Use Of Plasma Exchange Research Articles

Therapeutic plasma exchange in adults with severe COVID-19 infection

ObjectiveTo evaluate the therapeutic use of plasma exchange in COVID-19 patients compared to controls. MethodsA case series of critically ill adult men and non-pregnant women, ≥18 years of age, with laboratory-confirmed COVID-19, was studied at the Royal Hospital, Oman, from April 17 to May 11, 2020. Therapeutic plasma exchange (TPE) was performed on patients admitted to the intensive care unit (ICU) with confirmed or imminent acute respiratory distress syndrome (ARDS) or severe pneumonia. The analysis was performed using univariate statistics. ResultsA total of 31 COVID-19 patients were included with an overall mean age of 51±15 years (range: 27–76 years); 90% (n=28) were males, and 35% (n=11) of the patients had TPE as a mode of treatment. The TPE group was associated with higher extubation rates than the non-TPE cohort (73% versus 20%; p=0.018). Additionally, patients on TPE had a lower 14 days (0 versus 35%; p=0.033) and 28 days (0 versus 35%; p=0.033) post plasma exchange mortality compared to patients not on TPE. However, all-cause mortality was only marginally lower in the TPE group compared to the non-TPE group (9.1% versus 45%; p=0.055; power=66%). Laboratory and ventilatory parameters also improved post TPE (n = 11). ConclusionsThe use of TPE in severe COVID-19 patients has been associated with improved outcomes, however, randomized controlled clinical trials are warranted to draw final, conclusive findings.

One-Year Outcomes of Living Related Kidney Transplant in Patients With Preformed HLA Donor-Specific Antibodies: A Single-Center Experience in Malaysia

The shortage of deceased donors led to an increase of living related renal transplant performed in the presence of donor-specific antibodies (DSAs) or ABO incompatibilities. There are various desensitization protocols that have been proposed. Here, we describe the outcome of these sensitized patients.This is a prospective cohort study recruiting all kidney transplant recipients from August 2016 until June 2018. Deceased donations, ABO incompatible patients, and sensitized patients who were not prescribed on our desensitization protocol were excluded. Recipients were screened for the presence of HLA-antibodies 1 month before transplant. Those with positive DSA will undergo flow cytometry (risk stratification). We are using a protocol that consisted of intravenous rituximab 200 mg (day -14), intravenous antithymocyte globulin 5mg/kg (day 0-4), plasma exchange post transplant for patients with mean fluorescent intensity (MFI) < 3000, and negative flow cytometry. Those patients with MFI ≥ 3000 or positive flow cytometry need extra cycles pretransplant.A total of 40 patients were recruited, and 20 were sensitized patients. Among the sensitized group 4 of 20 had flow cytometry crossmatch positive, while all had preformed HLA-DSA. A total of 8 of 20 had class I HLA-DSA, 11 of 20 had class II HLA-DSA, and 1of 20 was positive for both class I and II HLA-DSA. Mean immunodominant MFI was 2133.4 (standard deviation [SD], 4451.24) and 1383.7 (SD, 2979.02) for class I and class II, respectively. At 1 year, mean serum creatinine was 108.90 (SD, 25.95) and 118.42 (SD, 31.68) in sensitized and unsensitized patients, respectively. One of 20 unsensitized patients had Banff 1B rejection at 3 months, and there was no significant rejection in sensitized patients at 6 months and 1 year. There was no difference in the occurrence of de novo HLA-DSA between the groups.Desensitization protocols may help to overcome incompatibility barriers in living donor renal transplant. The combination of low-dose rituximab, antithymocyte globulin, and judicious use of plasma exchange has worked well for our cohort.

Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis

BackgroundMore effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis.MethodsWe conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m2 of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD).ResultsDeath from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasma-exchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P=0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, −3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard-dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups.ConclusionsAmong patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K. National Institute for Health Research and others; PEXIVAS Current Controlled Trials number, ISRCTN07757494; ClinicalTrials.gov number, NCT00987389.)

Effect of Sugammadex on Postoperative Myasthenic Crisis in Myasthenia Gravis Patients: Propensity Score Analysis of a Japanese Nationwide Database.

