Rapid Tapering Research Articles

Pediatric CLIPPERS? Think Again! (P5-5.032)

<h3>Objective:</h3> To present a rare diagnosis of familial hemophagocytic lymphohistiocytosis (FLH) in an adolescent patient with clinical and imaging findings supportive of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). <h3>Background:</h3> CLIPPERS is an exceedingly rare and often under-recognized diagnosis in the pediatric population. One-third of adult patients presenting with CLIPPERS were recently found to have hemophagocytic lymphohistiocytosis (HLH) gene mutations. FLH is the result of mutations within the FHL-associated gene family, resulting in a dysfunctional inflammatory response. The central nervous system-restricted form of FLH is a potentially curable novel syndrome with limited published data. <h3>Design/Methods:</h3> Case report. <h3>Results:</h3> A 17-year-old right-handed young man presented subacutely with headache, diplopia, dysarthria, and ataxia, suggestive of a pontocerebellar syndrome. Brain magnetic resonance imaging (MRI) revealed T2 hyperintensities associated with miliary enhancement throughout the cortical, subcortical, and infratentorial white matter bilaterally, with a predilection to the pons and cerebellar peduncles, a pattern highly suggestive of CLIPPERS. He dramatically improved clinically and radiologically with empirical intravenous methylprednisolone. Unfortunately, a rapid tapering of prednisone resulted in disease recurrence. Workup for HLH per the Histiocyte Society guidelines-2004 was unremarkable. Serum perforin/granzyme B assay revealed markedly reduced perforin and unchanged granzyme expression in the natural killer and CD8 cells. Genetic testing revealed two heterozygous mutations in the PRF1 (perforin) gene. He was confirmed to have FLH, initiated emapalumab therapy, and received a hematopoietic stem cell transplantation. <h3>Conclusions:</h3> Our case supports the reported relationship between CLIPPERS and HLH. CLIPPERS might be a syndrome rather than a separate disease entity. While FHL is more likely in infancy, pediatric CLIPPERS is rare and calls for further investigations to reach a final diagnosis. However, FHL was recently reported in adults thanks to the continuous advancements in genetic testing for HLH, helping clinicians expedite the diagnosis and management of patients with HLH. <b>Disclosure:</b> Dr. Zhou has nothing to disclose. Dr. Darwish has nothing to disclose. Dr. Ford has nothing to disclose. Dr. Patel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sobi Inc. Sookyong Koh has nothing to disclose. Dr. Rathore has nothing to disclose. Dr. Zabad has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bayer. Dr. Zabad has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Zabad has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Zabad has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Celgene/BMS. Dr. Zabad has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genzyme. Dr. Zabad has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck Serono. Dr. Zabad has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Teva Neurosciences. Dr. Zabad has received personal compensation in the range of $500-$4,999 for serving as a Consultant for TG Therapeutics. Dr. Zabad has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Teva. Dr. Zabad has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Dr. Zabad has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Genentech. Dr. Zabad has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BMS. The institution of Dr. Zabad has received research support from Adamas. The institution of Dr. Zabad has received research support from Biogen. The institution of Dr. Zabad has received research support from Novartis. The institution of Dr. Zabad has received research support from Sun Pharma. The institution of Dr. Zabad has received research support from Parexel &amp; MedDay Pharmaceuticals.

NAFLD: A pretransplant and post-transplant conundrum.

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Sensitivity enhancement of gold nanospheres assisted CO2 laser tapered optical fiber for refractive index sensor

