosphoprotein 65 (pp65) Ag, and whole CMV lysate (wCMV). Of the 41 patients who underwent LT, 20 (48.8%) had csCMV. Most (17/20 patients) were asymptomatic and characterized as experiencing CMV reactivation. The onset of csCMV occurred approximately 7 weeks after LT (interquartile range: 4-12.9); csCMV rarely recurred after preemptive therapy. Lower pp65-specific CD8+ T cell response was associated with the occurrence of csCMV (p = 0.01) and correlated with increased viral load at the time of csCMV diagnosis (ρ = -0.553, p = 0.02). Moreover, those with csCMV had lower percentages of IE1-specific CD4+ and wCMV-reactive CD4+ T cells at 12 weeks after LT (p = 0.03 and p = 0.01, respectively). Despite intense immunosuppressive therapy, CMV-specific T cell immune reconstitution occurred in pediatric patients post-LT, which could confer protection against CMV reactivation.

Initiation of renin-angiotensin system inhibitors and first complete remission in patients with primary nephrotic syndrome: a nationwide cohort study.

Evidence on renin-angiotensin system inhibitors (RASis) effect in reducing urinary protein levels in patients with nephrotic syndrome is insufficient. We determined whether RASis can induce complete remission (CR) in patients on immunosuppressive therapy. This cohort study included 84 adults (median age, 65years; males, 57%) with primary nephrotic syndrome (excluding minimal change disease) not receiving RASis during enrollment in the Japanese Nephrotic Syndrome Cohort Study from January 2009 to December 2010, and were followed up for 5years. Exposure and outcome were RASi initiation and first CR, respectively. Marginal structural models and Poisson regression were used to account for time-varying covariates and estimate causal effects of RASis on CR. Overall, 51 (61%), 73 (87%), and 55 (66%) patients had membranous nephropathy, were prescribed immunosuppressive agents at baseline (1-month post-renal biopsy and/or at start of immunosuppressive therapy), and were prescribed RASis during the study period, respectively. Sixty-five patients experienced firstCR (incidence rate, 5.05/100 person-months). RASi use was associated with a higher (adjusted incidence rate ratio [aIRR] 2.27, 95% confidence interval [CI] 1.06-4.84), and lower (aIRR: 0.17, 95% CI 0.04-0.68) firstCR in patients with membranous nephropathy and other pathologies, respectively. RASis are beneficial as adjuvant therapy for inducing remission in patients with membranous nephropathy.

Severe infections and renal dysfunction during immunosuppressive therapy with cyclosporine A for aplastic anemia.

Although immunosuppressive therapy (IST) with cyclosporine A (CyA) has been widely used in patients with aplastic anemia (AA), little attention has been given to its safety. This study aimed to clarify the adverse events of IST in patients with AA. We retrospectively identified 42 patients with AA treated with IST. Seventeen of the 42 patients (40%) experienced severe infection at a median of 142days from the start of IST, and 18 (49%) experienced renal dysfunction at a median of 73days. A large proportion of infected patients had severe AA (90 vs. 14%, p = 0.056). Notably, all patients with severe infection showed poor response to IST at the time of infection onset. Analysis regarding risk factors for renal dysfunction showed that median age at the initiation of IST was significantly higher in patients with renal dysfunction than those without renal dysfunction (65years vs. 44years, p = 0.020). Only 2 of 18 patients showed improvement in serum creatinine levels despite reduction or discontinuation of CyA. Our results suggest that poor responders to IST and elderly patients are at higher risk of severe infection and renal dysfunction, respectively.