In myasthenia gravis (MG) patients, postoperative myasthenic crisis, and residual neuromuscular blocking agent (NMBA) can cause respiratory failure that requires mechanical ventilation. However, it remains unclear whether the use of sugammadex for NMBA reversal reduces postoperative myasthenic crisis in MG patients undergoing surgery. We analyzed the association between use of sugammadex and postoperative myasthenic crisis in patients with MG using a national inpatient database. Adult patients with MG who received thymectomy under general anesthesia were identified in the Japanese Diagnosis Procedure Combination database from July 1, 2010 to March 31, 2016. Patients who received sugammadex (sugammadex group) were compared with those who did not receive sugammadex (control group). The primary outcome was postoperative myasthenic crisis, and the secondary outcomes were postoperative pneumonia, tracheostomy, 28-day mortality, total hospitalization costs, and length of stay after surgery. Propensity scores were estimated by logistic regression based on the following variables: age; sex; body mass index (BMI); smoking index; history of cancer; Charlson comorbidity index (CCI); type of thymectomy; time from hospital admission to surgery; use of plasma exchange, immunosuppressants, corticosteroids, anticholinesterase, and oral benzodiazepine before surgery; type of hospital; and treatment year. The outcomes were compared using stabilized inverse probability of treatment weighting (IPTW) analyses to obtain good between-group balance. Of 795 patients identified, 506 patients received sugammadex and 289 patients did not. After stabilized IPTW, the sugammadex group was associated with a decrease in postoperative myasthenic crisis (22/507 [4.3%] vs 25/288 [8.7%]; odds ratio [OR], 0.48; 95% confidence interval [CI], 0.25-0.91), but not associated with a decrease in postoperative pneumonia (5/507 [1.0%] vs 7/288 [2.4%]; OR, 0.44; 95% CI, 0.17-1.14) or tracheostomy (7/507 [1.4%] vs 10/288 [3.5%]; OR, 0.38; 95% CI, 0.12-1.22) compared with the control group. The sugammadex group had significantly lower median (interquartile range) total hospitalization costs ($13,186 [$11,250-$16,988] vs $14,119 [$11,713-$20,207]; P < .001) and median length of stay after surgery (10 [8-15] vs 11 [8-18] days; P < .001), compared with the control group. In this retrospective observational study, sugammadex was associated with reductions in postoperative myasthenic crisis and total hospitalization costs in adult patients with MG who received thymectomy. Given the present findings, sugammadex should be routinely administered for MG patients undergoing thymectomy.

Interventions for renal vasculitis in adults.

Renal vasculitis presents as rapidly progressive glomerulonephritis and comprises of a group of conditions characterised by acute kidney injury (AKI), haematuria and proteinuria. Treatment of these conditions involve the use of steroid and non-steroid agents in combination with plasma exchange. Although immunosuppression overall has been very successful in treatment of these conditions, many questions remain unanswered in terms of dose and duration of therapy, the use of plasma exchange and the role of new therapies. This 2019 publication is an update of a review first published in 2008 and updated in 2015. To evaluate the benefits and harms of any intervention used for the treatment of renal vasculitis in adults. We searched the Cochrane Kidney and Transplant Register of Studies up to 21 November 2019 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 investigating any intervention for the treatment of renal vasculitis in adults. Two authors independently assessed study quality and extracted data. Statistical analyses were performed using a random effects model and results expressed as risk ratio (RR) with 95% confidence intervals (CI) for dichotomous outcomes or mean difference (MD) for continuous outcomes. Forty studies (3764 patients) were included. Studies conducted earlier tended to have a higher risk of bias due to poor (or poorly reported) study design, broad inclusion criteria, less well developed disease definitions and low patient numbers. Later studies tend to have improved in all areas of quality, aided by the development of large international study groups. Induction therapy: Plasma exchange as adjunctive therapy may reduce the need for dialysis at three (2 studies: RR 0.43, 95% CI 0.23 to 0.78; I2 = 0%) and 12 months (6 studies: RR 0.45, 95% CI 0.29 to 0.72; I2 = 0%) (low certainty evidence). Plasma exchange may make little or no difference to death, serum creatinine (SCr), sustained remission or to serious or the total number of adverse events. Plasma exchange may increase the number of serious infections (5 studies: RR 1.26, 95% CI 1.03 to 1.54; I2 = 0%; low certainty evidence). Remission rates for pulse versus continuous cyclophosphamide (CPA) were equivalent but pulse treatment may increase the risk of relapse (4 studies: RR 1.79, 95% CI 1.11 to 2.87; I2 = 0%) (low certainty evidence) compared with continuous cyclophosphamide. Pulse CPA may make little or no difference to death at final follow-up, or SCr at any time point. More patients required dialysis in the pulse CPA group. Leukopenia was less common with pulse treatment; however, nausea was more common. Rituximab compared to CPA probably makes little or no difference to death, remission, relapse, severe adverse events, serious infections, or severe adverse events. Kidney function and dialysis were not reported. A single study reported no difference in the number of deaths, need for dialysis, or adverse events between mycophenolate mofetil (MMF) and CPA. Remission was reported to improve with MMF however more patients relapsed. A lower dose of steroids was probably as effective as high dose and may be safer, causing fewer infections; kidney function and relapse were not reported. There was little of no difference in death or remission between six and 12 pulses of CPA. There is low certainty evidence that there were less relapses with 12 pulses (2 studies: RR 1.57, 95% CI 0.96 to 2.56; I2 = 0%), but more infections (2 studies: RR 0.79, 95% CI 0.36 to 1.72; I2 = 45%). One study reported severe adverse events were less in patients receiving six compared to 12 pulses of CPA. Kidney function and dialysis were not reported. There is limited evidence from single studies about the effectiveness of intravenous immunoglobulin, avacopan, methotrexate, immunoadsorption, lymphocytapheresis, or etanercept. Maintenance therapy: Azathioprine (AZA) has equivalent efficacy as a maintenance agent to CPA with fewer episodes of leucopenia. MMF resulted in a higher relapse rate when tested against azathioprine in remission maintenance. Rituximab is an effective remission induction and maintenance agent. Oral co-trimoxazole did not reduce relapses in granulomatosis with polyangiitis. There were fewer relapses but more serious adverse events with leflunomide compared to methotrexate. There is limited evidence from single studies about the effectiveness of methotrexate versus CPA or AZA, cyclosporin versus CPA, extended versus standard AZA, and belimumab. Plasma exchange was effective in patients with severe AKI secondary to vasculitis. Pulse cyclophosphamide may result in an increased risk of relapse when compared to continuous oral use but a reduced total dose. Whilst CPA is standard induction treatment, rituximab and MMF were also effective. AZA, methotrexate and leflunomide were effective as maintenance therapy. Further studies are required to more clearly delineate the appropriate place of newer agents within an evidence-based therapeutic strategy.