Tapered optical fibers (TOFs) have been intensively used as sensors due to their high sensitivity, simple structure, and excellent coupling efficiency. In this paper, we reported the successful rapid tapering of single mode and multimode fibers using CO2 laser beam at working wavelength of 10.6 μm. Clean and symmetric tapers could be produced in just 5 s using this method. Arduino-based microcontroller was included in the tapering set-up to precisely control the fiber pulling speed and distance. Smaller waist diameters that were observed in multimode than in single mode fibers generated more evanescent waves on the cladding of tapered multimode fibers (TMMFs). This implied that TMMFs performed better refractive index (RI) sensitivity, within the range of 1.3325–1.4266, than tapered single mode fibers (TSMFs). Furthermore, localized surface plasmon resonance (LSPR) effect was coupled with evanescent wave through AuNSs immobilization on the TOF surface. The AuNSs having average particle diameter of 12.70 nm was synthesized by citrate reduction route. The formation of AuNSs was confirmed by (ultraviolet–visible) UV–vis and high-resolution transmission electron microscopy (HRTEM) data. Self-assembly monolayer approach was conducted to immobilize AuNSs on the 3-mercaptopropyl trimethoxysilane (MPTMS)-functionalized surface of the TOFs. The AuNSs immobilization on TMMFs could improve the sensitivity up to 122 %. Besides sensitive to RI changes, the sensors were also excellent in terms of repeatability and reversibility performances. Finally, this paper described the amplitude modality-based RI sensing mechanism due to evanescent wave and LSPR effects.

Short-term decreased post transplant lymphoproliferative disorder risk after kidney transplantation using two novel regimens

BackgroundBelatacept is employed alongside calcineurin inhibitor (CNI) therapy to prevent graft rejection in kidney transplant patients who are Epstein-Barr virus (EBV) seropositive. Preliminary data suggested that rates of post-transplant lymphoproliferative disorder (PTLD) were higher in individuals treated with belatacept compared to CNI therapy alone. MethodsThe records of 354 adults who underwent kidney only transplantation from January 2015 through September 2021 at one medical center were evaluated. Patients underwent treatment with either low-doses of mycophenolate, tacrolimus and sirolimus (B0, n = 235) or low-doses of mycophenolate, tacrolimus and belatacept (B1, n = 119). All recipients underwent induction with antithymocyte globulin and a rapid glucocorticosteroid taper. Relevant donor and recipient information were analyzed and endpoints of PTLD were assessed. ResultsThere were no cases of PTLD in either cohort within the study period. Recipients in the belatacept cohort experienced lower estimated glomerular filtration rates at 12 months (B0: 67.48 vs. B1: 59.10, p = 0.0014). Graft failure at 12 (B0: 1.28% vs. B1: 0.84%, p = 1.0) and 24 months (B0:2.55% vs. B1: 0.84%, p = 0.431) were similar. There was no difference in rejection rates at 12 (B0: 1.27% vs. B1: 2.52%, p = 0.408) or 24 months (B0: 2.12% vs. B1: 2.52%, p = 1.000). Both groups had similar rates of malignancy, mortality and CMV/BK viremia. ConclusionNon-belatacept (MMF, tacrolimus and sirolimus) and belatacept-based (MMF, tacrolimus and belatacept) regimens do not appear to pose any increased risk of early onset PTLD. Both cohorts benefited from low rates of rejection, malignancy, mortality and graft failure. Recipients will continue to be monitored as PTLD can manifest as a long-term complication.

Antibody-Guided Therapy in Phospholipase A2 Receptor-Associated Membranous Nephropathy

A 6-month course of cyclophosphamide (CP) and steroids is effective in primary membranous nephropathy (MN), but unappealing because of long-term side effects. We evaluated efficacy of an "antibody-guided" treatment schedule. Patients with phospholipase A2 receptor (PLA2R)-related MN and high risk of progression were treated with CP 1.5 mg/kg/d and steroids in cycles of 8 weeks. Anti-PLA2R antibodies were measured by indirect immunofluorescence (IIFT) at 8, 16, and 24 weeks, and a negative test resulted in withdrawal of CP, and rapid tapering of prednisone. In patients with persistent anti-PLA2R antibodies at 24 weeks, CP was switched to mycophenolate mofetil. Treatment was repeated in patients with a relapse. Our analysis included 65 patients (48 males, 17 females), age 61 ± 12 years, estimated glomerular filtration rate (eGFR) 46 ml/min per 1.73 m2 (35-68), urine protein-to-creatinine ratio 7.7 grams/10 mmol creatinine (5.4-11.1) and serum albumin 20 g/l (16-26). Immunologic remission rate was 71% after 8 weeks, 86% after 16 weeks, 88% after 24 weeks, and 94% after 3 years. Twenty-seven patients (42%) had persistent clinical remission after only 8 weeks of therapy. Sixteen patients needed a second course of therapy because of immunologic or clinical relapse. Follow-up was 37 (26-58) months. Overall partial remission rate was 92%. One patient developed end-stage kidney disease. Antibody-guided therapy (ABG) was as effective as the standard 6-month course, whereas providing a lower cumulative dose of CP (11.1 [8.0-18.5] vs. 18.9 [14.2-23.6] grams). ABG is effective, and allows individualized therapy, with many patients responding to 8 weeks of CP-based therapy.