POS0911 DIAGNOSTIC VALUE AND CLINICAL RELEVANCE OF MUSCLE BIOPSY IN PATIENTS WITH SUSPECTED MYOSITIS

BackgroundDiagnosis of idiopathic inflammatory myopathies (IIM) represents a clinical challenge and muscle biopsy itself is regarded as the cornerstone for confirming diagnosis of IIM. However, the significance of muscle biopsy as diagnostical tool remains inconclusiveObjectivesTo determine the diagnostic accuracy and clinical relevance of muscle biopsy in patients with suspected myositis.MethodsIn this retrospective cohort study, histopathological findings of muscle biopsy specimens of adult (≥ 18 years of age) patients with clinically suspected or differential diagnosis of myositis referred from all over Austria to the Medical University of Vienna through the period of 01.01.2007-31.10.2021 were analyzed. Following information were extracted from handwritten assignment sheets: referral department, suspected diagnosis (inflammatory and/or non-inflammatory myopathy), sampling location, demographic, clinical, laboratory and serologic data, and imaging results.Histological findings were grouped in: 1) inflammatory, 2) non-inflammatory (neurogenic, metabolic etc.), 3) inflammatory and non-inflammatory mixed, and 4) normal. Clinical information on start of immunosuppressive treatment after muscle biopsy could be partly retrieved form electronical medical records (EMR). Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of histological results were calculated using clinical diagnosis (defined as initiation of immunosuppressive therapy) as gold standard.Results778 muscle biopsy specimens of 762 patients with suspected myositis (49.6% female, mean age of 56 years) were analyzed. Cohort descriptives are displayed in Table 1.Overall, 373/778 (47.9%) muscle biopsies revealed inflammatory features only or had mixed results with non-inflammatory characteristics. Out of 541 samples with suspected diagnosis of myositis, diagnosis was confirmed histologically in 300 (55.5%) cases; 46 (8.5%) specimens additionally showed co-features of non-inflammatory myopathy, whereas 221 (40.3%) were non-inflammatory at all and 15 (2.8%) were normal. Proportion of myositis was more pronounced, when CK was elevated at time of biopsy (Figure 1).Figure 1.From suspicion to histological verification depending on CK-levelsOut of 237 samples with differential diagnosis of non-inflammatory myopathy in addition to myositis, 53 (22.4%) were histology. confirmed as inflammatory only and 20 (8.4%) showed mixed features. 153 (64.6%) biopsies were non-inflammatory only and 8 (3.4%) normal. Samples with no pathological features were observed in 24/778 (2.3%) of the cases, with 0.8% sampling error (no muscle tissue).Of 421/778 (54.1%) patients, clinical data could be extracted from EMR of which 209/421 (49.6%) had histological features of inflammation. In 287/421 (68%) cases, information regarding initiation of immunosuppressive treatment were available on EMR. 224/287 (78%) patients received immunosuppression (steroids and/or disease-modifying anti-rheumatic drug [DMARD]), thus fulfilled clinical diagnosis of myositis. In 155/224 (69.2%) cases, muscle biopsy confirmed histology. features of inflammation. Tests on diagnostic accuracy of muscle biopsy using initiation of any immunosuppressive treatment as gold standard were performed. The sensitivity of the test (biopsy) for diagnosing IIM was 71.4% with a specificity of 79.6%. PPV was high (92.8%), whereas NPV low (43.1%).ConclusionLess than 50% of biopsy samples with suspected diagnosis of myositis histologically revealed an inflammatory myopathy. The percentage increased when CK levels were elevated. Sensitivity and specificity of muscle biopsy was moderate, when using start of immunosuppressive therapy as gold standard for IIM diagnosis.

Independent risk factors for myasthenic crisis and disease exacerbation in a retrospective cohort of myasthenia gravis patients

BackgroundMyasthenic crisis (MC) and disease exacerbation in myasthenia gravis (MG) are associated with significant lethality and continue to impose a high disease burden on affected patients. Therefore, we sought to determine potential predictors for MC and exacerbation as well as to identify factors affecting outcome.MethodsWe examined a retrospective, observational cohort study of patients diagnosed with MG between 2000 and 2021 with a mean follow-up of 62.6 months after diagnosis from eight tertiary hospitals in Germany. A multivariate Cox regression model with follow-up duration as the time variable was used to determine independent risk factors for MC and disease exacerbation.Results815 patients diagnosed with MG according to national guidelines were included. Disease severity at diagnosis (quantitative MG score or Myasthenia Gravis Foundation of America class), the presence of thymoma and anti-muscle specific tyrosine kinase-antibodies were independent predictors of MC or disease exacerbation. Patients with minimal manifestation status 12 months after diagnosis had a lower risk of MC and disease exacerbation than those without. The timespan between diagnosis and the start of immunosuppressive therapy did not affect risk. Patients with a worse outcome of MC were older, had higher MGFA class before MC and at admission, and had lower vital capacity before and at admission. The number of comorbidities, requirement for intubation, prolonged mechanical ventilation, and MC triggered by infection were associated with worse outcome. No differences between outcomes were observed comparing treatments with IVIG (intravenous immunoglobulin) vs. plasma exchange vs. IVIG together with plasma exchange.ConclusionsMC and disease exacerbations inflict a substantial burden of disease on MG patients. Disease severity at diagnosis and antibody status predicted the occurrence of MC and disease exacerbation. Intensified monitoring with emphasis on the prevention of infectious complications could be of value to prevent uncontrolled disease in MG patients.Graphical

Descriptive study of pneumococcal vaccination in cases of inflammatory disease: Analysis of practices