Efficacy of plasma exchange in patients with ischemia-reperfusion syndrome of the lower extremities

Aim. Optimization of treatment of patients with critical lower limb ischemia in ischemia-reperfusion syndrome by a combination of infusion therapy and plasma exchange.&#x0D; Methods. The study included 58 patients (48 men, 10 women) aged 52 to 87 years (mean age 67.1±6.2 years) operated for critical lower limb ischemia. In the postoperative period all patients received standard conservative treatment. Depending on its effectiveness, the patients were divided into two groups: group 1 (n=30) with a positive response to the treatment and group 2 (n=28) where plasma exchange was required. The indications for plasma exchange were a decrease in the rate of diuresis &lt;0.5 ml/kg/h after the surgery for 4-6 hours, exceeding 5 times the normal values of creatine phosphokinase and 3 times the level of myoglobin.&#x0D; Results. In 48% of patients (group 2), deterioration of the condition was registered, which manifested by deterioration of the state, increase in shortness of breath, decrease in the rate of diuresis. In the laboratory analysis of patients of group 2, attention was drawn to an increase in the level of myoglobin to 287.8±30.1 ng/ml, creatine phosphokinase activity to 1769.3±191.8 u/l, and that of lactate to 2.2±0.3 mmol/l. These parameters exceeded not only the normal values, but also the indicators of group 1. These changes indicated the manifestation of ischemia-reperfusion syndrome and the threat of acute kidney injury. Plasma exchange was accompanied by clinical improvement (decrease in shortness of breath, increase in the rate of diuresis) and pronounced positive dynamics of laboratory parameters. The inclusion of plasma exchange into the complex therapy of ischemia-reperfusion syndrome was accompanied by an increase in the rate of diuresis by 1.7 times (p &lt;0.05), a decrease in the level of myoglobin by 3.1 times (p &lt;0.05) and the activity of creatine phosphokinase by 2.8 times (p &lt;0.05).&#x0D; Conclusion. The use of plasma exchange during the first hours of clinical and laboratory manifestations of ischemia-reperfusion syndrome can prevent the development of fatal complications associated with the progression of this syndrome.

Is there randomized controlled trial evidence to support the use of plasma exchange for remission induction in adults with renal vasculitis?

Is there randomized controlled trial evidence to support the use of plasma exchange for remission induction in adults with renal vasculitis?

Reversal of Severe Multiorgan Failure Associated With Sickle Cell Crisis Using Plasma Exchange: A Case Series.

Red blood cell exchange (RBCE) is the standard of care for patients with sickle cell disease (SCD) who present with severe vaso-occlusive crisis (VOC). However, subsets of these critically ill patients have progressive multiorgan failure (MOF) despite RBCE therapy. The purpose of this case series is to describe the use of plasma exchange (PLEX) for the treatment of SCD-related MOF that is refractory to RBCE. A retrospective case review of patients with severe MOF from sickle cell crisis unresponsive to RBCE who underwent PLEX in a 14-bed adult medical intensive care unit (ICU) at a tertiary care university hospital over a 4-year time period. Key laboratory data including complete blood count, indices of hemolysis, and markers of organ failure were recorded before and after both RBCE and PLEX. Our primary objective is to evaluate the effectiveness of PLEX, in addition to RBCE, on organ dysfunction, laboratory indices, and mortality. Of the 7 patients, 6 survived. Of the patients who survived, all remained hemodynamically stable during PLEX sessions and showed both clinical and laboratory evidences of improvement in hemolysis and organ function. Average time from completion of first PLEX treatment to initial laboratory signs of organ failure reversal for patients who survived was 15.6 hours, the average length of stay in the ICU was 5.6 days, and the average total length of stay in the hospital was 14 days. Plasma exchange, in addition to RBCE, may be a novel synergistic treatment option to decrease risk of mortality in patients with refractory VOC and MOF.

