Tapering Dose Research Articles

Evaluation of the Clinical Efficacy of Prednisolone in the Treatment of Inflammatory Bowel Diseases with Different Dosage Methods

Aim: to investigate the clinical efficacy of two methods of oral dosing of prednisolone (in mg and mg/kg) for the induction of remission for patients with ulcerative colitis (UC) and Crohn's disease (CD) using the technology of constructing and evaluating the effectiveness function (dose-effect relationship).Material and methods. In this study were included 86 patients aged from 18 to 65 years with moderate or severe active inflammatory bowel disease (61 — UC, 25 — CD). All patients were treated with prednisolone at an initial daily dose from 30 to 60 mg with a subsequent tapering of dose. The clinical response to treatment was evaluated at the time of complete withdrawal of prednisolone using the generally accepted criteria. Two efficiency functions were constructed, compared and analyzed: the first — at the initial dosage of prednisolone in mg and the second calculating the dose in mg/kg of patient weight. The patients' body weight ranged from 41 to 98 kg. The “dose-effect” relationship for prednisolone was constructed with statistical transformation of the baseline clinical data and a quantitative expression of the actual doses and alternative responses into a graph of the effectiveness function. The mean value at each point was estimated based on the regression kernel scoring method.Results. Two graphs of the “dose-effect” of prednisolone in mg and mg/kg of patient weight were constructed. The optimal clinically effective dose (OCED) when calculated in mg/kg of weight was 0.70 ± 0.01 (0.68 + 0.72) mg/kg with the corresponding effect 79.25 ± 6.26 (66.62 91.88) %. When two graphs in mg and mg / kg of weight were superimposed, it is shown that when an initial dose of 40 mg is prescribed without taking into account the patient's weight, the effect of therapy will be 25 % lower. Prescribing a dose of 60 mg per day without weight will be optimal for patients with a body weight of 85-90 kg. With a lower body weight, the clinical effect will not decrease, but the likelihood of recognized side effects of prednisolone should be expected in proportion to the decrease in body weight.Conclusion. The clinical efficacy of two methods of prednisolone dosing (mg and mg/kg) for patients with IBD during the first induction course was compared.Using a new technology for constructing and evaluating the effectiveness function (dose-effect relationship) allowed us to prove a reliable relationship between the body weight of patients with the clinical effect of prednisolone in patients with UC and CD. Based on the analysis of the dose-effect relationship, the optimal clinically effective dose of prednisolone for patients with UC and CD during the first induction course was established, equal to 0.70 mg/kg, which can be recommended for use in clinical practice for calculating individual doses.

Practice patterns and opinions in the treatment of allergic eye disease: A survey among Indian ophthalmologists.

Management of allergic eye disease is seldom straightforward and often challenging. We conducted an online survey to elicit opinions on the preferred practice pattern in the treatment of allergic eye disease. An online survey questionnaire was sent to all practicing ophthalmologists using social media platforms. The respondents were asked about their clinical experience and preferred treatment in various scenarios such as mild-moderate vernal keratoconjunctivitis (VKC), chronic VKC, refractory VKC, steroid responders, giant papillae, and shield ulcer. Respondents were asked about the newer molecule (alcaftadine) and reservations regarding systemic immuno-suppressants and ordering allergy tests in their practice. Ninety - one participants responded to the survey. About 57.1% of ophthalmologists reported coming across more than 10 cases per week in their practice. The most common age group was 5-10 years (61.1%), but adult onset VKC was also reported at 41.6% (1-2 per month), 37.1% (3-5 per month), and 13.5% (more than 10 per month). The disease is perennially present (36.7%), and a mixed form has been reported by 47.8% of ophthalmologists. Dual-acting agents were preferred by 40% in mild-moderate clinical variants. Topical steroids in slow tapering dosage were preferred by 86.7% in their prescription. Tacrolimus 0.03% was preferred by 65.9% and given for at least 3 months of continuous usage by 47.6% of ophthalmologists. High-dose topical steroids were preferred for giant papillae (67.8%) and Shields ulcers (68.3%) in our survey. Supratarsal steroid injection was preferred by 50% in treating refractory VKC in our survey. Allergic eye disease is a common yet annoying disease. The signs and symptoms can vary from subtle, innocuous forms to devastating variants affecting vision and day-to-day work. This survey aims to elicit responses from clinicians spreading across different geographical areas and compares responses based on experience in practice.