Глюкокортикостероиды при системной красной волчанке: перспективы стероидосберегающей терапии

The isolation of glucocorticoids (GC) was a tremendous achievement in the history of medicine and had a clinical impact similar to that of the discovery of insulin or antibiotics. However, with the expansion of their use, multiple side effects have become evident even patients treated with low doses. GC remain one of the main agents in the treatment of systemic lupus erythematosus (SLE). The studies of genomic and nongenomic effects of GC justified their use in lower starting doses (e.g. 30 to 40 mg daily) even in patiens with lupus nephritis. Methylprednisolone pulses and early initiation of hydroxychloroquine and immunosuppressive agents may allow more rapid tapering and discontinuation of GC in SLE patients. Development of novel steroid-sparing agents, e.g. anifrolumab, a monoclonal antibody to interferon I receptor, or voclosporin, an oral calcineurin inhibitor, may result in further improvement in the efficacy and safety of treatment.

A Novel Method to Characterize Medical School Research Productivity among Radiation Oncology Residents

<h3>Purpose</h3> Altmetric score (AS) is a weighted average of the number of mentions on various websites, such as news outlets and social media, for publications. Prior studies have used h-index as a proxy for research impact, which relies on citation counts that may take years to accrue to a meaningful level. However, AS has been shown to follow social media dissemination trends, with a sharp increase in score upon publication followed by a rapid taper. The authors aim to explore research productivity of radiation oncology (RO) residents during their time in medical school using AS. <h3>Methods</h3> A PubMed search was performed for every RO resident in the class of 2024 to collect manuscripts published during medical school (January 1st, 2016 to December 31st, 2019). Extensive metadata were captured for each article, including AS and number of mentions on social media and other websites. Residents who completed a PhD or took longer than four years to graduate were excluded. Medical schools were divided into US News Top-40 and non-Top-40 schools. <h3>Results</h3> A total of 129 residents from 67 residency programs published 665 articles during medical school. Each resident published articles that accrued a mean total AS of 60.4 and an average AS of 9.9 per article. Residents who graduated from Top-40 medical schools obtained significantly higher total AS (p<0.001) and average AS (p<0.001) than those who graduated from non-Top-40 schools. While only 39.5% of residents graduated from Top-40 institutions, 55.4% of articles with the highest quartile of AS were published by those from these schools. <h3>Discussion</h3> The results of using AS to measure the impact of manuscripts published by RO residents appear to be consistent with those of traditional bibliometric studies. Residents from higher-ranked medical schools published more higher-impact articles than their counterparts from lower-ranked medical schools. Limitations of the study include possible differences in AS at time of residency application vs. current day and lack of control for possible confounders (e.g. possible increased research interest in Top-40 school students). Our data again suggests that students who attend higher-tier medical schools may have an advantage in access to potentially higher-impact research opportunities. With the recent shift of the Step 1 exam to a pass/fail format, there may be more emphasis placed on extracurricular activities such as research. Further work is needed to understand the optimal method by which holistic review can be incorporated into the RO residency selection process.

Clinical characteristics and outcomes of digital gangrene in connective tissue disorders: a longitudinal single-centre experience from Jodhpur, India.

