Initiation Of Steroids Research Articles

Low-dose Methotrexate has Similar Outcomes to High-dose Methotrexate in Combination with Anti-TNF Therapy in Inflammatory Bowel Diseases.

Methotrexate [MTX] is a well-known immunomodulator in the treatment of inflammatory bowel disease [IBD] and is often combined with biologic agents. The ideal MTX dose for combination therapy has not been determined. This study aimed to investigate the effect of varying doses of MTX on efficacy and safety outcomes when used with anti-TNF agents in IBD. This study included patients with Crohn's disease [CD] or ulcerative colitis [UC] receiving care between January 2005 and June 2018. Low-dose MTX was defined as ≤12.5 mg/week and high-dose as >12.5 mg/week. The primary efficacy outcome was a composite of need for IBD-related hospitalization or surgery, steroid initiation, or change of biologic agent within 1 year. Safety outcomes included side effects related to MTX, serious infections, malignancy, and need to discontinue MTX therapy within 1 year. Multivariable logistic regression models adjusting for relevant covariates were used to assess independent association between MTX dose and outcomes. Our study included 222 patients with IBD [163 CD, 59 UC]. Just under a third were receiving low-dose MTX [28%]. The primary efficacy composite outcome was noted in 75 patients [47%] in the high-dose MTX group compared with 23 patients [37%] in the low-dose MTX group [p = 0.15]. We found no significant associations between MTX dose and any side effect [odds ratio 1.59, 95% confidence interval 0.77-3.31, p = 0.21] or development of serious infections [odds ratio 1.19, 95% confidence interval 0.41-3.45, p = 0.76]. Low-dose and high-dose MTX combination therapy were equally effective, and no difference in infection or malignancy rates was observed.

Relapse patterns and predictors of IgG4-related diseases involved with autoimmune pancreatitis: A single-center retrospective study of 115 patients.

Autoimmune pancreatitis is an autoimmune disorder accompanied by clinicopathological manifestations that have been established as immunoglobulin (IgG)4-related diseases (IgG4-RD). Other IgG4-RD are often involved with autoimmune pancreatitis. They sometimes relapse despite a favorable response to steroid therapy. This study aimed to clarify the patterns and risk factors for extrapancreatic relapse. We reviewed the data of 115 patients diagnosed with definite autoimmune pancreatitis type 1 and followed up for > 1 year. We analyzed two items: the timing and pattern of extrapancreatic relapse, and risk factors for relapse with three common manifestations: IgG4-related sclerosing cholangitis (SC), IgG4-related dacryoadenitis and sialadenitis (DS), and IgG4-related retroperitoneal fibrosis (RF). Remission was achieved in all patients, except one. The extrapancreatic relapse rates were 11.0%, 19.7%, and 40% within 3, 5, and 10 years, respectively. Of 26 patients with extrapancreatic relapse, nine (34.6%) relapsed with a new IgG4-RD. Based on multivariate analysis, the interval between symptom onset and steroid initiation, and the presence of RF at onset were significant risk factors for relapse with SC and RF, respectively. Our results indicate that they may be various extrapancreatic relapse patterns especially in autoimmune pancreatitis with other organ involvement. Patients with a delayed initiation of steroids or RF at onset should be carefully followed up as high-risk groups for SC and RF relapse.

Bicalutamide-induced Eosinophilic Pneumonitis - A Serendipitous Diagnosis

Bicalutamide is a first-generation non-steroidal anti-androgen. Interstitial lung disease is a rare side effect of bicalutamide. Centres in the United States of America and Japan have previously reported bicalutamide-induced interstitial lung disease. This has not been reported in the United Kingdom.
 An 86-year-old Caucasian man with a history of advanced prostate cancer, on oral bicalutamide, presented to the emergency department with sudden onset dyspnoea and chest tightness.
 Bicalutamide-induced eosinophilic pneumonitis co-existing with community acquired pneumonia, and left ventricular systolic dysfunction were suspected, based on physical examination findings and investigation results that include blood tests, chest radiographs, echocardiogram, in addition to computed tomography pulmonary angiogram performed to rule out pulmonary embolism.
 There was a marked clinical, biochemical and radiological improvements after discontinuation of bicalutamide, initiation of a high-dose steroid, intravenous antibiotics, and diuretic. Prostate cancer retains a high incidence in the Western population. Recognising toxicities due to anti-androgen therapies is relevant to clinical practice.