752 CARDIOGENIC SHOCK AS THE FIRST PRESENTATION OF ACUTE ANTRACYCLINE CARDIOTOXICITY: A CLINICAL CASE

Abstract Background Several therapeutic strategies are available for cancer patients, leading to a longer life expectancy; however, each drug might have different side effects, which increase morbidity and mortality. Cardiovascular diseases are one of the most frequent and dramatic of these side effects, leading to interruption of a potentially lifesaving treatment or hesitating into heart failure. Clinical Case A 50 year-old female with recent diagnosis of breast cancer presented to our Emergency Department (ED) for asthenia, vomiting and dyspnea. A first dose of epirubicin and cyclophosphamide as neoadjuvant chemotherapy (CT) was administered three days before the onset of symptoms. Screening echocardiogram performed before starting the CT showed normal systolic ejection fraction, normal diastolic function and no valvular disease. At ED admission, the patient presented hypotension, tachycardia, sweating and mental confusion. The ECG showed sinus tachycardia with diffuse ST segment elevation and diffuse low QRS voltages. Echocardiogram proved severe left dysfunction (LVEF 15%) with low cardiac output (LVOT VTI 6 mm) and elevated ventricular filling pressure (E/e’ 26). EAB showed severe hyperlactacidemia. The diagnosis of cardiogenic shock was done and high doses of dobutamine and noradrenaline were started. Laboratory values confirmed multiorgan involvement, in absence of any signs of inflammation and infection. The coronary angiography performed revealed normal coronary arteries and elevated left ventricular end-diastolic pressure (LVEDP 29 mmHg). Despite pharmacological therapy, the patient's condition worsened so we proceeded to IMPELLA CP implantation and started methylprednisolone 10 mg/kg for three days with subsequent tapering doses. After 24 hours, we obtained hemodynamic stability and hyperlactacidemia clearance. Unfortunately, myelotoxicity and marked piastrinopenia (until 16 000*10 9/L) complicated the clinical course; for this reason, we stopped unfractionated Heparin (UHF) and no anticoagulant therapy, other the one in purge solution, was performed. CMR revealed diffuse signal enhancement during the T2w sequences associated with a global enhancement of T2 Mapping values due to general edema, a global intramyocardial strengthening, a significant enhancement of the T1 mapping values and extracellular volume were described at the delayed enhancement sequences. The hemodynamic conditions progressively improved during the hospitalization and the IMPELLA pump was removed. Serial echocardiograms documented an improvement of the ejection fraction and further mild reduction of ventricular filling pressure (E/e’ 8) normal right ejection fraction and initial inferior vena cava collapsibility. All the inotropic supports were suspended; we introduced beta-blocker, ACE-inhibitors, subsequently replaced with sacubitril/valsartan, well tolerated. Conclusion Acute cardiotoxicity with possible life-threatening conditions regardless of the basal cardiovascular risk class is a rare clinical condition, but needs further investigation. Future researches are warranted to determine the molecular mechanisms underlying cardiotoxicity to contain the side effects, maximize the benefit of the oncological therapy and, when necessary, select the best therapeutic option.

Opioid withdrawal symptoms after neurolytic splanchnic nerve block in cancer patients.

Few reports on opioid withdrawal (OW) due to opioid tapering in cancer patients have been published. The incidence of and risk factors for OW after neurolytic splanchnic nerve block (NSNB) are unknown. This study aimed to elucidate the incidence of and risk factors for OW among cancer patients who could have reduced opioid doses after NSNB. This was a multicenter, retrospective, observational study. We reviewed the medical charts of patients who underwent NSNB for intractable cancer pain at four tertiary hospitals in Yokohama City from April 2005 to October 2020. We included patients whose opioid dose was reduced by > 5mg/day (equivalent oral morphine dose) within 14days after NSNB. We classified the patients into two groups according to the presence or absence of OW symptoms and compared them. Of the 50 patients who underwent NSNB, 24 were included in the study. OW was observed in five (20.8%) patients. Pain and opioid use duration were significantly longer in OW patients than in non-OW patients (median pain duration 689 vs. 195days; P < 0.043 and median opioid use duration 486 vs. 136days; P < 0.030). The opioid tapering dose was significantly larger in patients with OW than in those without OW (median opioid tapering dose 75 vs. 40mg; P < 0.046). OW was observed in 20.8% of the patients in the study. A longer pain and opioid use duration and a larger opioid tapering dose may predispose patients to OW.

A prospective study comparing Itraconazole alone versus systemic steroids alone as adjuncts to topical steroids in the post-operative management of Allergic fungal rhinosinusitis.

The objective of this study was to compare the efficacy of Itraconazole and systemic steroids as an adjuvant to topical steroids in post-operative patients with Allergic Fungal Rhinosinusitis (AFRS) using both subjective and objective outcome measurements. A prospective comparative study was conducted in a tertiary care center on 60 patients diagnosed with AFRS. Patients with chronic systemic illness and those undergoing revision surgery were excluded. Post-operative patients were divided into two groups of 30 each which received Itraconazole 400 mg OD or Methylprednisolone in tapering doses over six weeks. The outcomes were measured at the end of 6 weeks -Kupferberg endoscopic staging, Absolute Eosinophilic Count (AEC), Serum Immunoglobulin (IgE), and Sino Nasal Outcome Test - 20 scores. Our study showed no statistical significance in outcomes between the two groups treated with Itraconazole and Methylprednisolone regarding recurrence, AEC, IgE, and Quality of Life Assessment (p<0.01). Itraconazole was comparable to Methylprednisolone in preventing disease recurrence in the post-operative management of AFRS. It may be a viable alternative to replacing systemic steroids where the latter may be contraindicated. Itraconazole given at a dose of 400 mg once daily for six weeks was a safe dose.

