Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial.

BACKGROUND: Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. METHODS: PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin-angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. FINDINGS: Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6-110) was -2·7 mL/min per 1·73 m2 per year versus -3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1-week 110) was -2·9 mL/min per 1·73 m2 per year versus -3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI -0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (-42·8%, 95% CI -49·8 to -35·0, with sparsentan versus -4·4%, -15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. INTERPRETATION: Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function. FUNDING: Travere Therapeutics.

Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomised controlled trial.

OBJECTIVE: Following induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with history of relapse. Relapses are associated with increased exposure to immunosuppressive medications, the accrual of damage and increased morbidity and mortality. The RITAZAREM trial compared the efficacy of repeat-dose rituximab to daily oral azathioprine for prevention of relapse in patients with relapsing AAV in whom remission was reinduced with rituximab. METHODS: RITAZAREM was an international randomised controlled, open-label, superiority trial that recruited 188 patients at the time of an AAV relapse from 29 centres in seven countries between April 2013 and November 2016. All patients received rituximab and glucocorticoids to reinduce remission. Patients achieving remission by 4 months were randomised to receive rituximab intravenously (1000 mg every 4 months, through month 20) (85 patients) or azathioprine (2 mg/kg/day, tapered after month 24) (85 patients) and followed for a minimum of 36 months. The primary outcome was time to disease relapse (either major or minor relapse). RESULTS: Rituximab was superior to azathioprine in preventing relapse: HR 0.41; 95% CI 0.27 to 0.61, p<0.001. 19/85 (22%) patients in the rituximab group and 31/85 (36%) in the azathioprine group experienced at least one serious adverse event during the treatment period. There were no differences in rates of hypogammaglobulinaemia or infection between groups. CONCLUSIONS: Following induction of remission with rituximab, fixed-interval, repeat-dose rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse. TRIAL REGISTRATION NUMBER: NCT01697267; ClinicalTrials.gov identifier.

Plasma exchange and glucocorticoids to delay death or end-stage renal disease in anti-neutrophil cytoplasm antibody-associated vasculitis: PEXIVAS non-inferiority factorial RCT.