Epidemiology, clinical presentation, and outcomes for digital gangrene in connective tissue disorders (CTD) remain underreported from tropical countries like India. In this series, we aimed to explore the clinical profile and outcomes of patients who presented with digital gangrene and a diagnosis of CTD. Hospital-based longitudinal observational study. Patients with digital gangrene and underlying diagnosis of CTD presenting to our tertiary-care centre in Jodhpur, India between1st January 2018 and 31st June 2021 were included. Clinical outcomes including mortality, limb outcomes, functional status and other systemic involvement were assessed. Of the 312 patients registered in the rheumatology clinic during this period, 22 (7%) patients were found to satisfy the inclusion criteria. Mean age was 46years and 90% were females. The most common underlying diagnosis was Mixed connective tissue disorder (MCTD). Digital gangrene was the presenting symptom in 13 (60%) patients. Half of the patients received only corticosteroids as immunosuppression. Two died due to systemic complications. Complete resolution occurred in 17 (85%), autoamputation in 3, and infection requiring surgical drainage in one patient. All surviving patients reported good functional limb outcome on 6months follow-up. MCTD is an important cause of digital gangrene in rheumatology practice. In patients presenting with digital gangrene, an active search for an underlying CTD is imperative, as this could result in timely initiation of appropriate limb-saving therapy. Corticosteroids alone with rapid tapering may be an appropriate option to consider in the initial management of digital gangrene in CTD. Key Points • Mixed connective tissue disorder is an important cause of digital gangrene in rheumatology practice in western India. • In patients presenting with digital gangrene, an active search for an underlying connective tissue disorder is imperative, as this could result in timely initiation of appropriate therapy and can prove limb saving. • Corticosteroids alone with rapid tapering may be an appropriate option to consider in the initial management of digital gangrene in connective tissue disorders.

Drug-induced autoimmune hepatitis: A minireview.

Drug-induced autoimmune hepatitis (DIAIH) is a specific phenotype of drug-induced liver injury that may lead to the devastating outcome of acute liver failure requiring liver transplantation. Drugs implicated in DIAIH include antimicrobials such as nitrofurantoin and minocycline, non-steroidal anti-inflammatory drugs, statins as well as anti-tumor necrosis agents. The clinical features of drug-induced liver injury are indistinguishable from idiopathic autoimmune hepatitis (AIH) as both may have positive AIH-related autoantibodies, elevated immunoglobulin G, as well as similar histopathological findings. In patients who show no clinical improvement, or there is progressive liver injury despite cessation of the suspected drug, a liver biopsy should be considered, whereby the presence of advance fibrosis on histology favors the diagnosis of idiopathic AIH. Empirical treatment with corticosteroids may be required in patients with non-resolving liver injury. A typical clinical scenario supportive of DIAIH includes a history of drug exposure with spontaneous resolution of liver injury after drug withdrawal and the absence of relapse after rapid steroid taper. In this article we report two cases of DIAIH secondary to Sorafenib and Atorvastatin along with a review of currently available literature. Early identification and treatment often lead to a favorable outcome in DIAIH.

Methylprednisolone Plus Low-Dose Methotrexate for Bullous Pemphigoid-A Single Center Retrospective Analysis.

Monomodal systemic glucocorticoids remain the mainstay of treatment for bullous pemphigoid (BP). In this retrospective, single-arm study, we evaluated the feasibility (efficacy and tolerability) of the combination of methylprednisolone and low-dose (up to 12.5 mg/week) methotrexate (MP + MTX) for BP. At week 12, 53/55 (96.4%) patients initiated on MP + MTX during a five-year period (potential follow up time: ≥4 years) remained on treatment. At this time-point, BP remission was achieved in all compliant patients (including n = 24 cases of dipeptidyl peptidase-4 inhibitors-associated BP; 12-week remission rate: 100% [95% CI: 91.9–100.0%]; mean time to remission: 29.5 days, SEM: 2.3 days) at a mean cumulative MP dose to disease control of 678.4 mg (SEM = 49.4 mg). Eight patients relapsed during follow up (10.81 [95% CI: 5.16–21.72] relapses/100 person years, py), and seven manifested a severe adverse event (6.80 [95% CI: 3.00–14.28] severe adverse events/100 py); however, 73.4% (±7.9%) had suffered neither a relapse nor a SAE at the three-years follow up. Continuing low dose MP intake (≤8 mg/day) beyond week 12 in combination with MTX minimized the risk of a feasibility limiting event (p = 0.013). Conclusively, the combination of methylprednisolone with methotrexate is a promising, safe, and efficient modality for BP patients, which enables rapid glucocorticoid tapering.