Recent tapering from long-term opioid therapy and odds of opioid-related hospital use.

The number of patients tapered from long-term opioid therapy (LTOT) has increased in recent years in the United States. Some patients tapered from LTOT report improved quality of life, while others face increased risks of opioid-related hospital use. Research has not yet established how the risk of opioid-related hospital use changes across LTOT dose and subsequent tapering. Our objective was to examine associations between recent tapering from LTOT with odds of opioid-related hospital use. Case-crossover design using 2014-2018 health information exchange data from Indiana. We defined opioid-related hospital use as hospitalizations, and emergency department (ED) visits for a drug overdose, opioid abuse, and dependence. We defined tapering as a 15% or greater dose reduction following at least 3 months of continuous opioid therapy of 50 morphine milligram equivalents (MME)/day or more. We used conditional logistic regression to estimate odds ratios (OR) with 95% confidence intervals (CI). Recent tapering from LTOT was associated with increased odds of opioid-related hospital use (OR: 1.50, 95%CI: 1.34-1.63), ED visit (OR: 1.52; 95%CI: 1.35-1.72), and inpatient hospitalization (OR: 1.40; 95%CI: 1.20-1.65). We found no evidence of heterogeneity of the effect of tapering on opioid-related hospital use by gender, age, and race. Recent tapering among patients on a high baseline dose (>300 MME) was associated with increased odds of opioid-related hospital use (OR: 2.95, 95% CI: 2.12-4.11, p < 0.001) compared to patients on a lower baseline doses. Recent tapering from LTOT is associated with increased odds of opioid-related hospital use.

Clinical efficacy and safety of sirolimus in childhood-onset systemic lupus erythematosus in real world.

To investigate the effectiveness and safety of sirolimus in childhood-onset systemic lupus erythematosus in a real world. This is a retrospective real world clinical study. All childhood-onset systemic lupus erythematosus patients treated with sirolimus in Children's Hospital of Hebei Province China were analyzed. They were treated with sirolimus and followed up regularly. The patients had systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, levels of antidouble-stranded DNA antibody, complement components C3 and C4, 24-hour proteinuria and corticosteroid reduction were recorded at baseline and at 6, 12, and 18 months. Adverse events were also collected. Thirty-two patients were enrolled in the study. SLEDAI-2K were improved on all time-points (P < .05). Complement levels increased and the levels of antidouble-stranded DNA antibody decreased during treatment. The mean dose of prednisone tapered and achieved significant reduction after 12 months therapy (15.4 ± 5.8 mg/d to 4.8 ± 2.1 mg/d; P < .05). Sirolimus was well tolerated and only 5 patients (15.6%) experienced adverse events, all of which were classified as infections (2 bacterial infection and 3 viral infections). No deaths, severe infusion reactions, or hypersensitivity reactions were found. Sirolimus use was associated with a decrease in disease activity and ability to tolerate tapering of oral glucocorticoid dose with a favorable risk-benefit profile.

Transverse myelitis with positive dengue virus serology: a case report

BackgroundTransverse myelitis is an inflammation of the spinal cord that spreads along the horizontal plane of a section of the spinal cord. Arboviruses, including dengue virus, are rare but known causative factors. However, this association and underlying pathophysiology is unclear. We report a case of transverse myelitis in a patient with a dengue viral infection.Case presentationA 38-year-old man presented with fever followed by acute paraplegia and urinary retention. His workup was positive for serum IgM antibodies against dengue virus and imaging of the spine showed inflammation in multiple sections of the spinal cord. A diagnosis of TM secondary to a dengue infection was made. He was managed with high dose of methylprednisolone for 5 days followed by oral tapering dose. The weakness subsequently improved with full recovery on follow-up visits.ConclusionsTM secondary to acute dengue infection is a rarely reported consequence. Timely diagnosis and treatment can cause significant reduction in the otherwise resultant morbidity.

Protocol and Primary Analysis of Lome: A Randomized Trial of Low- Versus Intermediate-Dose Immune Tolerance Induction with Recombinant Factor VIII (Omfiloctocog alfa, SCT800) in China