BACKGROUND: Anti-neutrophil cytoplasm antibody-associated vasculitis is a multisystem, autoimmune disease that causes organ failure and death. Physical removal of pathogenic autoantibodies by plasma exchange is recommended for severe presentations, along with high-dose glucocorticoids, but glucocorticoid toxicity contributes to morbidity and mortality. The lack of a robust evidence base to guide the use of plasma exchange and glucocorticoid dosing contributes to variation in practice and suboptimal outcomes. OBJECTIVES: We aimed to determine the clinical efficacy of plasma exchange in addition to immunosuppressive therapy and glucocorticoids with respect to death and end-stage renal disease in patients with severe anti-neutrophil cytoplasm antibody-associated vasculitis. We also aimed to determine whether or not a reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen with respect to death and end-stage renal disease. DESIGN: This was an international, multicentre, open-label, randomised controlled trial. Patients were randomised in a two-by-two factorial design to receive either adjunctive plasma exchange or no plasma exchange, and either a reduced or a standard glucocorticoid dosing regimen. All patients received immunosuppressive induction therapy with cyclophosphamide or rituximab. SETTING: Ninety-five hospitals in Europe, North America, Australia/New Zealand and Japan participated. PARTICIPANTS: Participants were aged ≥ 16 years with a diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis, and either proteinase 3 anti-neutrophil cytoplasm antibody or myeloperoxidase anti-neutrophil cytoplasm antibody positivity, and a glomerular filtration rate of < 50 ml/minute/1.73 m2 or diffuse alveolar haemorrhage attributable to active anti-neutrophil cytoplasm antibody-associated vasculitis. INTERVENTIONS: Participants received seven sessions of plasma exchange within 14 days or no plasma exchange. Oral glucocorticoids commenced with prednisolone 1 mg/kg/day and were reduced over different lengths of time to 5 mg/kg/day, such that cumulative oral glucocorticoid exposure in the first 6 months was 50% lower in patients allocated to the reduced-dose regimen than in those allocated to the standard-dose regimen. All patients received the same glucocorticoid dosing from 6 to 12 months. Subsequent dosing was at the discretion of the treating physician. PRIMARY OUTCOME: The primary outcome was a composite of all-cause mortality and end-stage renal disease at a common close-out when the last patient had completed 10 months in the trial. RESULTS: The study recruited 704 patients from June 2010 to September 2016. Ninety-nine patients died and 138 developed end-stage renal disease, with the primary end point occurring in 209 out of 704 (29.7%) patients: 100 out of 352 (28%) in the plasma exchange group and 109 out of 352 (31%) in the no plasma exchange group (adjusted hazard ratio 0.86, 95% confidence interval 0.65 to 1.13; p = 0.3). In the per-protocol analysis for the non-inferiority glucocorticoid comparison, the primary end point occurred in 92 out of 330 (28%) patients in the reduced-dose group and 83 out of 325 (26%) patients in the standard-dose group (partial-adjusted risk difference 0.023, 95% confidence interval 0.034 to 0.08; p = 0.5), thus meeting our non-inferiority hypothesis. Serious infections in the first year occurred in 96 out of 353 (27%) patients in the reduced-dose group and in 116 out of 351 (33%) patients in the standard-dose group. The rate of serious infections at 1 year was lower in the reduced-dose group than in the standard-dose group (incidence rate ratio 0.69, 95% confidence interval 0.52 to 0.93; p = 0.016). CONCLUSIONS: Plasma exchange did not prolong the time to death and/or end-stage renal disease in patients with anti-neutrophil cytoplasm antibody-associated vasculitis with severe renal or pulmonary involvement. A reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen and was associated with fewer serious infections. FUTURE WORK: A meta-analysis examining the effects of plasma exchange on kidney outcomes in anti-neutrophil cytoplasm antibody-associated vasculitis is planned. A health-economic analysis of data collected in this study to examine the impact of both plasma exchange and reduced glucocorticoid dosing is planned to address the utility of plasma exchange for reducing early end-stage renal disease rates. Blood and tissue samples collected in the study will be examined to identify predictors of response to plasma exchange in anti-neutrophil cytoplasm in antibody-associated vasculitis. The benefits associated with reduced glucocorticoid dosing will inform future studies of newer therapies to permit further reduction in glucocorticoid exposure. Data from this study will contribute to updated management recommendations for anti-neutrophil cytoplasm antibody-associated vasculitis. LIMITATIONS: This study had an open-label design which may have permitted observer bias; however, the nature of the end points, end-stage renal disease and death, would have minimised this risk. Despite being, to our knowledge, the largest ever trial in anti-neutrophil cytoplasm antibody-associated vasculitis, there was an insufficient sample size to assess clinically useful benefits on the separate components of the primary end-point: end-stage renal disease and death. Use of a fixed-dose plasma exchange regimen determined by consensus rather than data-driven dose ranging meant that some patients may have been underdosed, thus reducing the therapeutic impact. In particular, no biomarkers have been identified to help determine dosing in a particular patient, although this is one of the goals of the biomarker plan of this study. TRIAL REGISTRATION: This trial is registered as ISRCTN07757494, EudraCT 2009-013220-24 and Clinicaltrials.gov NCT00987389. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 38. See the NIHR Journals Library website for further project information.

Anti-neutrophil cytoplasm antibody vasculitis is a rare and severe disease in which the patient makes antibodies that damage their blood vessels. It can cause lung damage, kidney failure and early death. Treatment aims to suppress the harmful effects of the antibodies and associated inflammation. In particular: Plasma exchange aims to remove the antibodies from the bloodstream.Steroids aim to reduce the harmful activity of the antibodies. Unfortunately, plasma exchange is expensive and time-consuming, and we do not know if it really works long term to reduce kidney damage or the risk of death. We know steroids work, but they have many severe side effects that are related to higher doses. Again, we do not know if lower doses are equally effective. We conducted a randomised trial, PEXIVAS (Plasma Exchange In VASculitis), to measure the clinical effectiveness of plasma exchange and of reduced steroid doses. Anti-neutrophil cytoplasm antibody vasculitis patients with severe kidney or lung disease were allocated randomly to either plasma exchange or no plasma exchange. The same patients were then randomly allocated to a 'reduced' or 'standard' steroid dose. All patients received an immunosuppressive drug: cyclophosphamide or rituximab. The primary end point for both trials was the occurrence of either kidney failure or death. A total of 704 patients were recruited between 2010 and 2016, and they were followed up until the end of the trial in July 2017. Ninety-nine patients died and 138 developed kidney failure. Plasma exchange did not reduce the chances of death or kidney failure. There was also no difference between the two steroid dose groups in the number of deaths or patients developing kidney failure. However, there were fewer serious infections in the reduced steroid dose group. These results do not support the routine use of plasma exchange for all patients with severe vasculitis. They do show that the reduced-dose steroid regimen is just as effective as, and safer than, a 'standard'-dose steroid regimen. These results have the potential to save money and make the treatment of vasculitis patients safer in the future.