P058 LOW DOSE METHOTREXATE HAS SIMILAR OUTCOMES AS HIGH-DOSE METHOTREXATE IN COMBINATION WITH ANTI-TNF THERAPY IN INFLAMMATORY BOWEL DISEASES

Methotrexate (MTX) is a well-known immunomodulator in the treatment of inflammatory bowel disease (IBD) and often combined with biological agents. The ideal MTX dose for combination therapy has not been determined. Our aim is to investigate the effect of varying doses of MTX when used with anti-TNF agents in IBD on efficacy and safety outcomes. This study included patients with Crohn’s disease (CD) or ulcerative colitis (UC) receiving care between January 2005 and June 2018. Low-dose MTX was defined as ≤15mg/week and high-dose as >15mg/week. The primary efficacy outcome was a composite of need for IBD-related hospitalization or surgery, steroid initiation, or change of biologic agent within 1 year. Safety outcomes included side effects related to MTX, serious infections, malignancy and need to discontinue MTX therapy within 1 year. Multivariable logistic regression models adjusting for relevant covariates examined the independent association between MTX dose and outcomes. Our study included 222 patients with IBD (163 CD, 59 UC). Just over half were receiving low dose MTX (51%). We found no difference in gender, IBD type, disease location and behavior, disease duration, prior IBD treatments, serum albumin and CRP between the two groups. The primary efficacy composite outcome was noted in 51 patients (47%) in the high dose MTX group compared to 47 patients (42%) in the low-dose MTX group (p=0.436). After adjusting for relevant confounders, there remained no difference in primary outcome between the two dose groups of MTX (OR 0.62, 95% CI 0.31 – 1.24, p=0.179). Separately, we also observed no difference in hospitalization, surgery or steroid initiation within 1 year between the low-dose and high-dose MTX groups (Figure 1). MTX dosage was not associated with likelihood of side effects (high dose 22.9% vs low dose 27.4%, p=0.44). A total of 20 serious infections (9%) were reported during the first year of combination therapy but there was no significant difference between high versus low dose MTX (9.2% vs. 8.9%, p=0.93). We found no significant associations with MTX dose and any side effect (OR 1.34, 95% CI 0.67 – 2.70, p=0.410) or development of serious infections (OR 0.97, 95% CI 0.35 – 2.67, p=0.946). Two cases developed a malignancy (thyroid carcinoma and hepatocellular carcinoma) during the first year of combination therapy, both in the high dose MTX group. Discontinuation of MTX therapy occurred in one fourth of the low dose MTX patients (24.8%) and 29.5% in patients with high dose MTX (p=0.442). Low dose and high dose MTX combination therapy were equally effective and no difference in infection and malignancy rates was observed. There is an important need for prospective trials comparing low and high dose MTX when used in combination with biologic therapy to determine optimal dosing. Figure 1. Comparison of safety (a) and efficacy (b) outcomes between low dose MTX and high dose MTX combination therapy

P070 MEDICAL THERAPY BEFORE PEDIATRIC CROHN’S DISEASE DIAGNOSIS IS ASSOCIATED WITH DIAGNOSTIC DELAY, BUT DECREASED RISK OF PERIANAL FISTULA IN ADMINISTRATIVE CLAIMS DATA

Crohn’s disease (CD) commonly causes perianal fistulas (PF), which are difficult and costly to treat. With 10% having PF present at CD diagnosis, delay in diagnosis is associated with worse outcomes. Furthermore, >20% develop PF later, with few reliable predictors, and preventive strategies are nonexistent. We sought to characterize the variation in CD diagnosis to identify potential predictors of PF development. We hypothesize that timely diagnosis and treatment is associated with lower rate of PF development. We used OptumInsight Clinformatics Data Mart to identify patients with inflammatory bowel disease (IBD) diagnosis between 5-24 years during 2001-2014. Diagnosis required 3 CD claims; index date was 1st occurrence of any IBD claim. We required 6-month run-in period without IBD claims, and 2-years continuous follow-up after index date. IBD symptoms were defined by claims for common presenting symptoms associated with IBD. We searched for symptom claims prior to index date. PF was identified by a previously validated claims-based case definition, based on diagnosis (fistula, abscess), or procedures (seton, fistulotomy). We characterized IBD symptoms, and medication use prior to index date. Time from the 1st IBD symptom to index date, and PF development were evaluated. Of 3404 patients identified with CD, 2597 (76%) had ≥1 symptom claim within 90 days before or at index date (mean age 16.7 ± 0.2 years, 48% female, and 77% white). Median time from 1st symptom claim to index date was 110 (interquartile range [IQR]:516) days, with 9% having 0 day and 32% >1 year. Overall, 159 (6%) patients developed PF prior to or at index date, with a median 76 (IQR:413) days from 1st symptom claim to PF. Males had 2.14 (CI:1.46-3.16) greater likelihood of PF development than female. 1895 (73%) patients started medications prior to or at index date and before PF development if any, including aminosalicylates (5ASA; 38%), corticosteroids (36%), antibiotics (45%), immunomodulators (8%), and anti-tumor necrosis factor (anti-TNF; 1%). After adjusting patient characteristics, initiation of 5ASA, steroid, or immunomodulators/anti-TNF was associated with lower risk of PF development (odds ratio [OR]:0.05 (95% confidence interval [CI]:0.02-0.14), 0.29 (CI:0.16-0.52), 0.07 (CI:0.01-0.53), respectively). Initiation of 5ASA, steroid, and antibiotics were associated with 59, 102, and 286 days longer time from the 1st symptom claim to index date respectively (p<0.0001). Immunomodulators/anti-TNF were not associated with time difference from the 1st symptom claim to index date (p=0.07). This is the first report of medication use prior to pediatric CD diagnosis in a large commercial claims database. We found that pre-diagnosis therapy was associated with delay in diagnosis, but with decreased risk of PF at CD diagnosis.