Medium Versus High Initial Prednisone Dose for Remission Induction in Lupus Nephritis: A Propensity Score-Matched Analysis.

The existing guidelines for lupus nephritis (LN) recommend initial prednisone doses of 0.3-1.0 mg/kg/day. However, recent studies reported noninferior outcomes with lower doses. The aim of this study was to compare the complete renal response rates in LN patients treated with prednisone ≤30 mg/day or ≥40 mg/day. Patients with new-onset LN and standard immunosuppressive treatment were followed for at least 12 months, divided into medium (≤30 mg/day) and high prednisone groups (≥40 mg/day) and matched (propensity score) based on the baseline differences. Complete renal response was defined as proteinuria <0.5 gm/day and no worsening in renal function. Glucocorticoid-related damage was also assessed. High-dose prednisone patients (n = 103; mean ± SD dose 48.6 ± 12.3 mg/day) achieved better rates of complete response compared to the medium group (n = 103; mean ± SD dose 24.2 ± 4.6 mg/day) (61.8% versus 38.2%; P = 0.024) at 12 months. The difference in response rates was reproduced for several subgroups (concomitant immunosuppressive treatment, proliferative/nonproliferative LN). Complete remission rates were higher at 2 years (67.8% versus 39%; P = 0.002) and 3 years (64.9% versus 49.1%; P = 0.025) after LN diagnosis. Cumulative glucocorticoid dose was comparable at 2 and 3 years. Glucocorticoid-related damage was accelerated in both groups for the same period. Higher initial prednisone doses (median 45 mg/day) achieved significantly better rates of complete renal response at 12 months in new-onset LN. Cumulative glucocorticoid dose and damage accrual were not different at 2 and 3 years after LN. Damage was more prominent in the late phases of LN in both groups, underlining the importance of rapid tapering and the need to implement alternative strategies.

Coincidence of Events Causing Paradoxical Hypotension in a Patient with an Intra-Aortic Balloon Pump.

The left ventricular outflow tract is a region of the left ventricle that lies between the anterior leaflet of the mitral valve and the ventricular septum. Dynamic left ventricular outflow tract obstruction (LVOTO) has classically been observed in patients with hypertrophic obstructive cardiomyopathy (HOCM) where it occurs secondary to asymmetric septal hypertrophy and systolic anterior motion (SAM) of the mitral valve. However, there are some instances that lead to hypercontractility of the myocardium, and with a combination of other physiological conditions, result in SAM of a mitral valve leaflet, leading to LVOTO in the absence of phenotype.We present such a case of an acute inferolateral wall myocardial infarction that was complicated by cardiogenic shock, requiring an intra-aortic balloon pump (IABP) and inotropic support which paradoxically provoked LVOTO. A reduction in IABP counterpulsation from 1:1 to 1:3 and the addition of intravenous fluids and a beta blocker resulted in significant improvement in blood pressure with rapid tapering of pressors.Inotropes and IABP, although helpful in cardiogenic shock, have the potential to induce or worsen the LVOTO, which can lead to a vicious cycle of worsening hypotension and increasing adrenergic drive that further deteriorates myocardial viability. Timely diagnosis with an echocardiogram and the withdrawal of inotropic and IABP support has the potential to improve haemodynamics and, thereby, outcome.LEARNING POINTSDynamic left ventricular outflow tract obstruction (LVOTO) should be one of the differentials in patients with cardiogenic shock, especially if it is refractory in the setting of an intra-aortic balloon pump.The diagnosis of LVOTO by echocardiography should result in immediate implementation of therapy to eliminate the factors that can potentially intensify the obstruction.