The Sound of Interconnectivity; The European Vasculitis Society 2022 Report.

The first European Vasculitis Society (EUVAS) meeting report was published in 2017. Herein, we report on developments in the past 5 years which were greatly influenced by the pandemic. The adaptability to engage virtually, at this critical time in society, embodies the importance of networks and underscores the role of global collaborations. We outline state-of-the-art webinar topics, updates on developments in the last 5 years, and proposals for agendas going forward. A host of newly reported clinical trials is shaping practice on steroid minimization, maintenance strategies, and the role of newer therapies. To guide longer-term strategies, a longitudinal 10-year study investigating relapse, comorbidity, malignancy, and survival rates is at an advanced stage. Disease assessment studies are refining classification criteria to differentiate forms of vasculitis more fully. A large international validation study on the histologic classification of anti-neutrophil cytoplasmic antibody (ANCA) glomerulonephritis, recruiting new multicenter sites and comparing results with the Kidney Risk Score, has been conducted. Eosinophilic granulomatosis with polyangiitis (EGPA) genomics offers potential pathogenic subset and therapeutic insights. Among biomarkers, ANCA testing is favoring immunoassay as the preferred method for diagnostic evaluation. Consolidated development of European registries is progressing with an integrated framework to analyze large clinical data sets on an unprecedented scale.

Treatment preferences for primary membranous nephropathy: Results of a multinational survey among nephrologists in the South Asia Pacific region.

AIM: There is no clear consensus on how best to treat primary membranous nephropathy (PMN). This study aimed to ascertain prevailing views among nephrologists on their choice of immunosuppressive agents to treat this disease. METHODS: The Australasian Kidney Trials Network conducted a multinational online survey among nephrologists from the South Asia-Pacific region to identify prescribing practices to treat PMN. Survey questions focused on the types of immunosuppressive therapies used, preferred first-line and second-line therapies, indications for starting immunosuppressive therapy, the preferred mode of combining corticosteroid and cyclophosphamide, the use of serum phospholipase A2 receptor antibody testing in clinical practice, indications for anticoagulation, and interest in participating in future clinical trials in PMN. RESULTS: One hundered fifty-five nephrologists from eight countries responded to the online survey. The majority of them were senior nephrologists from Australia and India with significant experience managing patients with PMN. The combination of cyclophosphamide and corticosteroid was the preferred first-line therapy. Of those who used this combination, only 34.8% followed the Kidney Disease Improving Global Outcomes (KDIGO) 2012 guidelines by adding intravenous methylprednisolone. The combination of calcineurin inhibitor with corticosteroid was the most common second-line therapy. Most respondents considered prophylactic anticoagulation if serum albumin was less than 25 g/L. Most nephrologists were keen to participate in a clinical trial with a control arm consisting of cyclophosphamide and corticosteroids. CONCLUSION: The combination of corticosteroid with cyclophosphamide (without intravenous methylprednisolone) is the most commonly reported first-line immunosuppressive therapy for the management of PMN.

Characteristics and significance of "green snake" bites in Myanmar, especially by the pit vipers Trimeresurus albolabris and Trimeresurus erythrurus.