Background: Although the cohort and registry data support low-dose (LD; 50 IU/kg once every other day) and intermediate-dose (MD; 100 IU/kg daily) immune tolerance induction (ITI) are almost equally effective in inducing tolerance in people with severe hemophilia A, with inhibitors (PwHI)1-3, there has been no prospective randomized trials, especially in China. Here, we present the protocol and results of the primary analysis in LOME (ChiCTR2200056603). Methods LOME is a multicenter, prospective, randomized comparison of LD and MD ITI, in severe hemophilia A (HA) patients (FVIII level < 1%) with peak historical inhibitor ≥ 5 and < 200 Bethesda Unite (BU/ml). In the first year of recruitment (Part A), patients with age ≤ 8 years at time of randomized will be included. In the second year of recruitment (Part B), patients with age ≤ 12 years at time of randomized will be included. Patients have received ITI therapy before randomization will be excluded. Subjects were randomized 1:1 to LD or MD ITI with the first domestic recombinant factor VIII (rFVIII) (Omfiloctocog alfa, SCT800) approved in China. Factor III (FVIII) inhibitor screening, ITI monitoring and dose tapering will be based on the consensus from United Kingdom Hemophilia Center Doctors' Organization (UKHCDO)4. If (a) there is an upward trend in titer over 3-6 months period; or (b) fall in chromogenic Bethesda titer of less than 20% in 6 months period after initial peak inhibitor titer; or (c) titer ≥ 200BU/ml during ITI therapy; or (d) spontaneous bleeding > 1 monthly over 3-6 months period, modify the regimen as below: In the LD arm, increase to 100IU/kg daily;In the MD arm, rituximab 375 mg/m2 weekly × 4 weeks (maximum 600 mg) and prednisone 2 mg/kg daily × 1 month (maximum 60 mg, tapering over 3 months) would be added. Once the patient had achieved Success, taper dose as below: In the LD arm, the FVIII dose would be reduced slowly to 25IU/kg three times a week for continuing prophylaxis;In the MD arm, the FVIII dose would be reduced slowly to LD ITI, then same as LD arm. The primary endpoints are ITI outcomes (Success: negative inhibitor titer and FVIII recovery ≥ 66% of expected) and the time taken to ITI Success, in PwHI with LD ITI compared to those with MD ITI. Key secondary endpoints include annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR) for any bleeds and treated bleeds; joint and bone health assessed by Hemophilia Joint Health Score 2.0 (HJHS 2.0) and ultrasound; quality of life measured by the Canadian Hemophilia Outcomes-Kids Life Assessment Tool 2.0 (CHO-KLAT 2.0) and numbers of days out of school; average consumption cost (per kg body weight) was calculated based on the intermediate number of treatment doses consumed to achieve Success. This included the cost of rFVIII and rituximab for ITI, prothrombin complex concentrate (PCC) or recombinant activated factor VII (rFVIIa) for treatment of breakthrough bleed, and intravenous immunoglobulin (IVIG) for infection prevention in patients receiving immunosuppressants. Safety was also a secondary endpoint. Results: Ten subjects were randomized into the study with median follow-up time of 1.64 [range (minimum, maximum), 0.23, 3.91] months in LD arm, and 2.66 (0.26,3.91) months in MD arm. Baseline includes age at time of randomized, age of inhibitor detection, exposure days before inhibitor detection, initial inhibitor titer, inhibitor titer at start of ITI and so on, between two arms are summarized in Table 1. Twenty percent (1/5) in MD arm achieved Success after 7 weeks of treatment and still maintained until the latest follow-up. No one achieved Success in LD arm. The bleeds between the treatment arms are summarized in Table 2. Nearly 2-fold difference in mean ABR and AJBR for treated bleeds, between treatment arms, and 3- to 4-fold in ABR and AJBR for any bleeds. Conclusions: It is planned to enroll 40 patients in Part A and 60 patients in Part B, who will be followed for up to 2 years. The study is ongoing and, currently, 10/40 (25%, in Part A) PwHI from 4 HTCs have been included. LOME study is the first, multicenter, prospective, randomized trial of LD vs MD ITI with domestic rFVIII (Omfiloctocog alfa, SCT800) in Chinese PwHI. This study is likely to contribute with the choice of optimal ITI regimen. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Low Dose Ruxolitinib in Indian Haplo-Identical Transplant Patients with Steroid Refractory Acute Graft Versus Host Disease

Background: The number of allogeneic bone marrow transplants done in India is increasing by year. Unlike west, this region had got its own unique complications in the post-transplant period especially multi drug resistant gram negative bacterial sepsis reflecting in a higher transplant related mortality. With increasing number of Haplo-identical transplants, the problem of steroid refractory Graft versus host disease (GVHD) is a major reason for post-transplant morbidity and mortality. As most available immunosuppressive agents worsen cytopenia and in turn sepsis, we need a relatively safer method of managing steroid refractory GVHD in our setting. In this observational study, we used a lower dose of 5mg per day Ruxolitinib for a period of minimum 60 days post-transplant to look into clinical benefit. This dose was chosen considering the recovering platelet count and financial considerations in our resource limited setting. Method: This observational study was conducted from July 2019 to January 2022. A total of 11 steroid refractory GVHD Haploidentical transplant patients were chosen for data analysis that completed the scheduled dosage regimen of Ruxolitinib. Nine out of 11 patients were Acute Myeloid leukemia and two were Acute Lymphoblastic leukemia. The standard conditioning regimen in all was Fludarabine / Busulfan & Cyclophosphamide based conditioning. Additional GVHD medications used were PTCy, Tacrolimus, MMF and steroids with oral budesonide. Tab Ruxolitinib was started around Day +5 post steroids in people who were fitting into steroid refractory acyte GVHD at a fixed dose of 5mg OD for a minimum period of ten weeks. Two cases had one week dose interruption due to cytopenia. Results : At start of Ruxolitinib seven patients had Grade III gut and liver GVHD and rest four had grade II GVHD. Skin was grade II in all patients. When evaluated at Day +58 of Ruxolitinib, all patients were alive and nine of them were on tapering doses of steroids. All continued Tacrolimus at therapeutic doses. No excess bleeding or cytopenia requiring transfusion support happened during this period. As mentioned earlier two cases Ruxolitinib was stopped in view of platelet counts going below 20,000. On evaluation at day +100 post transplant, two patients continued to have grade II Liver, gut and skin GVH and one patient expired on day +48 to sepsis. Rest of eight patients had a Grade I skin, liver and gut GVHD and were able to continue Ruxolitinib further. We started Ruxolitinib taper in cases where steroids were stopped. As case numbers were very low and it's a pilot observation study, we didn't do detailed statistical analysis which may be misleading and give false promises. Conclusion: In our setup, we were finding it a difficulty to use the prescribed 10mg BD Ruxolitinib dose in adults due to fear of worsening cytopenia /sepsis and financial toxicity. We tried to observe the benefit of a lower dose in steroid refractory GVHD post Haplo-identical bone marrow transplant. No pharmaco-genetic assays were done and it's a very small sample size. This observational study revealed a better efficacy and tolerability of this dosing regimen in Indian Haplo-identical patients with a considerable response without compromising blood counts. The results are looking more promising to conduct this study in a bigger scale to benefit our patients from resource limited settings. Reference Zhao Y, Shi J, Luo Y, Gao F, Tan Y, Lai X, Yu J, Wei G, Huang H. Calcineurin Inhibitors Replacement by Ruxolitinib as Graft-versus-Host Disease Prophylaxis for Patients after Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2020 May;26(5):e128-e133. doi: 10.1016/j.bbmt.2020.01.012. Epub 2020 Jan 23. PMID: 31982545.