IntroductionPneumococcal infections are frequent and potentially serious in patients with inflammatory diseases treated with immunosuppressants and/or biotherapies. This patient population considered to be at very high risk of infection is subject to national vaccination recommendations. The main objective of this study was to assess pneumococcal vaccine coverage in a day hospital (internal medicine and vascular disease) in patients treated with immunosuppressants. MethodsAn observational, descriptive, retrospective, and single-center study. We included 150 consecutive patients for 3 months (February to April 2018). We studied pneumococcal vaccination coverage and the time elapsed between the date of vaccination with the 13-valent polysaccharide conjugate vaccine (PCV13) and the start of immunosuppressive therapy. ResultsAmong the 150 patients included in the study, vaccination coverage with PCV13 was 85% (127/150) and decreased to 46.7% (70/150) for the recommended vaccination schedule. Taking into account vaccine efficacy according to the date of initiation of the treatment, only 28.7% (43/150) of the patients in the study were able to benefit from an optimal complete vaccination schedule, i.e. 33.8% (43/127) among patients vaccinated with PCV13. ConclusionDespite official recommendations, vaccination coverage against pneumococcus remains insufficient in patients under immunosuppressants and/or biotherapies. In addition to the continued training of doctors, optimizing computer prescription of vaccines in view of facilitating vaccination tracing and having vaccination carried out at the site of consultation are avenues for improvement to be considered.

Study of the Outcome of Pediatric Patients with Aplastic Anemia treated with Immunosuppressive Therapy at Ain Shams University Pediatric Hospital

Abstract Background Aplastic anemia (AA) is life threatening disorder in pediatric age group with an increasing incidence nowadays. Hematopoietic stem cell transplant being the 1st line therapy; immunosuppressive therapy (IST) is the alternative therapy and is the most commonly used modality of treatment especially in the developing countries. Aim of the Work to assess the outcome of IST in children with severe and very severe AA. Patients and Methods Data for 23 children treated with IST from January 201 0 to January 201 9 (10 years) were retrieved from clinic records. IST included rabbit anti thymocyte globulin (ATG) along with cyclosporine A and another group were treated by sandimmune alone. Results Patient characteristics included median age (9) with 73.9% male and 26.1% female. With median interval between diagnosis and start of IST 2(1 -5) months and around 30.4% with hepatitis A associated aplastic anemia. Complete response, and no response were seen in 4 (50%) patients and 4(50%) patients, respectively in patients received ATG and sandimune. While in patients received sandimune alone complete response, partial response and no response were seen in 7(46.7%) patients, 5 (33.3%) patients, and 3 (20%) patients respectively. The median time to best response in the whole cohort was 2 months. There was no difference in outcome related to severity of AA, or higher Hb or platelet level. There was a significantly better rate of response in both groups of patients with higher initial TLC count (p = 0.001) initial ANC (p = 0.002), initial ALC (p = 0.001), and initial ARC (p = 0.014) before start of IST. An overall response rate in both groups around of 43.47% reported a 5-year OS. With 45.5 of patients with complete response had HAAA. A delayed time to complete response with prolonged requirement of cyclosporine therapy was detected in the study. Conclusion In a developing country setting, IST with ATG and cyclosporine seems to be an alternative treatment for children with aplastic anemia lacking MRD.

Study of the Outcome of Pediatric Patients with Aplastic Anemia treated with Immunosuppressive Therapy at Ain Shams University Pediatric Hospital

Abstract Background Aplastic anemia (AA) is life threatening disorder in pediatric age group with an increasing incidence nowadays. Hematopoietic stem cell transplant being the 1st line therapy; immunosuppressive therapy (IST) is the alternative therapy and is the most commonly used modality of treatment especially in the developing countries. Aim of the Work to assess the outcome of IST in children with severe and very severe AA. Patients and Methods Data for 23 children treated with IST from January 201 0 to January 201 9 (10 years) were retrieved from clinic records. IST included rabbit anti thymocyte globulin (ATG) along with cyclosporine A and another group were treated by sandimmune alone. Results Patient characteristics included median age (9) with 73.9% male and 26.1% female. With median interval between diagnosis and start of IST 2(1 -5) months and around 30.4% with hepatitis A associated aplastic anemia. Complete response, and no response were seen in 4 (50%) patients and 4(50%) patients, respectively in patients received ATG and sandimune. While in patients received sandimune alone complete response, partial response and no response were seen in 7(46.7%) patients, 5 (33.3%) patients, and 3 (20%) patients respectively. The median time to best response in the whole cohort was 2 months. There was no difference in outcome related to severity of AA, or higher Hb or platelet level. There was a significantly better rate of response in both groups of patients with higher initial TLC count (p = 0.001) initial ANC (p = 0.002), initial ALC (p = 0.001), and initial ARC (p = 0.014) before start of IST. An overall response rate in both groups around of 43.47% reported a 5-year OS. With 45.5 of patients with complete response had HAAA. A delayed time to complete response with prolonged requirement of cyclosporine therapy was detected in the study. Conclusion In a developing country setting, IST with ATG and cyclosporine seems to be an alternative treatment for children with aplastic anemia lacking MRD.