Abstract TP475: A Case of Suspected Vertebral Giant Cell Arteritis Causing Cervico-medullary Ischemia

Objective: To present a rare case of cervico-medullary ischemia suspected to be from giant cell arteritis (GCA). Background: In patients with GCA, vertebral artery involvement occurs in 3-4% of ischemic events and manifests by disturbances, cranial nerve palsies, cerebellar signs, weakness and altered consciousness (1,2). Design: Case Report. Results: A 79-year-old man presented with 2-week history of vertigo right-sided weakness, right-sided neck pain and occipital headaches with magnetic resonance imaging (MRI) brain and cervical spine without contrast showing right distal medulla and cervico-medullary junction infarct and magnetic resonance angiogram (MRA) neck showing bilaterally diminutive/atherosclerotic vertebral arteries with absence of flow in right vertebral C2 segment. Relevant tests showed an elevated white cell count of 14 K/mm 3 , C-reactive protein (CRP) of 171 mg/L, erythrocyte sedimentation rate (ESR) of 67 mm/hour, antinuclear antibodies (ANA) of 1: 1280 and unrevealing Reichlin profile, temporal artery ultrasound, carotid duplex, PET/CT and cerebrospinal fluid infectious workup. After initiation of Prednisolone 60 mg PO daily, patient reported improvement in pain and levels of inflammatory markers decreased. As patient was on Clopidogrel, temporal artery biopsy (TAB) was delayed and performed 14 days after initiation of steroids and showed no signs of inflammation. Patient is being planned for gradual steroid taper and monitoring of response. Conclusion: Vertebral GCA is a high fatality condition. A combination of persistently elevated inflammatory markers, unusual stroke location, bilateral vertebral artery disease with multiple areas of stenosis, improvement in weakness and pain after initiation of steroids were all highly suggestive of GCA vasculitic process. High index of suspicion is crucial as specific and curative treatment exists. In select cases where TAB is delayed, treatment should not be withheld.

Healthcare Resource Utilization (HCRU) and Costs Among Patients with Steroid-Resistant (SR) Chronic Graft-Vs-Host Disease (cGVHD) in the United States: A Retrospective Claims Database Analysis