Snakebite is an important problem in Myanmar. Regionally, bites by Eastern Russell's vipers, Daboia siamensis (Viperidae, Viperinae), and monocled cobras, Naja kaouthia are considered medically important, but those categorised as "green snake" bites are not. However, these may include bites by green pit vipers, Trimeresurus spp. (Viperidae, Crotalinae) for which no antivenom is available in Myanmar. Elsewhere in Southeast Asia, these snakes are reported to cause local and systemic envenoming. As part of the Myanmar Snakebite Project, prospective case data were collected over 3 years from five hospitals in the Mandalay region. These included 3803 snakebite cases reported from Mandalay region. Of these, 355 were listed as bites by a witnessed green-coloured snake. In 22 cases, the snakes responsible were retained and preserved, then expertly identified; 21 were medically important white-lipped pit vipers (Trimeresurus albolabris), and one as an Asian vine snake, Ahaetulla prasina (Colubridae, Ahaetuliinae) which is not of medical importance. Among confirmed Trimeresurus albolabris bites, 15/21 developed swelling of the bitten limb, and 3/21 coagulopathy, defined as a positive 20-min whole blood clotting test (20WBCT). None developed necrosis, blistering, thrombocytopenia or acute kidney injury (AKI). Of the remaining 333 patients bitten by green snakes that were not specifically identified, 241 (72%) developed swelling of the bitten limb, and 62 (19%) coagulopathy. AKI occurred in 21/333 patients, but only one required dialysis. At least 10/21 of the cases with AKI in this study were more likely to represent bites from Trimeresurus spp. than D. siamensis because the snake responsible was brought into the hospital, examined and described by the treating physician as "green-coloured". This study describes a previously unpublished case of AKI from envenoming by T. erythrurus in Yangon, and reviews cases of AKI following bites by this species and T. albolabris in Myanmar. This confirms that, at least on rare occasions, Trimeresurus spp. envenoming can cause AKI. This has important implications for snakebite management in Myanmar as the finding of local swelling, coagulopathy and AKI is generally considered pathognomonic of D. siamensis envenoming. Further collection of confirmed Trimeresurus spp. bites is required in Myanmar in order better to define the syndrome of envenoming and to assess the possible need for antivenom against Trimeresurus spp. in this country.

Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis.

OBJECTIVES: Evaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial. METHODS: Patients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse. RESULTS: 188 patients were studied: 95/188 (51%) men, median age 59 years (range 19-89), prior disease duration 5.0 years (range 0.4-34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections. CONCLUSIONS: This large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies.

Clinical importance of the Mandalay spitting cobra (Naja mandalayensis) in Upper Myanmar - Bites, envenoming and ophthalmia.

Examination of 18 cobras brought to three hospitals in the Mandalay Region by patients bitten or spat at by them distinguished 3 monocled cobras (Naja kaouthia) and 15 Mandalay spitting cobras (N. mandalayensis), based on their morphological characteristics. We confirm and extend the known distributions and habitats of both N. mandalayensis and N. kaouthia in Upper Myanmar. Clinical symptoms of local and systemic envenoming by N. mandalayensis are described for the first time. These included local swelling, blistering and necrosis and life-threatening systemic neurotoxicity. More information is needed about the clinical phenotype and management of bites by N. mandalayensis, the commoner of the two cobras in Upper Myanmar. Since the current cobra antivenom manufactured in Myanmar has lower pre-clinical efficacy against N. mandalayensis than N. kaouthia, there is a need for more specific antivenom therapy.

Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis.

BACKGROUND: More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: We 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). RESULTS: Death 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. CONCLUSIONS: Among 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.).

Tracheobronchial calcification on bronchoscopy in a patient with end stage renal failure: an unusual cause of chronic cough.

Pulmonary calcification can develop as a complication of end-stage renal failure. Most patients are asymptomatic, with characteristic parenchymal changes incidentally detected on computed tomography (CT) imaging and a clinical course that is usually benign. In this report, we describe a 64-year-old female with a history of inadequate peritoneal dialysis who presented with severe chronic cough, a symptom that persisted despite treatment for respiratory tract infection. On follow-up bronchoscopic examination, white nodular tracheobronchial mucosal changes persisted. The presence of calcium deposits within these nodules was histologically confirmed, although CT imaging had not suggested the presence of calcific tracheobronchial changes. We believe that the bronchoscopic findings represent a highly unusual presentation of metastatic pulmonary calcification and an uncommon cause of chronic cough amongst patients with end-stage renal failure.