Anti-PLA2R1 Antibodies as Prognostic Biomarker in Membranous Nephropathy

IntroductionPersonalized treatment for patients with membranous nephropathy requires accurate prediction of the disease course at an early stage. In this study, we evaluated the value of baseline anti–phospholipase A2 receptor (PLA2R1) antibody titer as a prognostic biomarker in patients with PLA2R1-associated membranous nephropathy.MethodsIn this cohort study, we included 168 patients (118 men, 50 women) referred to our nephrology center between February 1995 and November 2016. Mean age was 52 ± 13 years. There were 156 patients with new-onset disease and 12 patients with a relapse (n = 10) or recent use of immunosuppressive therapy (n = 2). We measured anti-PLA2R1 titer at baseline and analyzed progression to severe disease (30% increase of serum creatinine or start of immunosuppressive therapy) as a primary study endpoint over 60 months.ResultsThere was a clear association between anti-PLA2R1 antibody titer and severity of the nephrotic syndrome. In univariate analysis, anti-PLA2R1 antibody titer was also associated with disease progression. However, in Cox proportional hazard models that included proteinuria and serum creatinine, anti-PLA2R1 antibody titer was no longer associated with clinical outcome. Results were similar when limiting the analysis to the patients with new-onset disease.ConclusionOur study questions the relevance of single measurement of anti-PLA2R1 antibodies at baseline as a prognostic biomarker in membranous nephropathy. Future studies are needed to determine the possible role of sequential measurements of anti-PLA2R1 antibodies as a prognostic biomarker of disease progression.

POS-138 SEVERE INFECTIONS IN ANTINEUTROPHIL CYTOPLASMIC ANTIBODY-ASSOCIATED VASCULITIS: CLINICO-BACTERIOLOGICAL PROFILE AND RISK FACTORS

Infections are the leading cause of morbidity and mortality in patients with Antineutrophil Cytoplasmic Antibody (ANCA) Associated Vasculitis (AAV) especially during the first year of follow-up. Indeed, patients with AAV are at high risk of infection because of immunodepression secondary to the vasculitis itself and to immunosuppressive therapies. Few studies have looked at this subject in our country. The aim of our study is to determine the clinical biological and bacteriological profile as well as the factors of gravity of severe infections during AAV. It was a retrospective monocentric study carried out in the department of internal medicine A at Charles Nicolle Hospital including patients followed for AAV between January 1973 and December 2016 who presented at least one severe infection. An infection was considered severe if it required hospitalization or intravenous antibiotic therapy or if it resulted in death. 68 patients were followed for AAV during the study period. 18 patients had at least one severe infection, that was 26.5% of all patients with AAV. The mean age at diagnosis was 50 +/-14 years. The sex ratio was 1. 39% of patients were hypertensive 22% diabetics and 50% smokers. The subtypes of VAA were: nine cases of microscopic polyangiitis, eight cases of granulomatosis with polyangiitis and one case of eosinophilic granulomatosis with polyangiitis. ANCA were positive in all of our patients. Renal involvement was noted in all cases, kidney biopsy was performed in 72% of cases. VAA treatment included corticostreroids cyclophosphamid mycophenolate mofetil and Rituximab. We have identified 55 infections, the median was three infections per patient [2-3,25]. The first infection occurred 41 days [1-443] after diagnostic confirmation and 30.5 days [-9 - 443] after the start of immunosuppressive therapy. Two of our patients died from infection before receiving any immunosuppressive treatment. The other patients received at least one immunosuppressive treatment before the first infection. The most frequent infectious sites were pulmonary (29% of cases) and urinary (20%). 74% of infections were bacterial 20% fungal and 6% viral. Microbiological documentation was possible in 55% of cases. Opportunistic infections accounted for 26.7% of documented infections. Eight patients received cotrimoxazole pneumocystosis prophylaxis. Seven deaths from septic shock resulted in an infection mortality of 10.3%.Age, comorbidities, type of vasculitis, the type of immunosuppressive therapy lymphopenia and the location of infection did not have a statistically significant relationship with death from septic shock. However, lymphopenia and plasma exchange were associated with hospitalization in intensive care. Infections are a common and serious complication during AAV. Preventive measures should be adopted such as anti-pneumocystosis prophylaxis but also the generalization of anti-pneumococcal vaccination and antiviral prophylaxis.