MON-308 MANAGEMENT OF HENOCH-SCHONLEIN PURPURA NEPHRITIS IN AUSTRALIA AND NEW ZEALAND: DOES IT DIFFER FROM KIDNEY DISEASE IMPROVING GLOBAL OUTCOMES GUIDELINES?

Henoch-Schönlein purpura (HSP) is the most common systemic vasculitis in children, with renal involvement occurring in 40-60% of paediatric patients within 4 to 6 weeks of the initial presentation. Majority of paediatric patients with HSP nephritis (HSPN) have mild disease, however a small proportion of patients present with renal impairment, nephrotic syndrome, or both. Kidney Disease Improving Global Outcomes (KDIGO) guidelines assist with management of different severities of HSPN but with low level of evidence. We aimed to evaluate the variance in current practice in management of paediatric HSPN by paediatric nephrologists in Australia and New Zealand. We designed an electronic survey consisting of various clinical scenarios of different severities in paediatric patients with HSPN. All of the questions were in multiple-choice format; majority allowing for participants to provide multiple management choices if required. The link to the survey was e-mailed to all members (trainees and consultants) of the Australian and New Zealand Paediatric Nephrology Association (ANZPNA). Survey was sent to 55 members of ANZPA. The responses were collated and analysed. The response rate was 30%, majority of the respondents being Staff Specialists of more than 10 years of experience. Majority of the respondents would commence treatment for mild HSPN with angiotensin converting enzyme inhibitors (ACEi), which is consistent with KDIGO guideline. Prednisolone was added in conjunction with ACEi for HSPN International Study of Kidney Diseases in Children (ISKDC) classification II and above. More complex HSPN including macroscopic haematuria and nephrotic-range proteinuria highlighted variability in practice amongst the ANZPNA group. For ISDKC classification IIIb and more, a non-steroid based immunosuppressive therapy was added to other therapies, but there was no consistency in treatment of choice. Rapidly progressive glomerulonephritis (RPGN) scenario was usually treated with IV methylprednisolone and cyclophosphamide with occasional use of plasma exchange. The majority of Australia and New Zealand Paediatric Nephrologists follow the KDIGO recommendations for treatment of mild HSPN. There is a wide variation in practice for moderate-to-severe HSPN with no consistency in choice of non-steroid immunosuppression, based on clinical presentation or histological findings except for RPGN. The wide variation in clinical practice highlights the lack of current evidence-based recommendations for HSPN treatment.

Rituximab for treatment of immune thrombocytopenia and thrombotic thrombocytopenic purpura

Although immune thrombocytopenia (ITP) and thrombotic thrombocytopenic purpura (TTP) appear similar, their symptoms differ. The number of domestic patients diagnosed with ITP and TTP annually has been estimated to be around 24,000 and 400, respectively. Moreover, no major differences in the incidence rate, age of onset, and prognosis have been observed between Europe, the United States (US), and Japan. Both ITP and acquired TTP are autoimmune diseases that require immunosuppressive therapy, though lethal TTP requires the use of plasma exchange in combination with immunosuppression. In Europe and the US, the monoclonal antibody rituximab has been widely used for ITP and TTP since approximately 10 years ago. However, no public health insurance indication has been available for rituximab in Japan. For this reason, investigator-initiated clinical trials were conducted. As a result, rituximab had subsequently been indicated for ITP in 2017. Meanwhile, TTP was designated as an intractable disease in Japan in 2015, and the first clinical practice guidelines were published in 2017. A single-arm study involving rituximab was conducted on high-risk patients in whom treatment with five plasma exchanges was ineffective or ADAMTS13 inhibitor was >2 BU/ml. Approval for the new indication of rituximab for acquired TTP is expected in 2019.

Visual Outcomes of Plasma Exchange Treatment of Steroid-Refractory Optic Neuritis: A Retrospective Monocentric Analysis

Introduction: In acute inflammatory optic neuritis (ON) as a typical onset of multiple sclerosis (MS), only few studies have investigated plasma exchange (PLEX) as a sequential treatment after insufficient response to high-dose intravenous glucocorticosteroids. Therefore, we aimed to investigate treatment outcome on visual acuity (VA) with PLEX in patients with steroid-refractory ON. Methods: In our retrospective monocentric study, medical records were screened for patients with acute ON as their first relapse with sequential MS diagnosis or with an established MS diagnosis from the Bern University Hospital (Switzerland) that were treated with PLEX between 2016 and 2018 due to lacking steroid response. VA prior to steroid administration, and before and after PLEX were assessed and compared using the Friedman multiple comparison test. Results: In total, 18 patients were included in the analysis. Interval from symptom onset to PLEX was 20.3 days (mean, 95% CI 14.8–25.9). Relevant functional improvement (VA of ≥0.5, after a mean of 15.9 (13.3–18.5) days after start of PLEX) was detected in 16/18 (88.9%) with a significant amelioration as compared to VA before glucocorticosteroids and before PLEX (p < 0.0001). VA improvement at a later time point (38.1 weeks, 25.2–51.0) was present in 15/16 (93.8%) patients. No serious adverse events were detected. PLEX could be performed via peripheral access in 13/18 patients (72.2%). Conclusion: Our study demonstrates significant improvements of VA with PLEX in a cohort of MS patients with steroid-refractory ON. High response rates may be due to the timely treatment initiation. Despite the small sample size, our data support the early use of PLEX in steroid-refractory ON with a favorable safety profile.