Inadequate knowledge about snakebite envenoming symptoms and application of harmful first aid methods in the community in high snakebite incidence areas of Myanmar.

INTRODUCTION: Every year millions of people in developing countries suffer from snakebite, causing a large number of deaths and long term complications. Prevention and appropriate first aid could reduce the incidence and improve the health outcomes for those who suffer bites. However, many communities where snakebite is a major issue suffer from a lack of information about prevention and first aid measures that a family or community member could take to prevent severe envenoming, complications and poor outcomes. Myanmar suffers from a high burden of snakebites with a large number of deaths. As part of a health services and community development program, a community survey was conducted to identify communities' knowledge about snakebite and their sequelae, and knowledge and practice about first aid and health services use. METHOD: 4,276 rural residents of Kyaukse and Madaya townships in the Mandalay region were recruited by cluster sampling, involving random selection of 144 villages and random sampling of 30 households from each village. One adult member of each household was interviewed using a structured questionnaire. RESULTS: The incidence of snakebite was 116/100,000 people. Respondents reported 15 different types of snakes in the area, with Russell's Viper, Cobra and Green snakes as the most common. 88% of the people informed that working in the fields and forests was when most of the bites occur. A majority knew about snakebite prevention methods such as wearing long boots. However, only a few people knew about the specific symptoms caused by snakebites. Only 39% knew about the correct methods of first aid. More than 60% mentioned tourniquet as a first aid method, though this may cause significant complications such as ischaemia of the limb. 88% said that they would take a snakebite victim to a government hospital, and 58% mentioned availability of antivenom as the reason for doing this. At the same time, the majority mentioned that traditional methods existed for first aid and treatment and 25% mentioned at least one harmful traditional method as an effective measure that they might use. CONCLUSION: The community is aware of snakebites as a major public health issue and know how to prevent them. However, the high incidence of snakebites point to lack of application of preventive methods. The community recognise the need for treatment with antivenom. However, inadequate knowledge about appropriate first aid methods, and a reliance on using tourniquets require a targeted education program. Existing knowledge in communities, albeit insufficient, provides a good starting point for mass media educational campaigns.

Mycophenolate mofetil versus cyclophosphamide for remission induction in ANCA-associated vasculitis: a randomised, non-inferiority trial.

OBJECTIVES: Cyclophosphamide induction regimens are effective for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but are associated with infections, malignancies and infertility. Mycophenolate mofetil (MMF) has shown high remission rates in small studies of AAV. METHODS: We conducted a randomised controlled trial to investigate whether MMF was non-inferior to cyclophosphamide for remission induction in AAV. 140 newly diagnosed patients were randomly assigned to MMF or pulsed cyclophosphamide. All patients received the same oral glucocorticoid regimen and were switched to azathioprine following remission. The primary endpoint was remission by 6 months requiring compliance with the tapering glucocorticoid regimen. Patients with an eGFR <15 mL/min were excluded from the study. RESULTS: At baseline, ANCA subtype, disease activity and organ involvement were similar between groups. Non-inferiority was demonstrated for the primary remission endpoint, which occurred in 47 patients (67%) in the MMF group and 43 patients (61%) in the cyclophosphamide group (risk difference 5.7%, 90% CI -7.5% to 19%). Following remission, more relapses occurred in the MMF group (23 patients, 33%) compared with the cyclophosphamide group (13 patients, 19%) (incidence rate ratio 1.97, 95% CI 0.96 to 4.23, p=0.049). In MPO-ANCA patients, relapses occurred in 12% of the cyclophosphamide group and 15% of the MMF group. In PR3-ANCA patients, relapses occurred in 24% of the cyclophosphamide group and 48% of the MMF group. Serious infections were similar between groups (26% MMF group, 17% cyclophosphamide group) (OR 1.67, 95% CI 0.68 to 4.19, p=0.3). CONCLUSION: MMF was non-inferior to cyclophosphamide for remission induction in AAV, but resulted in higher relapse rate. TRIAL REGISTRATION NUMBER: NCT00414128.