Itacitinib and Corticosteroids As Initial Treatment for Chronic Graft-Versus-Host Disease: Phase 1/2 Results from Gravitas-309

Background: Itacitinib is a potent, selective oral Janus kinase (JAK) 1 inhibitor with broad anti-inflammatory activity. GRAVITAS-309 was designed as a 2-part, multicenter, randomized trial to assess the efficacy and safety of itacitinib in combination with corticosteroids (CS) as first-line treatment for moderate or severe chronic graft-versus-host disease (GVHD). We describe preliminary results from the open-label, dose-finding portion of the study. Methods: The study initially investigated itacitinib at doses of 200 mg once daily (qd; n=11) and 300 mg qd (n=10) in combination with CS. Both doses were well tolerated. The trial was then expanded to test itacitinib 400 mg qd and 300 mg twice daily (bid); the initial 300-mg qd cohort was expanded, and a CS monotherapy cohort was added (Figure 1). The expected CS starting dose was 0.5-1 mg/kg per day prednisone (or methylprednisolone equivalent) with a dose taper initiated on Day 14 or earlier during the second week of treatment and following published recommendations (Flowers and Martin. Blood. 2015;125[4]:606-15). Itacitinib dosage was initially reduced by 100 mg when given concomitantly with a strong CYP3A4 inhibitor (sCYP3A4i; eg, azole antifungals). A total of 140 patients (pts) (35/treatment group) with moderate or severe chronic GVHD were to be randomized 1:1 using chronic GVHD risk status (moderate vs severe) as a stratification factor. The primary objective was to identify the appropriate dose and schedule of itacitinib for further development. The data cutoff was January 31, 2022. Results: 103 pts were enrolled and received at least one dose of itacitinib. The cohorts were well balanced for pt and disease characteristics. Median age was 57 years (range, 23-76) for the itacitinib cohorts and 59 years (range, 28-75) for the CS cohort. Approximately two-thirds of pts had moderate chronic GVHD. At the time of data cut, 39 (38%) pts in the itacitinib cohorts and 10 (28%) pts in the CS cohort continued study treatment. Median duration of study treatment was 27-28 weeks for the itacitinib cohorts (including 13-16 weeks of concomitant CS) and 17 weeks for the CS cohort. The itacitinib 300-mg bid dose cohort was discontinued early due to malignancy relapse occurring in 4/29 (14%) pts and more pts requiring dose reductions compared with the 400-mg qd and 300-mg qd cohorts (28% vs 17% and 8%, respectively), mostly due to cytopenias. Incidence of grade ≥3 treatment-emergent adverse events (AEs) was higher in the itacitinib cohorts than with CS (65% vs 31%) and were reported most commonly in the system organ classes of infections (44% vs 6%) and blood and lymphatic system disorders (23%-34% vs 6%). Cytomegalovirus (CMV) infections occurred in 10%-15% of pts in itacitinib cohorts (including CMV pneumonia [n=3], esophagitis [n=1], enteritis [n=1]) vs 3% with CS. The all-cause mortality rate was 14%-18% in itacitinib cohorts vs 11% with CS, with infections the leading cause. The overall response rate (ORR) at 6 months was 46% (complete response [CR], 14%) with 300-mg qd and 53% (CR, 32%) with 400-mg qd, vs 36% (CR, 18%) with CS. A preliminary exposure-response analysis showed a bell-shaped curve with maximum efficacy decreasing at higher exposures, consistent with increasing incidence of AEs. 60%-70% of patients received coadministration with a sCYP3A4i at any time point during study treatment, which increased itacitinib exposure across all doses, requiring dose reduction by 200 mg qd. Conclusion: Preliminary results for first-line treatment of moderate or severe chronic GVHD showed an increase in ORR and CR rate with itacitinib + CS vs CS alone in both the 300-mg qd and 400-mg qd cohorts, at the expense of increased rates of cytopenias, infections, and mortality. This benefit:risk ratio does not support moving the combination of itacitinib + CS to a later phase of development in first-line therapy of chronic GVHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Psychiatric Manifestations of Withdrawal Following Domperidone Used as a Galactagogue.