Association of Opioid Dose Reduction With Opioid Overdose and Opioid Use Disorder Among Patients Receiving High-Dose, Long-term Opioid Therapy in North Carolina

Rapid reduction or discontinuation of long-term opioid therapy may increase risk of opioid overdose or opioid use disorder (OUD). Current guidelines for chronic pain management caution against rapid dose reduction but are based on limited evidence. To characterize the association between rapid reduction or abrupt discontinuation of opioid therapy (vs maintained or gradual reduction) and incidence of opioid overdose and OUD among patients prescribed high-dose, long-term opioid therapy (HDLTOT). This retrospective cohort study was conducted among patients aged 18 to 64 years who were prescribed HDLTOT (≥90 daily morphine milligram equivalents for ≥90% of 90 days) from January 2006 to September 2018, with follow-up up to 4 years after cohort entry. Claims data were drawn from a large private health insurer in North Carolina and analyzed from March 1, 2006, to September 30, 2018. Time-varying exposure of rapid dose reduction or discontinuation (>10% dose reduction/week) vs maintenance, increase, or gradual reduction or discontinuation. The main outcome was incident opioid overdose (fatal or nonfatal) or diagnosed OUD. Inverse probability-weighted cumulative incidence of outcomes were estimated using the cumulative incidence function and hazard ratios (HRs) using marginal structural Fine-Gray models as a function of rapid dose tapering or discontinuation (vs gradual reduction or discontinuation or maintained or increased), accounting for competing risks. A total of 19 443 patients (median [IQR] age, 49 [41-55] years; 10 073 [51.8%] men) who received HDLTOT were identified. Rapid reduction or discontinuation was associated with higher risk of fatal and nonfatal overdoses compared with gradual reduction after the first year (year 1: HR, 1.43; 95% CI, 0.94-2.18; years 2-4: HR, 1.95; 95% CI, 1.31-2.90). There was no association between rapid reduction or discontinuation and diagnosed OUD through 2 years of follow-up; however, the hazard of incident OUD among patients exposed to rapid tapering or discontinuation was greater 25 to 48 months after the start of follow-up (HR, 1.28; 95% CI, 1.01-1.63). In this cohort study, rapid dose reduction or discontinuation was associated with increased risk of opioid overdose and OUD during long-term follow-up. These findings reinforce prior concerns about safety of rapid dose reductions for patients receiving HDLTOT and highlight the need for caution when reducing opioid doses.

Eltrombopag improves refractory thrombocytopenia in patients with Sjögren's syndrome.

Eltrombopag, a kind of thrombopoietin (TPO) receptor agonist, plays the role on the megakaryocyte to activate the platelet production and rapidly increase the number of circulating platelets in patients with primary immune thrombocytopenia (ITP). Eltrombopag provides an opportunity for rapid tapering and/or cessation of corticosteroid therapy. However, it is not clear about the platelet response to Eltrombopag in ITP associated with Sjögren's Syndrome(SS). A retrospective research was conducted on the clinical course of three patients, each with ITP secondary to SS, and initially received therapy of corticosteroids or other immunomodulatory. They took this drug for bleeding diseases. Referring to the description, Eltrombopag was prescribed and adjusted with an initial dose of 25 mg daily, then weekly, then monthly according to the monitoring of platelet counts. All patients maintained a satisfactory level of platelet counts (>100,000/mm3 for >2 years) following corticosteroid withdrawal. Meanwhile, Eltrombopag was well-tolerated, and there were no adverse effects, such as thrombotic events. Eltrombopag is effective and safe for patients with ITP associated with SS during corticosteroid withdrawal. Thus it may be a crucial therapeutic strategy for reducing corticosteroid-related side effects in SS patients with ITP.

Paradoxical reaction presenting with orbital signs in possible intraocular tuberculosis

We report an unusual presentation of paradoxical reaction (PR) with orbital signs in a case of possible intraocular tuberculosis (POTB). A 15-year-old boy presented with vitreous hemorrhage in the right eye (OD) and multifocal choroiditis in the left eye (OS) and progressed to develop bilateral proptosis, lid edema, chemosis, subretinal lesions, and progression of choroidal lesions following the rapid tapering of oral steroids with anti-tubercular therapy for POTB. The orbital reaction and progressing posterior segment lesions were managed with pulse steroid therapy, oral steroids, intravitreal anti-vascular endothelial growth factor (anti-VEGF), and steroid implant. The orbital involvement is rarely seen in POTB with PR.