Early Predictors of Short-Term Prognosis in Acute and Acute Severe Autoimmune Hepatitis.

Presentation of autoimmune hepatitis (AIH) can differ from nonacute to acute autoimmune hepatitis (A‐AIH) with jaundice and acute severe autoimmune hepatitis (AS‐AIH) with jaundice and coagulopathy. The aim of the study was to evaluate the short‐term prognosis of different presentations of AIH and the influence of liver function improvement on short‐term prognosis. In this single‐center retrospective cohort study, AIH patients with repeatedly tested liver function at diagnosis and during at least 1 year of follow‐up were included. A‐AIH was defined as bilirubin >45 µmol and international normalized ratio (INR) <1.5. AS‐AIH was defined as bilirubin level >45 µmol/L and INR ≥1.5. Of the 81 included patients, 17 (21%) presented with A‐AIH, and 14 (17%) presented with AS‐AIH. After the start of immunosuppressive therapy, bilirubin, albumin, and INR normalized in 70%, 77%, and 69%, respectively, in a median of 2.6 months, 3 months, and 4 weeks, respectively, in patients with A‐AIH and AS‐AIH. Liver transplantation (LT)–free survival rate was 100% in nonacute AIH, 94% in A‐AIH, and 57% in AS‐AIH at 12 months after diagnosis. An increase of INR or bilirubin at 2 weeks was the best predictive factor for the need of LT within 12 months with a Youden’s index of 0.85. A‐AIH was present in 21%, and AS‐AIH was present in 17% of AIH patients. In the majority of patients, bilirubin, albumin, and INR normalized in the first months of treatment. Deterioration of liver function after 2 weeks of treatment should lead to rapid evaluation for LT and consideration of second‐line medication.

PS1121 ABSENCE OF GPI‐NEGATIVE CELLS AT DIAGNOSIS AND LOW NEUTROPHIL COUNT 2 MONTHS AFTER ATGAM BASED TREATMENT ARE ASSOCIATED WITH LOWER 6‐MONTH RESPONSE RATE IN ADULTS WITH (VERY) SEVERE APLASTIC ANEMIA

Background:In aplastic anemia (AA), allogeneic stem cell transplantation (AlloSCT) is proposed as first line treatment for young patients with a sibling donor. For all other patients, ATGAM‐based immunosuppressive therapy (IST) is the treatment of choice. After IST, recovery of blood counts can take up to 6 months. Patients with (very) severe AA ((V)SAA), with a neutrophil count &lt;0.2 or &lt;0.5 x 109/L respectively, remain at risk for infectious complications until blood count recovery. Timely identification of patients less likely to respond to IST could lead to earlier selection for second line treatment (either alloSCT or second line IST) in order to prevent prolonged neutropenia. In AA, the presence of glycophosphatidylinositol (GPI) negative cell clones at diagnosis is associated with a better response to IST in some studies. We hypothesized that the absence of GPI negative cells (&lt;0.1%) before IST and low neutrophil count 2 months after start of treatment are associated with a lower response rate 6 months after IST in (V)SAA patients.Aims:To Determine whether the presence of GPI negative cell clones before IST and a neutrophil count &lt;0.2 x 109/L 2 months after IST can predict for treatment refractoriness at 6 months in adult (V)SAA patients.Methods:The Dutch registry of adults with acquired aplastic anemia receiving ATGAM (40 mg/kg for 4 days intravenously) and ciclosporin as first‐line treatment contains data on all consecutive patients treated in 8 major hospitals (LUMC, A‐UMC, UMCG, R‐UMC, UMCN, EMC, MST and AZN) including baseline and monthly follow‐up data. Response at 6 months was defined as transfusion independency and neutrophil count &gt;0.5 x 109/L. Overall survival (OS) was evaluated with the Kaplan‐Meier method.Results:Between 2012 and February 2019, 73 patients, 47 with SAA and 26 with VSAA were registered. Median age at start of IST was 58 years (18–79) and the median follow up time was 21 months. The 6‐month OS probability was 96% for SAA and VSAA combined (88% for VSAA and 100% for SAA). 62 patients were evaluable for response 6 months after start of IST. Response was seen in 35 patients (56% (CI 44–68%)). At diagnosis, 36 patients had a detectable GPI negative cell clone. In 25 patients, GPI‐negative cells were not detected and in 12 patients the presence of GPI‐negative cells was not tested. The response rate 6 months after start of IST for patients with a GPI‐negative clone at diagnosis was 63% (CI 47–80%) versus 40% (CI 20–60%) for patients without a GPI‐negative clone. Median neutrophil count 2 months after start of IST was available for 57 patients. The majority of the patients (53) had a neutrophil count ≥ 0.2 x 109/L and in this group the response rate at 6 months was 58% (CI 45–71%). In contrast, of the 4 patients with neutrophil counts &lt;0.2 x 109/L at 2 months after IST, 1 died 3 months after IST and the remaining 3 patients were alive but non‐responding to IST at 6 months.Summary/Conclusion:Our analysis of a relatively old (V)SAA patient cohort treated with ATGAM based IST suggests that presence of GPI negative cells at diagnosis and the neutrophil count at 2 months could be used to predict response to first line IST. This knowledge could aid in the decision to start second line treatment (alloSCT or second‐line IST) in this vulnerable patient group.