Therapeutic Plasma Exchange in Children With Thrombocytopenia-Associated Multiple Organ Failure: The Thrombocytopenia-Associated Multiple Organ Failure Network Prospective Experience.

The objective was to compare the resolution of organ dysfunction, 28-day mortality, and biochemical markers in children with thrombocytopenia-associated multiple organ failure who received therapeutic plasma exchange versus no therapeutic plasma exchange. Observational longitudinal cohort study. Nine U.S. PICUs. Eighty-one children with sepsis-induced thrombocytopenia-associated multiple organ failure. Therapeutic plasma exchange. Adjusted relative risk for 28-day mortality was modeled using standard multivariate regression with propensity score weighting to reduce covariate confounding. Change from baseline Pediatric Logistic Organ Dysfunction scores between therapeutic plasma exchange and no therapeutic plasma exchange differed in temporal pattern during the first week (p = 0.009). By day 4, mean Pediatric Logistic Organ Dysfunction score declined by 7.9 points (95% CI, -10.8 to -5.1) in the therapeutic plasma exchange-treated group compared with no change with no therapeutic plasma exchange. Use of therapeutic plasma exchange was associated with reduced 28-day mortality by multivariate analysis (adjusted relative risk, 0.45; 95% CI, 0.23-0.90; p = 0.02) and by propensity score weighting (adjusted relative risk, 0.46; 95% CI, 0.22-0.97; p = 0.04). Therapeutic plasma exchange use in thrombocytopenia-associated multiple organ failure was associated with a decrease in organ dysfunction. After accounting for several risk factors, 28-day all-cause mortality was lower in children treated with therapeutic plasma exchange compared with those receiving no therapeutic plasma exchange. A multicenter randomized clinical trial is necessary to determine a causal relationship.

Single Centre UK Comparison of Biosimilar Rituximab (Truxima) with the Originator (MabThera) in Patients with Immune Mediated Thrombotic Thrombocytopenic Purpura

INTRODUCTIONImmune thrombotic thrombocytopenic purpura (iTTP) is an acute, multisystem thrombotic microangiopathy mediated by immunoglobulin G (IgG) antibodies. These antibodies target the metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), which is vital for cleavage of von Willebrand factor. The resulting ADAMTS13 deficiency leads to microthrombi through platelet aggregation to Ultra-Large von Willebrand factor. If untreated the mortality rate in iTTP is in excess of 90%, but the use of plasma exchange (PEX) and immunosuppression has significantly reduced this (to between 10%-20%). Rituximab (a humanised anti-CD20 antibody, MabThera; Roche Pharmaceuticals), is now used routinely in iTTP in relapsed/refractory patients, but also acutely to prolong disease free-survival. The pre-emptive administration of rituximab in patients with a low ADAMTS13 has been shown to be effective in preventing clinical relapse.In 2013 the patent for rituximab expired in Europe and will expire in 2018 in the United States. The European Medicine Agency has now approved two Rituximab biosimilars for use in Europe. Biosimilar products are designed to have no meaningful differences from the reference/originator product. Truxima (CT-P10, a rituximab biosimilar) is approved for the treatment of RA, CLL and NHL in Europe, and we began using Truxima in iTTP in May 2017. Many other rituximab biosimilars exist and are in development.METHODOLOGYHere we report a retrospective cohort study of our patients with iTTP. Data from 84 patients was examined from a two-year time period May 2016-and May 2018, based on our pharmacy registry (having switched to the rituximab biosimilar in May 2017). 45 patients were treated with MabThera and 39 with the rituximab biosimilar Truxima. Laboratory parameters recorded included the patient's platelet counts, ADAMTS13 activity, and CD19 levels at D1, D28 and 3months following treatment. In addition, adverse reactions, and infective complications following treatment were also recorded. Statistical analysis was performed and means +/- 90% confidence interval calculated, with clinical equivalency compared based on clinically significant values.RESULTSFollowing MabThera/Truxima administration on D1, at 28 days the mean platelet count (+/- SEM, x10^9/L) was 263.3 (+/-10.69) in patient treated with MabThera and 263.8 (+/-11.81) with Truxima (90% CI -24.95 to 27.91), and remained similar at 3months at 275.8 (+/- 10.05) and 275.9 (+/- 12.2) respectively (90% CI -25.96 to 26.2). The ADAMTS13 (+/- SEM) at 28 days was 50.87 iu/dL (+/-4.899) in patients treated with MabThera and 50.88 iu/dL (+/- 4.371) for Truxima (90% CI 11.01-11.03), rising to 85.4 iu/dL (+/- 5.237) and 81.35 iu/dL (+/- 4.549) respectively at 3 months (90% CI 15.84-7.71). CD19 levels at 28 days in patients treated with MabThera had fallen to 0.00259 (x10^9/L)(+/- 0.00049) and 0.02151 (+/- 001161) with Truxima (90% CI 0.00073 to 0.037120), and were 0.01782 (+/- 0.01033) and 0.02098 (+/- 0.01042) respectively at 3 months (90% CI -0.02139 to 0.02771), all demonstrating a marked reduction from baseline means of 0.3247(+/-0.05721) and 0.2456 (+/-0.03016) respectively. The median number of infusions in both groups was 4 (range 1-8). Infusion reactions were comparable between both groups, with infusion reactions occurring in 33% of the MabThera treated patients, and 40% in the Truxima group. Infective complications (principally urinary tract infections) were comparable between both groups, 15% in the MabThera group and 18% in the truxima cohort. The mean saving per patient per treatment course cost was >£4000.DISCUSSIONRituximab is now off patent in Europe, and the EMA approval of Biosimilars offers an opportunity for significant cost savings as demonstrated here. Rituximab has been well established in iTTP, and rituximab biosimilars have demonstrated equivalence to the originator in rheumatoid arthritis and follicular lymphoma. Here we report the first published series of the rituximab biosimilar Truxima in iTTP, and demonstrate equivalence in terms of ADAMTS13 recovery, CD19 depletion, and platelet count at 28days and 3 months post administration, in addition to showing comparable infusion and infective complications. DisclosuresCheesman:Celltrion: Other: Speaker Fee; Roche: Other: Advisory board. Scully:Novartis: Honoraria, Other: Member of Advisory Board, Speakers Bureau.