Pharmacologic Strategies for Post-Transplant Maintenance in Acute Myeloid Leukemia: It Is Time to Consider!

Simple SummaryAllogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapeutic procedure for patients with high risk acute myeloid leukemia. Its anti-leukemic activity is mainly derived from the intensity of the conditioning regimen used and the graft-versus-leukemia effect exerted by the donor T lymphocytes. Despite major progress in the allo-HCT procedure in recent years with the achievement of lower non-relapse mortality and long-term disease control. However, up to 45% of patients still experience relapse. Therapeutic strategies post-transplant aiming at preventing disease relapse are discussed in this review.Patients with high-risk acute myeloid leukemia are offered allogeneic hematopoietic cell transplantation (allo-HCT) in first remission to reduce risk of relapse. However, disease recurrence remains the major reason of allo-HCT failure, occurring in around 35–45% of patients, and leading to dismal outcomes. Strategies to reduce the risk of relapse are greatly needed, especially in the early post-transplant phase where the graft-versus-leukemia (GVL) effect is not yet activated. Some practices include the use of myeloablative conditioning regimens, close monitoring of measurable residual disease and donor chimerism, rapid tapering of immunosuppression, and implementation of pre-emptive strategies as the use of donor lymphocyte infusion. However, it’s time to consider prophylactic pharmacologic interventions post allo-HCT that aim at maintaining leukemic clones under control by both direct cytotoxic activity and by enhancing the GVL effect. In this current review, available data on drugs targeting epigenetic pathways like azacitidine, or actionable mutations like FLT3 and IDH1/2 inhibitors used as maintenance post allo-HCT, will be discussed.

Tocilizumab in patients with new onset polymyalgia rheumatica (PMR-SPARE): a phase 2/3 randomised controlled trial

BackgroundPolymyalgia rheumatica is the second most common inflammatory rheumatic disease of people >50 years. Glucocorticoid therapy is highly effective, but many patients require treatment for several years. Effective glucocorticoid sparing...

Treatment of pemphigus in Australia: Aligning current practises with global recommendations.

Pemphigus encompasses of a group of rare, and often severe, intraepidermal bullous dermatoses that are mediated by autoantibodies that act against adhesion proteins of the desmosome. The current international consensus is that the use of intravenous CD20 inhibitors should be first-line in the management of moderate-to-severe cases of pemphigus, however Australia is yet to adopt this. Systemic corticosteroids, combined with conventional corticosteroid-sparing immunosuppressive agents such as azathioprine, mycophenolate mofetil, cyclosporin and methotrexate is still recommended as first-line therapy in Australia despite overwhelming evidence that combining rituximab with a rapid corticosteroid tapering regime is more effective in the treatment of moderate-to-severe pemphigus, and leads to fewer severe adverse effects. We propose a therapeutic approach that echoes the international consensus and recommend that rituximab, an anti-CD20 monoclonal antibody, be listed in the formularies of Australian Public Hospitals and on the Pharmaceutical Benefits Schemefor use in moderate to severe pemphigus.

Rapid versus slow withdrawal of antiepileptic drugs.