The Effectiveness of Eltrombopag at the Different Stages of Aplastic Anemia and Probability of Clonal Expansion

Background. New insight into pathogenesis of aplastic anemia (AA) in conjunction with effectiveness of Eltrombopag allowes to recommend it for initial treatment of de novo AA. However, eltrombopag was an attractive option for patients at different stages of the therapy.Aim. In our study we present various application points of eltrombopag as a therapeutic option in patients (pts) at different stages of the disease.Materials and patients. We are presenting our single-center experience, that include 11 pts with acquired aplastic anemia (SAA/NSAA = 10/1) on different stages of the disease. All pts were divided into four groups. In the 1st group we included refractory pts after two (n=3) or three (n=2) lines of antithymocyte globulin (ATG) therapy. The 2nd group included two pts who received the second ATG course in combination with eltrombopag, after faild first ATG. In the 3rd group included 2 pts with refractoriness after 1 course of ATG, who couldn't receive the second ATG/CsA because of severe infections. The 4th group included two pts with one lineage thrombocytopenia but transfusion independent. The median time from the start of immunosuppressive therapy (IST) to beginning of eltrombopag was Me(min-max): 56(12-115), 51(8-94), 1(1-1), 69(37-100) months respectively. The daily dose of eltrombopag for pts was 100-150 mg.Results. Hematological response are present in 3 out of 5 pts in the 1st group. Median duration of eltrombopag treatment was 8,5 (3-12) months. It is necessary to note that responding pts were refractory to 2nd (n=1) or 3rd (n=2) ATG and transfusion dependence. All pts in the 2nd group achieve PR (Me duration eltrombopag treatment was 12 months). All pts from 3rd group achieved granulocytic response, that allowed to recover get out from infections and to hold the 2nd ATG. However in 1 pt monosomy 7 was detected by FISH in bone marrow after therapy. It was noted that before eltrombopag administration there were not cytogenetic aberrancies but there were myelodysplastic features by flow cytometry (low index of granularity in granulocytes, low HLA-DR expression of monocytes and high CD56 expression in both granulocytes and monocytes) and PNH-clone. After eltrombopag treatment and monosomy 7 detection we performed a FACS sorting and FISH-study for PNH+ and PNH- granulocytes. Monosomy 7 was found in PNH- but not in PNH+ granulocytes. From the 4th group thrombocytopenia resolved in 1 pt (11 months eltrombopag duration), in over case present threelineage relapse subsequently.Conclusion. Eltrombopag can be used in pts with long-term ineffective IST and as a bridge to the next step of IST. It is necessary to remain cautious about the earlier development of clonal complications, even in patients from the so-called favorable risk group with the PNH clone. DisclosuresNo relevant conflicts of interest to declare.