A comprehensive approach to managing a neglected, neglected tropical disease; The Myanmar Snakebite Project (MSP).

Snakebite is predominantly an occupational disease affecting poor rural farmers in tropical regions and was recently added to the World Health Organisation list of Neglected Tropical Diseases (NTD). We document an overview of methodologies developed and deployed in the Myanmar Snakebite Project, a foreign aid project largely funded by the Australian Government, with the core aim to "improve outcomes for snakebite patients". A multidisciplinary team of experts was assembled that worked in a collaborative manner with colleagues in Myanmar, first to identify problems related to managing snakebite and then develop interventions aimed to improve selected problem areas. A broad approach was adopted, covering antivenom production, antivenom distribution and health system management of snakebite. Problems identified in antivenom production included poor snake husbandry resulting in poor survival of captive specimens, lack of geographical diversity; poor horse husbandry, resulting in high mortality, inadequate stock acquisition protocols and data collection, and inappropriate immunisation and bleeding techniques; and inadequate production capacity for freeze dried antivenoms and quality control systems. These problems were addressed in various ways, resulting in some substantial improvements. Antivenom distribution is being reorganised to achieve better availability and utilisation of stock. Health system management of snakebite was assessed across all levels within the area selected for the study, in Mandalay region. A comprehensive community survey indicated that hospital statistics substantially underestimated the snakebite burden, and that access to care by local villagers was delayed by transport and cost issues compounded by lack of antivenom at the most peripheral level of the health service. A health system survey confirmed under-resourcing at the local village level. Prospective case data collection initiated at tertiary hospitals indicated the extent of the snakebite burden on health resources. Interventions initiated or planned include training of health staff, development of a core of senior trainers who can "train the trainers" nationwide in a sustainable way, development and deployment of management guidelines and algorithms for snakebite and a distribution of solar powered fridges to remote health facilities to allow storage of antivenom and prompt treatment of snakebite cases before transfer to major hospitals, thereby reducing the "bite to needle" time.

Twelve month prospective study of snakebite in a major teaching hospital in Mandalay, Myanmar; Myanmar Snakebite Project (MSP).

The Myanmar Snakebite Project is an Australian government (Department of Foreign Affairs and Trade) supported foreign aid project in collaboration with the Myanmar government with the aim of improving outcomes for snakebite patients in Myanmar. As part of the project a case record database was established to document prospective cases of snakebite presenting to Mandalay General Hospital, in Upper Myanmar. The study period was 12 months (1-2-2016 to 31-1-2017). Snake identity was based on a mixture of identified dead snakes brought with patients, doctor's clinical opinion and patient identification. 965 patients were enrolled during the 12 month period, of whom 948 were included for analysis. The male: female ratio was 1.58:1. Most cases involved bites to the lower limbs (82.5%) and adults involved in farm work, confirming snakebite as an occupational disease in this community. Motorised transport was by far the most common form of transport to health care and most patients sought care from the health system (87.7%), not traditional healers (11.5%) as their first point of contact. The officially promoted application of a pressure pad, bandage and immobilisation as first aid for snakebite was almost never used, while most patients used some form of tourniquet (92.0%). 85.4% of cases where a snake ID was listed were bitten by Russell's vipers. Russell's viper bites were responsible for all fatalities (9.8% of cases) and all cases of Acute Kidney Injury (AKI). For all cases, clinical features included local swelling (76.5%), local pain (62.6%), AKI (59.8%), incoagulable blood (57.9%), regional lymphadenopathy (39.8%), nausea/vomiting (40.4%), thrombocytopenia (53.6%), abdominal pain (28.8%), shock (11.8%), secondary infection (8.6%), panhypopituitarism (2.1%). AKI required renal replacement therapy (RRT) in 23.9% of cases, all ascribed to Russell's viper bite. Green pit viper bites were the next most common cause of bites (7.6%) and were associated with incoagulable blood (29%) and occasionally shock (5%) and local necrosis (3%), and in one case AKI not requiring RRT. In contrast to Russell's viper bites, green pit viper bite was most likely to occur in the home (49%). Some green pit viper patients were treated with Russell's viper antivenom (15%), presumably because they had incoagulable blood, although this antivenom is not effective against green pit viper envenoming. For the entire patient group, antivenom was given in 80.5% of cases. The most common indications were presence of coagulopathy/non-clotting blood (59.8%), local swelling (47.4%), oliguria/anuria (19.8%), heavy proteinuria (19.4%). A febrile reaction to antivenom was reported in 47.9% of cases, while anaphylaxis, occurred in 7.9% of cases.