Background: Domperidone is a dopamine-2 antagonist used off-label to increase breast milk production. Dosages commonly promoted for lactation are often far above those of studied on-label indications and might pose additional risks, especially upon discontinuation of the drug. Patients: Three U.S. patients are presented who used domperidone for lactation and experienced varying degrees of psychiatric withdrawal symptoms lasting months during dosage tapering and after cessation. Conclusion: Domperidone as a galactagogue may pose a significant psychiatric risk upon discontinuation. This presentation is commonly confused with, but clinically distinct from, postpartum depression. Lactating mothers who present with psychiatric symptoms should be explicitly probed about domperidone use, even in areas where domperidone is not authorized for use. Maternal hesitancy to disclose domperidone use may lead to suboptimal outcomes for the patient and delay management of withdrawal manifestations. The best course of treatment remains unknown, but a slow hyperbolic taper to gently discontinue domperidone may minimize withdrawal symptoms in these patients. Individuals exploring domperidone use should be informed of potential risks upon withdrawal, including psychiatric manifestations, requisite taper, and potential impacts of using unstudied high doses.

Abstract 10594: Cardiac Tamponade in a Covid-19 Positive Patient With Idiopathic Capillary Leak Syndrome: A Perilous Combination

Introduction: Clarkson’s disease, more known as idiopathic systemic capillary leak syndrome (SCLS) is a rare condition characterized by hypotensive episodes due to capillary hyperpermeability and can manifest as fluid accumulation in any organ or potential space. This may cause a range of complications: respiratory failure (from pulmonary edema or pleural effusion), mesenteric hypoperfusion (from hepatic congestion and severe intestinal edema), compartment syndrome and rhabdomyolysis, and even shock from hypovolemia or cardiac tamponade. Very few cases of cardiac tamponade in Clarkson's disease and COVID-19 have been reported, and when present, is certainly a serious and life-threatening complication. Case Summary: A 44-year-old female - with prior episodes of angioedema, pleural and pericardial effusions aggravated by menstruation and infection - presented with hypotension and diaphoresis. She was exposed to a COVID patient and eventually tested positive for COVID-19 infection. Persistent hypotension warranted triple inotropic support. Initial laboratories revealed hemoconcentration and hypoalbuminemia. Urinalysis was normal. 2D echocardiography showed normal left ventricular ejection fraction but with large pericardial effusion and signs of cardiac tamponade, hence, she underwent emergency pericardial windowing. She then developed pleural effusion which was drained surgically. Hepatitis, mycoplasmal and Epstein-Barr virus were negative. Direct and indirect Coomb’s test, and Lupus panel were unremarkable. Serum free light chain panel, immunopathology and C1 inhibitor results were non-diagnostic. Patient was managed as a case of idiopathic SCLS or Clarkson's disease. Methylprednisolone pulse therapy (MPPT) and intravenous immunoglobulin (IVIg) were administered. Patient was discharged with tapering doses of oral steroids and scheduled monthly IVIg infusion. Conclusions: Cardiac tamponade is a very rare but life-threatening complication of Clarkson’s disease, and on top of a COVID-19 infection, warrants emergent intervention. The pathogenesis is not yet fully elucidated. Diagnosis of SCLS is challenging thus recurrent pericardial and pleural effusions should raise the clinician’s index of suspicion.

Lisdexamfetamine for the treatment of acute methamphetamine withdrawal: A pilot feasibility and safety trial

BackgroundThere is no effective treatment for methamphetamine withdrawal. This study aimed to determine the feasibility and safety of a tapering dose of lisdexamfetamine for the treatment of acute methamphetamine (MA) withdrawal. MethodsOpen-label, single-arm pilot study, in an inpatient drug and alcohol withdrawal unit assessing a tapering dose of oral lisdexamfetamine dimesylate commencing at 250 mg once daily, reducing by 50 mg per day to 50 mg on Day 5. Measures were assessed daily (days 0–7) with 21-day telephone follow-up. Feasibility was measured by the time taken to enrol the sample. Safety was the number of adverse events (AEs) by system organ class. Retention was the proportion to complete treatment. Other measures included the Treatment Satisfaction Questionnaire for Medication (TSQM), the Amphetamine Withdrawal Questionnaire and craving (Visual Analogue Scale). ResultsTen adults seeking inpatient treatment for MA withdrawal (9 male, median age 37.1 years [IQR 31.7–41.9]), diagnosed with MA use disorder were recruited. The trial was open for 126 days; enroling one participant every 12.6 days. Eight of ten participants completed treatment (Day 5). Two participants left treatment early. There were no treatment-related serious adverse events (SAEs). Forty-seven AEs were recorded, 17 (36%) of which were potentially causally related, all graded as mild severity. Acceptability of the study drug by TSQM was rated at 100% at treatment completion. Withdrawal severity and craving reduced through the admission. ConclusionA tapering dose regimen of lisdexamfetamine was safe and feasible for the treatment of acute methamphetamine withdrawal in an inpatient setting.