Rationale for the use of immunosuppressive therapy in patients with acute myocarditis

To date, the expediency of immunosuppressive treatment with corticosteroids in patients with myocarditis is one of the most controversial issues of modern cardiology. The purpose of the study was to establish predictors of corticosteroid therapy efficiency in patients with acute myocarditis. 47 patients with acute myocarditis were examined, who received immunosuppressive therapy for 6 months. All patients underwent for immune state assessment, echocardiography and cardiac magnetic resonance imaging. Statistical processing of the results was performed using Excel XP and Statistica for Windows v. 6.0 programming studying Student's criterion, parametric correlation analysis and distribution of the studied indicators by binary scale. It has been established that the appointment of immunosuppressive therapy in patients with high activity of immunopathological reactions of humoral type in the debut of myocarditis after 6 months of treatment leads to a decrease in the activity of autoimmune damage of the myocardium, recovery of left ventricular systolic function and improvement of heart failure functional class. The predictors of heart failure functional class improvement after 6-months of corticosteroid treatment were determined as: concentrations of immunoglobulin M&gt;2,5 g/l, CD19+ lymphocytes &gt;0,23 × 109/l, tumor necrosis factor α&gt;200 pg/ml, interleukin-1β &gt;150 pg/ml, content of circulating immune complexes &gt;75 un. opt. sq., titre of antibodies to myocardium &gt;20.0 conv. un. before the start of immunosuppressive therapy, as well as the absence of fibrotic changes in the left ventricular myocardium on cardiac MRI. Thus, early prognostic markers of the effectiveness of glucocorticoid therapy in patients with acute myocarditis were established. Further research should focus on the search for criteria of immunosuppressive therapy effectiveness and the introduction of clear recommendations for clinical practice that will contain indications and contraindications for its management in patients with myocarditis.

Risk Factors for Mortality in Pneumocystis jirovecii Pneumonia in Patients with Inflammatory Bowel Disease

Background: Pneumocystis jirovecii pneumonia (PJP) is highly fatal once infection is established. In this study, we investigated the risk of PJP mortality in patients with inflammatory bowel disease (IBD). Methods: We conducted a retrospective observational study of case data from IBD patients who developed PJP, compiled from 17 collaborating institutions. Parameters such as age, sex, medications used, and blood test results were analyzed to identify risk factors for mortality. Results: The mortality rate among the 28 IBD patients who developed PJP was 17.9%. A low serum albumin level at the start of IBD treatment was identified as a risk factor for mortality and showed the following association with probability of death (P): P = 1/[1 + exp(–5.5 + 2.4 × Alb). The probability of death exceeded 0.5 when serum albumin was 2.2 g/dL or lower. Conclusion: Patients with IBD who develop PJP have a high mortality rate and often cannot continue treatment with medication alone. Therefore, it is necessary to pay attention to albumin levels at the start of immunosuppressive therapy when creating a treatment plan.

Copeptin, a surrogate marker for arginine vasopressin, is associated with disease severity and progression in IgA nephropathy patients.

Besides its essential role for water homeostasis, arginine vasopressin (AVP) may have deleterious effects on the kidney. Copeptin, a surrogate marker for AVP, has been shown to be related to renal outcome in patients with diabetic nephropathy and polycystic kidney disease. We investigated the association of copeptin with disease severity and progression in immunoglobulin A nephropathy (IgAN). We included a prospective cohort of 59 patients with biopsy proven IgAN. Urinary excretion of α1 microglobulin (α1m), β 2 microglobulin (β2m), kidney injury molecule-1, neutrophil gelatinase-associated lipocalin and total protein were measured at baseline. Plasma copeptin was determined from stored baseline serum samples. Cox regression was performed for the composite renal outcome defined as doubling of serum creatinine, end-stage renal disease (ESRD) or start of immunosuppressive therapy, and for the individual components during 5-year follow-up. In IgAN patients [male: 72%, age: 42 ± 13 years, mean arterial pressure (MAP): 101 ± 12 mmHg, proteinuria: 1.4 (0.7-2.3) g/day, estimated glomerular filtration rate (eGFR): 48 ± 21 mL/min/1.73 m 2 ] median copeptin was 9.4 (5.3-18.4) pmol/L. At baseline, copeptin was associated with α1m [standardized beta (St. β) = 0.34, P = 0.009], β2m (St. β = 0.33, P = 0.01) and proteinuria (St. β = 0.36, P = 0.053), adjusted for sex and eGFR. During follow-up, the highest tertile of baseline copeptin was positively associated with the incidence of the composite renal outcome as well as with the individual components of doubling of creatinine, ESRD and start of immunosuppressive therapy. In Cox regression models, copeptin showed prognostic value over MAP, proteinuria and eGFR for the composite renal outcome. Copeptin is associated with disease severity and prognosis in IgAN patients and may have additional prognostic value besides established risk markers.

Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies treated with anticancer therapy.