The ideal objective of treating a person with epilepsy is to induce remission (free of seizures for some time) using antiepileptic drugs (AEDs) and withdraw the AEDs without causing seizure recurrence. Prolonged usage of AEDs may have long-term adverse effects. Hence, when a person with epilepsy is in remission, it is logical to attempt to discontinue the medication. The timing of withdrawal and the mode of withdrawal arise while contemplating withdrawal of AEDs. This review examines the evidence for the rate of withdrawal of AEDs (whether rapid or slow tapering) and its effect on seizure recurrence. This is an updated version of the Cochrane Review previously published in 2020. To quantify risk of seizure recurrence after rapid (tapering period of three months or less) or slow (tapering period of more than three months) discontinuation of antiepileptic drugs in adults and children with epilepsy who are in remission, and to assess which variables modify the risk of seizure recurrence. For the latest update, on 8 November 2021, we searched: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid), and SCOPUS. There were no language restrictions. CRS Web includes randomized or quasi-randomized, controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), CENTRAL, and the Specialized Registers of Cochrane Review Groups including Epilepsy. Randomized controlled trials that evaluated withdrawal of AEDs in a rapid or slow tapering after varying periods of seizure control in people with epilepsy. Two review authors independently assessed the trials for inclusion and extracted the data. The outcomes assessed included seizure freedom after one, two, or five years of AED withdrawal; time to recurrence of seizure following withdrawal; occurrence of status epilepticus; mortality; morbidity due to seizure, such as injuries, fractures, and aspiration pneumonia; and quality of life (assessed by validated scale). There are two included studies in this review. One study randomized 57 children with epilepsy with seizure freedom for at least two years to taper down the AED over one or six months. The study was not blinded and there were no details of randomization. Over the period of 54 months of follow-up, 20/30 participants in the one-month group remained seizure-free compared to 15/27 participants in the six-month group (no evidence of a difference). There was no information on time of seizure recurrence for each group to allow a comparison. The other study involved 149 children. There was a non-significant trend towards a lower risk of seizure recurrence after one year of AED withdrawal in participants allocated to slow tapering (risk ratio (RR) 0.76, 95% confidence interval (CI) 0.58 to 1.01; P = 0.06; very low-certainty evidence). At the end of two years, 30 participants were seizure free in the rapid-tapering group and 29 participants in the slow-tapering group (RR 0.87, 95% CI 0.58 to 1.29; P = 0.48; very low-certainty evidence). At the end of five years, 10 participants were seizure free in the rapid-tapering group and six participants in the slow-tapering group (RR 1.40, 95% CI 0.54 to 3.65; P = 0.49; very low-certainty evidence). There were no data for the other outcomes. Due to the methodological heterogeneity and the difference in the duration of tapering, we did not perform a quantitative synthesis of these studies. Currently, one Italian trial is ongoing that is investigating if a slow or a rapid withdrawal schedule of AEDs influences return of seizures (relapse) in adults with focal or generalized epilepsy who have been seizure free for at least two years (no preliminary results available). In view of methodological deficiencies, and small sample size of the two included studies, we cannot draw any reliable conclusions regarding the optimal rate of tapering of AEDs. Using GRADE, we assessed the certainty of the evidence as very low for outcomes for which data were available. We judged both studies to be at an overall high risk of bias. Further studies are needed in adults and children to investigate the optimal rate of withdrawal of AEDs and to study the effects of variables such as seizure types, aetiology, intellectual disability, electroencephalography abnormalities, presence of neurological deficits, and other comorbidities on the rate of tapering.

Post-COVID Neurological Complication; A Case Series and Review of the Literature

Introduction: There are certain post-coronavirus disease (COVID) neurological syndromes which have been reported such as cerebrovascular diseases, cerebral venous thrombosis, peripheral neuropathy, encephalitis, encephalopathy, cerebellar ataxia, facial palsy, and myositis. However, most of these are isolated case reports. In this case series, we discuss the post-COVID neurological complications such as facial palsy, lateral rectus palsy, cerebellar ataxia, peripheral neuropathy, and stroke which occurred within 2 weeks after complete recovery from COVID. Methods: This multicentric case series is from three large tertiary care hospitals in northern and central India. We have reviewed seven patients with recent-onset neurological symptoms who had recovered from COVID infection within 2 weeks. We have retrospectively studied the clinical profile and radiological imaging during COVID infection. Results: Three out of these seven patients had received steroids during COVID treatment. None of our cases had any neurological manifestations during their COVID infection. The likelihood of neurotransmission through the cribriform plate via the olfactory bulb was low, as none of our patients had anosmia. None of the patients in the case series showed features of systemic hyperinflammatory syndrome, making the possibility of macrophage activation syndrome less likely. Conclusion: We hypothesize that antibodies against the coronavirus post recovery from COVID are responsible for these post-COVID neurological complications. Higher likelihood of these complications after rapid tapering off steroids may further corroborate this mechanism, as the antibody levels rise after steroid withdrawal. Titers of antibodies to SARS COV-2 virus in the postinfection period in these cases may have further helped prove our hypotheses which can be considered in future studies on the subject.