ODP615 Emergence of Graves’ Ophthalmopathy in the Setting of Sudden Hypothyroidism: Possible Mechanisms Explored

Abstract Background Ninety percent of thyroid eye disease (TED) patients are hyperthyroid and at least 10% of TED occurs in the setting of euthyroidism or hypothyroidism. When Graves’ hyperthyroidism is diagnosed, 74% may not present with ophthalmopathy. Clinical Case A 58 year old woman diagnosed with Multinodular nontoxic goiter without nodule suspicious for malignancy was carefully monitored. No Levothyroxine treatment started. In 2017, patient had sudden onset of tremors, weight loss and palpitations. There were no signs of thyroid associated orbitopathy. Her TSH was &amp;lt;0. 009 uIU/ml (0.30-4) and FT4 29. 06pmol/L (10-22). Thyroid scan showed elevated 2- and 24-hours RAI uptake (as high as 80%) in both lobes. She was started on Methimazole but developed adverse reactions hence RAI (10 mci) was given. A month after RAI, she was rendered hypothyroid with of TSH 73.48uIU/ml (0.27-3.75), FT4 2.257pmol/L (8.8-44). She was maintained on Levothyroxine and remained euthyroid for four years. One year post RAI, ultrasound showed a small sized thyroid gland (right lobe: 3×0.6×1.5cm and left lobe: 2.2×0.3×1.3cm). May 2021, she followed up due to bulging eyes with scratchy sensation. She was noncompliant with Levothyroxine for several months. TSH was elevated to 46.19 uIU/ml (0.3-4. 00) and FT4 12.35 pmol/L (10.20-22.50). Levothyroxine dose was adjusted and repeat TSH was normal to 0.38 uIU/ml (0.30-4. 00) with FT4 of 22.40 pmol/L (10.20-22.50). Despite euthyroidism, there were progressive eye protrusion, conjunctival redness, pain and blurring of vision. TSHrAb was elevated to 21.62 U/L (N: &amp;lt;1 U/L). TSI was elevated to 6.59 IU/L (N: &amp;lt;0.10). . MRI of the orbit showed findings suggestive of Graves’ ophthalmopathy. She was started on Prednisone 60mg/day. Repeat TSHrAb was 9.85 U/L (&amp;lt;1U/L) after 3 weeks of steroids. Levothyroxine was stopped to check whether she had recurrence of Graves’ disease. When Levothyroxine was discontinued, there was worsening of eye disease and it was confirmed that patient was hypothyroid with TSH of 48.91 uIU/ml (0.55-4.78). Levothyroxine was resumed at 100mcg 1 tablet once daily and continued with Prednisone in tapering doses. Conclusion There were possible mechanisms that can lead to Graves’ ophthalmopathy in patients who had RAI and suddenly became hypothyroid. The rapid and protracted hypothyroidism caused increased secretion of TSH that stimulate antigen production by thyrocytes or induce proliferation in retro-orbital preadipocytes which express the TSH receptor. The protracted hypothyroidism can also be related to fluctuating TSHrAb post RAI. It was suggested that remission of TSH-receptor autoimmunity after RAI is less common. Clinicians should acquire baseline and monitoring of TSHrAb or ophthalmology consultation for all patients undergoing RAI regardless of whether they have eye signs or not. Maintenance of euthyroidism will help prevent emergence of Graves’ ophthalmopathy. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

LBSUN288 Improved Glycemic Control Following Oophorectomy In A Post-menopausal Woman With Ovarian Hyperthecosis