Hepatitis due to hepatitis B virus (HBV) reactivation can be severe and potentially fatal, but is preventable. HBV reactivation is most commonly reported in patients receiving cancer chemotherapy, especially rituximab-containing therapy for hematological malignancies and those receiving stem cell transplantation. All patients with hematological malignancies receiving anticancer therapy should be screened for active or resolved HBV infection by blood tests for hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti-HBc). Patients found to be positive for HBsAg should be given prophylactic antiviral therapy to prevent HBV reactivation. For patients with resolved HBV infection, no standard strategy has yet been established to prevent HBV reactivation. There are usually two options. One is pre-emptive therapy guided by serial HBV DNA monitoring, whereby antiviral therapy is given as soon as HBV DNA becomes detectable. However, there is little evidence regarding the optimal interval and period of monitoring. An alternative approach is prophylactic antiviral therapy, especially for patients receiving high-risk therapy such as rituximab, newer generation of anti-CD20 monoclonal antibody, obinutuzumab or hematopoietic stem cell transplantation. This strategy may effectively prevent HBV reactivation and avoid the inconvenience of repeated HBV DNA monitoring. Entecavir or tenofovir are preferred over lamivudine as prophylactic therapy. Although there is no well-defined guideline on the optimal duration of prophylactic therapy, there is growing evidence to recommend continuing prophylactic antiviral therapy for at least 12 mo after cessation of chemotherapy, and even longer for those who receive rituximab or who had high serum HBV DNA levels before the start of immunosuppressive therapy. Many novel agents have recently become available for the treatment of hematological malignancies, and these agents may be associated with HBV reactivation. Although there is currently limited evidence to guide the optimal preventive measures, we recommend antiviral prophylaxis in HBsAg-positive patients receiving novel treatments, especially the Bruton tyrosine kinase inhibitors and the phosphatidylinositol 3-kinase inhibitors, which are B-cell receptor signaling modulators and reduce proliferation of malignant B-cells. Further studies are needed to clarify the risk of HBV reactivation with these agents and the best prophylactic strategy in the era of targeted therapy for hematological malignancies.

C-Reactive Protein in Idiopathic Inflammatory Myopathies

AbstractObjectives: To characterize C-reactive protein [CRP] in polymyositis [PM], dermatomyositis [DM], Jo-1 syndrome [Jo-1] and sporadic inclusion body myositis [sIBM].Methods: C-reactive protein obtained before the start of immunosuppressive therapy was analyzed retrospectively in 61 therapy naive patients [PM n = 27, DM n = 15, Jo-1 n = 5, sIBM n = 14]. All patients had a diagnosis of idiopathic inflammatory myopathy confirmed by muscle biopsy.Results: C-reactive protein was significantly higher in DM and Jo-1 compared to PM and sIBM [ANOVA p < 0.001]. The CRP levels less than twice the upper limit were found in 79% of sIBM patients, 85% of PM patients, 20% Jo-1 of patients, 53% of DM patients. C-reactive protein showed no correlation with creatine kinase and erythrocyte sedimentation rate.Conclusions: The CRP is elevated in a minority of patients with myositis, mostly associated with interstitial lung disease and malignancies.

Prevention of hepatitis B virus reactivation in patients receiving immunosuppressive therapy or chemotherapy

With the increasing use of potent immunosuppressive therapy, reactivation of hepatitis B virus (HBV) in endemic regions is becoming a clinical problem requiring special attention. A recent annual nationwide survey clarified that HBV reactivation related to immunosuppressive therapy has been increasing in patients with malignant lymphoma, other hematological malignancies, oncological or rheumatological disease. In the survey, rituximab plus steroid-containing chemotherapy was identified as a risk factor for HBV reactivation in hepatitis B surface antigen (HBsAg) negative patients with malignant lymphoma. In this setting, HBV reactivation resulted in fatal fulminant hepatitis regardless of the treatment of nucleoside analog. The Intractable Hepatobiliary Disease Study Group and the Study Group for the Standardization of Treatment of Viral Hepatitis Including Cirrhosis jointly developed guidelines for preventing HBV reactivation. The essential features of the guideline are as follows. All patients should be screened for HBsAg by a sensitive method before the start of immunosuppressive therapy. Second, hepatitis B core antigen (HBcAb) and hepatitis B surface antibody (HBsAb) testing should be performed in HBsAg negative patients, especially those receiving intensive immunosuppressive therapy. Prophylaxis with nucleoside analogs is essential for preventing HBV reactivation in HBsAg positive patients. In contrast, HBsAg negative with HBcAb and/or HBsAb positive patients should be monitored monthly for an increase in serum HBV DNA during and 12 months after completion of chemotherapy. Nucleoside analogs should be administrated immediately when HBV DNA becomes positive during this period. This strategy facilitates commencement of nucleoside analogs at an early stage of HBV reactivation and results in prevention of severe hepatitis.