Introduction cGVHD remains the most serious nonrelapse complication affecting long-term survivors of allogeneic hematopoietic stem cell transplant (allo-HSCT). The therapeutic mainstay for cGVHD is steroids; however, the overall response rate is only approximately 50%. Objective To estimate HCRU and costs associated with SR cGVHD following allo-HSCT in the United States. Method Administrative claims from the Optum Research Database were used to identify allo-HSCT patients from 01/01/10 to 08/31/16. Patients with cGVHD had ≥2 outpatient or ≥1 inpatient claim with cGVHD diagnosis specified as (1) cGVHD (ICD-9 279.52 or ICD-10 d89.811) within study period or (2) unspecified GVHD (ICD-9 279.50 or ICD-10 D89.813) beyond 120 days after HSCT. Patients with SR cGVHD were those treated with additional therapy at least 7 days after initiation of systemic steroids based on outpatient treatment records. The no-GVHD group had no GVHD claim during the follow-up. Patients were included if ≥12 years old, enrolled in commercial or Medicare Advantage plan ≥6 months preceding and ≥360 days post-HSCT (≥720 days for 720-day analysis) while surviving. All-cause HCRU and costs (uninflated amount in US dollars) during 360 and 720 days post-HSCT were compared between patients with SR cGVHD and no GVHD using chi-square test for categorical variables and nonparametric test for costs. Result 296 (178) patients with SR cGVHD and 227 (158) patients with no GVHD were included in the 360-day (720-day) analysis. Mean age (50 vs 49 years) and female (40% vs 41%) were similar in patients with SR cGVHD and no GVHD (P>0.05). The primary diagnoses for HSCT were acute myeloid leukemia (42% vs 36% in patients with SR cGVHD and no GVHD), non-Hodgkin lymphoma (13% vs 15%), and acute lymphoblastic leukemia (12% vs 10%). Median time from cGVHD diagnosis to initiation of second-line therapy was 60 days (interquartile range [IQR]: 33–121). 75% of patients with SR cGVHD used ≥4 lines of therapy over the period of follow-up. SR cGVHD patients had significantly more office visits, outpatient consultations, emergency room visits, and inpatient admissions within both 360 and 720 days post-HSCT than patients with no GVHD (all P Conclusion Most patients with SR cGVHD received multiple lines of therapy and additionally used significantly more outpatient and inpatient resource through 2 years post-HSCT than those without GVHD. Improved prevention as well as early and effective treatment of cGVHD may substantially reduce their costs of care.

Ruxolitinib for Steroid-Refractory Acute Graft-Versus-Host Diseas

Background Acute graft-versus-host-disease (aGVHD) is one of the leading causes of non-relapse morbidity and mortality following allogeneic hematopoietic cell transplant (allo-HCT). Ruxolitinib (RUX) may be a viable option for patients with steroid-refractory (SR)-aGVHD but limited data currently exists. Methods We performed retrospective chart review to identify patients treated with RUX for S-R-aGVHD 2015-2016 at our center. Primary aGVHD and overlap syndrome were included. Patients who received ≥14 days of RUX were considered evaluable for response assessment. A complete response (CR) was defined as the absence of any symptoms related to aGVHD. A partial response was defined as the improvement of at least one stage in the severity of aGVHD in one organ without deterioration in any other organ. Responses must have maintained for ≥21 days. Results Thirty-six patients were included in the analysis. None were treated on prospective trials of RUX. Demographics are described in Table 1. The median time from allo-HCT to start of RUX was 83 days (range 34-741). The median time from steroid initiation to RUX imitation was 16.5 days (range 2-280) and the median number of prior therapies for S-R-aGVHD was 2 (range 0-5). The majority of patients (72%) were initiated on 5mg BID RUX; 25% were initiated on 10mg BID; 1 patient was initiated on 5mg daily. The median duration of RUX treatment was 21.5 days (range 1-560); 67% received at least 14 days of treatment and were evaluable for response. The overall response rate was 58% with 25% obtaining a CR. RUX was well tolerated; hematologic toxicity was generally mild and not dose limiting and there were no cases of treatment-related mortality. The majority of patients discontinued due to treatment failure or clinical deterioration. Four patients discontinued for toxicity and six for issues in obtaining RUX. Overall, the estimated median overall survival (OS) was 4.9 months (95% CI 2.7-7.0). Of those who were evaluable for response, the median OS was 7.4 months (95% CI UTQ-15.9) for responders compared to 0.9 months (95% CI 0.7-1.1) for non-responders (p Conclusion In this population of high-risk, S-R-aGVHD, RUX is well tolerated and the ORR is 58% (95% CI 38%-78%) in patients receiving ≥14 days of treatment.

Use of corticosteroids for remission induction therapy in patients with new-onset ulcerative colitis in real-world settings

ABSTRACTBackground: Corticosteroids may be temporarily effective for ulcerative colitis (UC), but long-term use increases the risk of adverse drug reactions.Objective: The goal of the study was to examine steroid use in remission induction therapy after diagnosis of UC.Study Design: A retrospective observational study using the Japan Medical Data Center (JMDC) Claims Database from January 2008 to December 2014.Setting: Clinics, university hospitals, and national/public hospitals.Intervention: Initiation of steroids after diagnosis of UC.Main outcome measures: Start time and annual rate of steroid use, and use during the first 6 months of remission induction therapy.Results: The subjects were 399 patients were newly diagnosed with UC in the study period. The rate of steroid use after diagnosis was 58.4% in 2009, and showed a significant decreasing trend yearly after 2010 (p ≤ 0.0001). Regarding the start time, 52.2% of patients began steroids within 60 days after diagnosis of UC. At 6 months after initiation, 23.7% continued to use steroids and 73.9% of these patients used high-dose steroids.Conclusion: In treatment of UC after diagnosis, many patients continue to use steroids for >6 months after initiation. Reduced use of steroids based on clinical practice guidelines for UC should be promoted.