Abstract Introduction While androgens are associated with decreased risk for type 2 diabetes in males, the opposite is seen in females. Despite this, a "chicken or the egg" argument exists regarding hyperandrogenism and insulin resistance in women. Ovarian hyperthecosis, a condition that mostly affects post-menopausal women, causes androgen excess due to hyperplasia of the theca interna of the ovaries. Akin to polycystic ovarian syndrome, it is associated with obesity and insulin resistance. We describe a case of ovarian hyperthecosis in a woman with type 2 diabetes with improved glycemic control following oophorectomy. Case A 63-year-old post-menopausal female with a history of autoimmune hepatitis, primary biliary cirrhosis, and chronic pancreatitis presented for recently diagnosed type 2 diabetes, discovered on routine point-of-care Hemoglobin A1c (HbA1c) testing in December 2020 (HbA1c 7.1%, weight: 86 kg). In January, she started repaglinide which was titrated to 2 mg with meals, also that month started prednisone for autoimmune hepatitis. Despite tapering doses of prednisone, her hyperglycemia paradoxically worsened and persisted following completion in June. In May, HbA1c was 7.8%. In August, she endorsed hirsutism, present for 2 years but worsening over the past few months. Labs showed elevated total testosterone (508 ng/dL), free testosterone (32.7 pg/mL), and androstenedione (305 ng/dL), with normal sex hormone binding globulin. DHEA-S was low (28.9 ug/dL, range: 29.4-220.5), midnight salivary cortisol was elevated (0.12 mcg/dL; range: &amp;lt;0. 09), and morning serum ACTH and cortisol were within normal range, with appropriate suppression to dexamethasone. Estradiol was above post-menopausal range (68.1 pg/mL; range: &amp;lt;6. 0-54.7). FSH and LH were within the post-menopausal range, with an approximate 1: 1 ratio. A pelvic ultrasound revealed two intramural myomas and a simple cyst of the right ovary, but otherwise unremarkable. She underwent bilateral salpingo-oophorectomy in October 2021. Post-surgical total testosterone was 27 ng/dL. Surgical pathology revealed unremarkable fallopian tubes and bilateral stromal hyperplasia and hyperthecosis of the ovaries. At one month follow-up, HbA1c was 6.5%, weight decreased from 89 kg pre-surgery to 86, and she endorsed improved hirsutism but frequent hypoglycemia on repaglinide 2 mg with meals. Repaglinide was decreased to 0.5 mg with meals. Three months later, HbA1c was 6.3% with unchanged weight. Conclusion Improved glycemic control, corresponding with timing of oophorectomy but not discontinuation of steroids, suggests insulin resistance in this case may be due to hyperandrogenism. Though some studies and case reports suggest hyperandrogenism causes insulin resistance, others suggest the contrary. The relationship between androgens and insulin sensitivity is likely complex, and further research is necessary. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Deprescribing proton pump inhibitors.

Proton pump inhibitors (PPIs) are indicated for disorders including peptic ulcer disease and gastro-oesophageal reflux disease; however, they are often used for longer and at higher doses than recommended, or for indications that are not supported by evidence. The aim of this article is to outline evidence-based approaches to deprescribing PPIs. PPIs are generally well tolerated; however, use beyond eight weeks is rarely indicated and increases the risk of adverse events. PPI deprescribing should be considered when there is no indication for long-term therapy. Evidence supports a patient-centred approach to PPI deprescribing involving stepping down the dose before ceasing or switching to pro re nata (PRN; 'as needed') use. Abrupt PPI discontinuation may result in short-term rebound acid hypersecretion that can mimic symptom return. This can be minimised with gradual dose tapering prior to discontinuation and managed with PRN treatment. Prescribers should discuss the rationale for PPI deprescribing and involve patients indeveloping the deprescribing plan.

Biologic tapering for patients with psoriasis with low disease activity: data from the French PsoBioTeq Registry.

Dose tapering strategies with biologics in psoriasis may lower the treatment burden over time, while enabling high therapeutic response maintenance in patients benefiting from them. Our results should contribute to developing clinical guidelines to fill the current gap in knowledge on this promising therapeutic approach

Effective antibiotic dosing in the presence of resistant strains.

Mathematical models can be very useful in determining efficient and successful antibiotic dosing regimens. In this study, we consider the problem of determining optimal antibiotic dosing when bacteria resistant to antibiotics are present in addition to susceptible bacteria. We consider two different models of resistance acquisition, both involve the horizontal transfer (HGT) of resistant genes from a resistant to a susceptible strain. Modeling studies on HGT and study of optimal antibiotic dosing protocols in the literature, have been mostly focused on transfer of resistant genes via conjugation, with few studies on HGT via transformation. We propose a deterministic ODE based model of resistance acquisition via transformation, followed by a model that takes into account resistance acquisition through conjugation. Using a numerical optimization algorithm to determine the 'best' antibiotic dosing strategy. To illustrate our optimization method, we first consider optimal dosing when all the bacteria are susceptible to the antibiotic. We then consider the case where resistant strains are present. We note that constant periodic dosing may not always succeed in eradicating the bacteria while an optimal dosing protocol is successful. We determine the optimal dosing strategy in two different scenarios: one where the total bacterial population is to be minimized, and the next where we want to minimize the bacterial population at the end of the dosing period. We observe that the optimal strategy in the first case involves high initial dosing with dose tapering as time goes on, while in the second case, the optimal dosing strategy is to increase the dosing at the beginning of the dose cycles followed by a possible dose tapering. As a follow up study we intend to look at models where 'persistent' bacteria may be present in additional to resistant and susceptible strain and determine the optimal dosing protocols in this case.

ANSWERS LIE IN THE COMPLETE BLOOD COUNT: A CASE OF EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS PRESENTING WITH ACUTE ST-WAVE ELEVATION MYOCARDIAL INFARCTION

ANSWERS LIE IN THE COMPLETE BLOOD COUNT: A CASE OF EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS PRESENTING WITH ACUTE ST-WAVE ELEVATION MYOCARDIAL INFARCTION