Thrombotic Microangiopathies Associated with Pregnancy: Diagnostic and Therapeutic Challenges

Several serious disorders may present during pregnancy or postpartum with thrombotic microangiopathy (p-TMA). Signs of microangiopathic hemolytic anemia and thrombocytopenia may arise due to pregnancy complications such as severe preeclampsia (sPE) and HELLP-syndrome (hemolysis, elevated liver enzymes, and low platelets) or severe independent diseases: atypical hemolytic uremic syndrome (aHUS), thrombotic thrombocytopenic purpura (TTP). Recent evidence and clinical similarities suggest a link sPE/HELLP to aHUS, a disease of excessive activation of the alternative complement pathway. Pregnancy-associated aHUS is a severe disorder with a high risk of maternal and fetal morbidity and mortality, defined by the occurrence of comlement-mediated TMA without ADAMTS13 deficiency. Triggered by pregnancy and another complement-amplifying conditions women develop the syndrome, leading to a disastrous hemolytic disease characterized by diffuse endothelial damage and platelet consumption. Delivery is the treatment of choice of sPE and HELLP, but can lead to progression in case of aHUS: even now it is associated with unfavorable outcomes.We observe 116 women with p-TMA: 43 aHUS, 36 HELLP, 35 sPE, 2 TTP. PE diagnosed in accordance with the WHO criteria of 2008. HELLP- in accordance with Tenessee criteria (laboratory parameters normalized beyond 48-72 hours after delivery). TTP was associated with ADAMTS 13 deficiency <10%. We compare results with those of 28 healthy pregnant women. All patients with aHUS and TTP received plasma therapy (30-40ml/kg), in 20 cases of aHUS eculizumab was administered.The overall outcomes differed depending on the TMA type. Condition of PE/HELLP patients improved only with supportive treatment in 28-72 hours after delivery. Women with TTP received successful prolonged plasma exchange. Survival was the worst in aHUS patients 32(74.4%), among other patients with TMA no one died. Neonates survived in 33(76,7%) mothers with aHUS, 70(98,6%) with PE and HELLP. Sepsis diagnosed only in aHUS-15(34,9%). Acute kidney injury registered in 100% aHUS patients, neurological symptoms had 61%, respiratory distress syndrome- 55%, dilated cardiomyopathy- 16,7%. 61,3% required hemodialysis, 51,8%- respiratory care. All of patients who died had 2 “waves” of TMA: first wave damaged 2-5 organs without any proved infections, but treated with combination of antibiotics. Second TMA wave was fatal due to superimposed septic disorders, resistant to antibiotic therapy. Patients on eculizumab treatment had more severe disease at debut with shorter history of aHUS and responded well to eculizumab (recovery of TMA laboratory signs - 87,2%, but a full course was not held anyone). Survival of aHUS patients on eculizumab treatment was 81,4%, without it - 66,5%.All p-TMA are life-threatening disorders with different therapeutic approaches. Start therapy before specification of the diagnosis can be carried out with the use of plasma exchange for 24-48 hours. Patients with aHUS have a worst prognosis and require the rapid differential diagnosis. The revealed regularities allow us to assume the presence of the following triggers for the development of aHUS: surgical interventions and gestational complications. Early specific therapy complement inhibitor in complex with escalation treatment of multiple organ failure can contribute to the improvement of aHUS outcomes. DisclosuresNo relevant conflicts of interest to declare.