Snakebite incidence in two townships in Mandalay Division, Myanmar.

INTRODUCTION: The global incidence of snakebite is estimated at more than 2.5 million cases annually, with greater than 100,000 deaths. Historically, Myanmar has one of the highest incidences of venomous snakebites. In order to improve the health outcomes of snakebite patients in Myanmar, access to accurate snakebite incidence data is crucial. The last population-based study in Myanmar was conducted more than a decade ago. In 2014, the Ministry of Health and Sports data from health facilities indicated an incidence of about 29.5 bites/ 100,000 population/year (a total of 15,079 bites). Since data from health facilities lack information about those who do not seek health care from government health services, a new population-based survey was conducted in 2 rural areas of Mandalay region. The survey data were compared to those obtained from healthcare services. METHOD: 4,276 rural respondents in Kyaukse and Madaya townships in Mandalay Division were recruited using cluster sampling that involved random selection of 150 villages and random sampling of 30 households from each village. One adult member of each household was interviewed using a structured questionnaire. RESULTS: One respondent from each of 4,276 households represented 19,877 residents from 144 villages. 24 people in these households had suffered snakebite during the last one year giving an annual incidence of 116/100,000. During the last ten years, 252 people suffered snakebites. 44.1% of the victims were women. 14% of the villages reported 4 or more bites during the last ten years, whereas 27% villages reported no snakebites. 92.4% of the victims recovered fully, 5.4% died, and 2% suffered long term health issues. One victim was reported to have died from causes unrelated to the snakebite. While there was no statistically significant difference between outcomes for children and adults, 4 of 38 of those under 18 years of age died compared to 7 of 133 adults between 19 to 40 years of age. CONCLUSION: This incidence reported by the community members points to substantially more snakebites than the number of snakebite patients attending health facilities. This higher incidence points to the need for a nation-wide population-based survey, community education about gaining access to care where antivenom is available, and to the potential need for a larger supply of antivenom and expansion of medical care in rural areas.

Development of an ELISA assay to determine neutralising capacity of horse serum following immunisation with Daboia siamensis venom in Myanmar.

Snakebite envenoming is a serious problem in Myanmar. The great majority of snakebite in this country is due to Russell's Viper (Daboia siamensis). For many years, the Burma Pharmaceutical Industry has produced a monovalent antivenom to Russell's Viper in horses. At present, the only way of determining the level of antibody against D. siamensis venom in hyperimmune horse serum is to perform venom neutralisation tests in mice. In this study, we describe the development of an in vitro ELISA assay to estimate neutralising capacity of horse serum. We found a strong correlation between the ELISA assay and the venom neutralisation test in mice (r = 0.982). The assay is robust and has sufficient sensitivity (92%) and specificity (96%) to replace the venom neutralisation test in mice during the immunisation phase in horses.

Why snakebite patients in Myanmar seek traditional healers despite availability of biomedical care at hospitals? Community perspectives on reasons.

BACKGROUND: Snakebite is a major public health problem in many developing countries. Farmers are particularly exposed to snakes, and due to their rural location often experience delays in accessing formal healthcare. The reasons to use traditional healers may include difficulties in accessing formal healthcare, certain beliefs about snakes and snake venom, tradition, and trust in the capacity of traditional healers. Traditional healing, however, may have serious consequences in terms of delays or added complications. There is little in-depth current information about the reasons for its continued use for snakebite. As part of a health services development project to improve health outcomes for snakebite patients, community attitudes to the use of traditional healers were explored in the Mandalay region of Myanmar. METHODOLOGY & FINDINGS: With the objective of learning from local communities, information was generated in three communities using participatory appraisal methods with the communities, and focus group discussions with the local healthcare staff. Many snakebite victims in these communities use traditional healing. Reasons include transport difficulties, low cost for traditional healing, inadequacy of anti-snake venom in the formal healthcare sector, and traditional beliefs, as traditional healing practices are rooted in many cultural and traditional factors. The communities reported that even if access to medical care were improved, traditional healing would continue to be used. CONCLUSION: These findings point to the need for working with traditional healers for prevention, appropriate first aid and timely access to effective treatment for snakebite.