In vivo pathogenicity of IgG from patients with anti-SRP or anti-HMGCR autoantibodies in immune-mediated necrotising myopathy

ObjectivesIn autoimmunity, autoantibodies (aAb) may be simple biomarkers of disease or true pathogenic effectors. A form of idiopathic inflammatory myopathy associated with anti-signal recognition particle (SRP) or anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)...

Systematic review and meta-analysis for 2017 clinical practice guidelines of the Japan research committee of the ministry of health, labour, and welfare for intractable vasculitis for the management of ANCA-associated vasculitis

Objectives: To provide evidence for the revision of clinical practice guideline (CPG) for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) by the Japan Research Committee for Intractable Vasculitis.Methods: PubMed, CENTRAL, and the Japan Medical s Society were searched for articles published between January 1994 and January 2015 to conduct systematic review (SR), and the quality of evidence was assessed with GRADE approach.Results: Nine randomized controlled trials (RCTs) and two non-RCTs were adopted for remission induction therapy, three RCTs and two non-RCTs for plasma exchange, and five RCTs and one non-RCT for remission maintenance therapy. A significant difference was found in efficacy and safety for the following comparisons. In the non-RCT adopted for remission induction therapy, glucocorticoid (GC) + cyclophosphamide (CY) was significantly superior to GC monotherapy regarding remission. GC + intravenous CY for remission induction therapy was superior to GC + oral CY regarding death at one year, serious adverse events, and serious infection. Concomitant use of plasma exchange for remission induction therapy of AAV with severe renal dysfunction reduced risk of end-stage renal disease versus non-users at month 3.Conclusion: This SR provided necessary evidence for developing CPG for the management of ANCA-associated vasculitis.

Description of the Use of Plasma Exchange in Dogs With Cutaneous and Renal Glomerular Vasculopathy.

Cutaneous and renal glomerular vasculopathy (CRGV) is a rare disease affecting dogs, with a recent apparent increase in prevalence since 2012 in the UK. This disease is characterized by a vasculopathy affecting small vessels of the kidney and skin, leading to thrombotic microangiopathy. The underlying etiology remains unknown although clinicopathological and histological findings resemble features of certain forms of thrombotic microangiopathy in people, for which plasma exchange (PEX) is considered an important component of therapy. The objective of the present study is to describe the use of PEX as adjunctive treatment in dogs diagnosed with CRGV. A retrospective review of dogs diagnosed with CRGV between 2014 and 2016 treated with PEX was performed. Clinical records were reviewed and data relating to signalment, diagnostic tests and management strategies were summarized. Information and complications relating to PEX were recorded. Six dogs were diagnosed with CRGV (n = 2 ante-mortem, n = 4 post-mortem) and underwent PEX as part of their therapy. All dogs had cutaneous lesions and were azotemic with oliguria or anuria. All dogs underwent at least one PEX cycle; one dog had a single cycle PEX, three dogs two cycles PEX, and two dogs had one cycle PEX and one cycle of prolonged intermittent renal replacement treatment. Complications seen during PEX therapy included hypothermia (n = 4), tachycardia (n = 2), hypotension (n = 2), and hypocalcemia (n = 6). Two dogs survived to discharge, the remaining four dogs were euthanized. The positive outcome in two dogs treated with PEX despite the reported high mortality rate once acute kidney injury with oliguria/anuria occurs does not confirm success of this treatment. However, survival in two dogs that were initially oligoanuric highlights that further consideration and evaluation of PEX for this patient group is warranted for this specific disease. Additional studies are urgently needed to identify the underlying etiology of CRGV before more targeted therapies can be developed. Based on our findings, further evaluation of the role of PEX in this specific disease are warranted.

T69. Continuous Electroencephalogram (CEEG) as a biomarker for progression of Herpes Simplex Virus Encephalitis (HSE)