Long-term outcomes of end-stage kidney disease for patients with lupus nephritis.

Patient outcomes in end-stage kidney disease (ESKD) secondary to lupus nephritis have not been well described. To help define this we compared dialysis and transplant outcomes of patients with ESKD due to lupus nephritis to all other causes. All patients diagnosed with ESKD who commenced renal replacement therapy in Australia and New Zealand (1963-2012) were included. Clinical outcomes were evaluated in both a contemporary cohort (1998-2012) and the entire 50-year cohort. Of 64,160 included patients, 744 had lupus nephritis as the primary renal disease. For the contemporary cohort of 425 patients with lupus nephritis, the 5-year dialysis patient survival rate was 69%. Of 176 contemporary patients with lupus nephritis who received their first renal allograft, the 5-year patient, overall renal allograft, and death-censored renal allograft survival rates were 95%, 88%, and 93%, respectively. Patients with lupus nephritis had worse dialysis patient survival (adjusted hazard ratio 1.33, 95% confidence interval 1.12-1.58) and renal transplant patient survival (adjusted hazard ratio 1.87, 95% confidence interval 1.18-2.98), but comparable overall renal allograft survival (adjusted hazard ratio 1.19, 95% confidence interval 0.84-1.68) and death-censored renal allograft survival (adjusted hazard ratio 1.05, 95% confidence interval 0.68-1.62) compared with ESKD controls. Similar results were found in the entire cohort and when using competing-risks analysis. Thus, the ESKD of lupus nephritis was associated with worse dialysis and transplant patient survival but comparable renal allograft survival compared with other causes of ESKD.

Long-term outcomes of end-stage kidney disease for patients with IgA nephropathy: A multi-centre registry study.

BACKGROUND: Clinical outcomes of patients with end-stage kidney disease (ESKD) receiving renal replacement therapy (RRT) secondary to IgA nephropathy (IgAN) have not been well described. AIM: To investigate the characteristics, treatments and outcomes of ESKD because of kidney-limited IgAN and Henoch-Schönlein purpura nephritis (HSPN) in the Australian and New Zealand RRT populations. METHODS: All ESKD patients who commenced RRT in Australia and New Zealand between 1971 and 2012 were included. Dialysis and transplant outcomes were evaluated in both a contemporary cohort (1998-2012) and the entire cohort (1971-2012). RESULTS: Of 63 297 ESKD patients, 3721 had kidney-limited IgAN, and 131 had HSPN. For the contemporary cohort of IgAN patients on dialysis (n = 2194), 10-year patient survival was 65%. Of 1368 contemporary IgAN patients who received their first renal allograft, 10-year patient, overall renal allograft and death-censored renal allograft survival were 93%, 82% and 88%, respectively. Using multivariable Cox regression analysis, patients with IgAN had favourable dialysis patient survival (adjusted hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.57-0.69), overall renal allograft survival (HR 0.67, 95% CI 0.57-0.79) and renal transplant patient survival (HR 0.58, 95% CI 0.45-0.74) compared with ESKD controls. Similar results were found in the entire cohort and when using competing-risks models. Compared with kidney-limited IgAN patients, those with HSPN had worse dialysis patient survival (HR 1.94, 95% CI 1.02-3.69), overall renal allograft survival (HR 3.40, 95% CI 1.00-11.55) and renal transplant patient survival (HR 3.50, 95% CI 1.03-11.92). CONCLUSION: IgAN ESKD was associated with better dialysis and renal transplant outcomes compared with other forms of ESKD. The survival outcomes of ESKD patients with HSPN were worse than kidney-limited IgAN.