Introduction HSE is the most common cause of sporadic fatal encephalitis worldwide and remains a devastating disease despite antiviral therapy. Clinically, it is often characterized by fever, headache, seizures and focal neurologic signs. EEG can be an important tool in the diagnosis of HSV. In the acute stage, EEG can show different EEG patterns, commonly including lateralized periodic discharges (LPDs), sharp waves, focal or generalized slowing. As such, EEG can be used to monitor the progression of the disease in patients with treatment refractory HSE. Methods Case report of a patient with HSE who was monitored on CEEG throughout course of her disease. Results A 62-year old female with no history of neurologic disease, who presented with generalized weakness and lethargy for 2 weeks and rapidly deteriorated with encephalopathy, fever, and seizures. Lumbar puncture demonstrated elevated protein and WBC with positive HSV DNA. CEEG initially showed right prefrontal 2-Hz LPD’s. Over the next 48 h, these evolved into focal right prefrontal status epilepticus. After a period of iatrogenic burst suppression, the CEEG showed right frontotemporal LPD’s which evolved into right frontotemporal electrographic seizures. As the CEEG progressed, the right sided seizures appeared to have a more posterior temporal focus. Later, there was additional independent semi-rhythmic 2–4 Hz delta over the left frontotemporal region which was on the ictal-interictal continuum but did not clearly evolve into seizures. As the recording continued, there were left frontal LPD’s more than right-sided ones. The final CEEG demonstrated bilateral independent sharp waves and generalized periodic discharges (GPD’s) with triphasic morphology with resolution of electrographic seizures. As the CEEG revealed evolution of the underlying disease, treatment was escalated with a 21 day course of acyclovir, multiple anti-epileptic agents, including suppressing medications (i.e., midazolam and ketamine), as well as use of plasma exchange and steroids given the refractory seizures. MRI was obtained at three points during hospital stay and confirmed what CEEG heralded. Initially, there was diffusion restriction of the bilateral (right > left) insular cortices and right hippocampus/amygdala. Repeat MRI showed diffusion normalization with T2-weighted and FLAIR hyperintensity in the right > left insula and new involvement of the right temporal lobe. The final MRI demonstrated involvement of the bilateral inferior frontal regions and left temporal lobe, consistent with evolution from the prior studies and with new findings seen on CEEG, suggesting spread of HSE to these regions. Conclusion We report the case of a patient with HSE who was monitored on CEEG and propose that CEEG can be used as a marker for progression of disease and thus may prompt escalation in therapy. While imaging studies may confirm spread of disease, using CEEG may prevent the delay of treatment and lead to more rapid therapy in cases of refractory HSE.

De novo antineutrophil cytoplasmic antibody-associated vasculitis in pregnancy: a systematic review on maternal, pregnancy and fetal outcomes.

ABSTRACTBackground De novo antineutrophil cytoplasmic antibody-associated vasculitis typically arises in post-reproductive years, but can occur during pregnancy. Concerns of treatment-related teratogenicity persist, while efficacy and safety of new therapies including intravenous immunoglobulin (IVIG) and rituximab are uncertain. There remains a paucity of maternal, fetal and pregnancy outcome data in these women, and therefore a lack of guidance on safe treatment for clinicians.MethodsWe conducted a systematic review of the literature and a local, retrospective chart review of women with de novo antibody-associated vasculitis (AAV) in pregnancy. Cochrane, Embase and PubMed databases and relevant conference abstracts were searched. Patient demographics, clinical presentation, management and outcomes (maternal, fetal and pregnancy-related) were analyzed.ResultsTwenty-seven cases of de novo AAV in pregnancy were included. Women presented were from 5 to 39 weeks' gestation, of which a majority were in the second trimester (median 20 weeks). The median gravida of women was 2 and the median parity was 1. Women were treated with steroids (89%), cyclophosphamide (CYC) (37%), other immunosuppressive agents [azathioprine (AZA), IVIG, plasma exchange (PLEX)] or no therapy (11%). High rates of serious complications, including preeclampsia (29%) and maternal death (7%), were reported; however, most pregnancies resulted in live birth (73%). Prematurity was common; 73% of live births occurred prior to 37 weeks’ gestation and 40% prior to 34 weeks’ gestation. The majority of infants were born in the third trimester (median 34.5 weeks). Rates of pregnancy termination were high (23%) and only one intrauterine death was reported, shortly after initiation of therapy (4%). Congenital abnormalities were rare, with one infant having a solitary, pelvic kidney (6%) after maternal treatment with steroids, CYC and PLEX. Use of PLEX, IVIG and AZA increased after 2005, whereas CYC use decreased. Remission often occurred postpartum (60%).Conclusions De novo AAV in pregnancy can result in uncomplicated pregnancies; however, serious maternal risks exist. Further data on potentially pregnancy compatible therapies such as IVIG and rituximab are needed in this population.

Use of plasma exchange in pediatric severe sepsis in children's hospitals

Pediatric severe sepsis (PSS) is an important cause of death in children. Mortality increases in those with sepsis and multiple organ dysfunction syndrome (MODS). Plasma exchange (PE) has been used as an adjuvant therapy in sepsis, with trials demonstrating variable success. This observational retrospective cohort study aimed to characterize patient demographics, PE use, mortality and resource utilization in septic children from 43 children’s hospitals from 2004 to 2012. Of 49,153 PSS cases, 1.8% utilized PE. Utilization increased to 4.8% in those with sepsis and MODS. Comorbidities affected 72-74% of patients. PE patients noted a longer hospitalization than PSS patients (39 vs 17 days). Overall mortality was 14.1% in PSS, increasing to 32.1% in PSS patients receiving PE. Mortality was 22% and 44.4% in PE patients without and with MODS respectively. Mortality decreased over the study period in both PE subgroups. In conclusion, PE utilization in PSS remained stable throughout the study period while PSS mortality decreased over time. Children utilizing PE had a higher associated mortality, but also greater comorbidities and MODS prevalence, likely representing a predilection towards use in more critically ill patients. These data can provide demographic and outcome results to inform future PE trials in sepsis.