Adverse Effects of Immune Checkpoint Inhibitors (Programmed Death-1 Inhibitors and Cytotoxic T-Lymphocyte-Associated Protein-4 Inhibitors): Results of a Retrospective Study.

In recent years the use of immunomodulating therapy to treat various cancers has been on the rise. Three checkpoint inhibitors have been approved by the Food and Drug Administration (ipilimumab, pembrolizumab and nivolumab). The use of these drugs comes with serious adverse events related to excessive immune activation, collectively known as immune-related adverse events (irAEs). We conducted a system-based review of 139 case reports/case series that have described these adverse events between January 2016 and April 2018, found in the PubMed database. There was a broad spectrum of presentations, doses and checkpoint inhibitors used. The most common check point inhibitor observed in our literature review was nivolumab. The most common adverse effects encountered were colitis (14/139), hepatitis (11/139), adrenocorticotropic hormone insufficiency (12/139), hypothyroidism (7/139), type 1 diabetes (22/139), acute kidney injury (16/139) and myocarditis (10/139). The treatment most commonly consisted of cessation of the immune checkpoint inhibitor, initiation of steroids and supportive therapy. This approach provided a complete resolution in a majority of cases; however, there were many that developed long-term adverse events with deaths reported in a few cases. The endocrine system was the mostly commonly affected with the development of type 1 diabetes mellitus or diabetic ketoacidosis being the most frequently reported adverse events. While immunomodulating therapy is a significant advance in the management of various malignancies, it is capable of serious adverse effects. Because the majority of the cases developed pancreatic dysfunction within five cycles of therapy, in addition to the evaluation of other systems, pancreatic function should be closely monitored to minimize adverse impact on patients.

Validation of Minnesota Acute GVHD Risk Score and Identification of New Factors Associated with Initial Response to Steroids: Not All GVHD Is Created Equal

Introduction: We recently reported on the Minnesota acute GVHD Risk Score that is based on the number of involved organs and severity of GVHD at onset. Using clinical grouping, descriptive statistics and recursive partitioning, we identified poorly responsive, high-risk (HR) acute GVHD by the number of involved organs and severity of GVHD at onset. Patients with HR GVHD were 3 times less likely to respond to steroid therapy and had >2 fold increased risk of mortality and transplant-related mortality (TRM) than patients in the standard risk (SR) GVHD group. This GVHD Risk Score more accurately predicts response, survival and TRM than other published GVHD risk scores based upon clinical grading criteria (BBMT.2015,21:761).Methods: To validate this Risk Score, we examined a new cohort (2008-2016) of 355 patients (median age 49 years, range <1-75) at the University of Minnesota diagnosed with acute GVHD and treated with prednisone 60 mg/m2/d for 14 days, followed by an 8-week taper.Results: All patients had >6 months follow-up after steroid initiation (median 3.2 years). 79 (22%) patients had HR GVHD and 276 (78%) had SR GVHD. Demographics were similar in the two groups (Table). Overall response [complete response (CR)+partial response (PR)] was significantly higher in the 276 SR vs 79 HR GVHD patients at day 14 (71% vs 56%, p<0.01), day 28 (74% vs 59%, p=0.02) and day 56 (68% vs. 49%, p<0.01) after steroid initiation (Figure A). Day 28 CR/PR did not differ by initial GVHD grade being 64%, 77%, 65% and 50% for grade I, II, III and IV (p=0.07). HR GVHD was observed in 31% single UCBT recipients, 19% double UCBT recipients and 22% BMT/PBSCT recipients. Notably, Day 28 responses were significantly higher in UCB recipients than others (Figure B). In multiple regression analysis, the odds of day 28 CR/PR were lower in HR vs SR GVHD patients (OR 0.5, 95% CI 0.3-0.8) and in HLA matched URD donor vs other recipients (OR 0.5, 95% CI,0.3-1.1, p<0.01). OR of response was 2 fold higher in UCB (OR 2.2, 95% CI,1.3-3.7, p=0.01) vs. BM/PBSC recipients. Factors significantly associated with greater 2 year TRM included HR GVHD (HR 1.4, 95% CI,1.0-1.9, p=0.05), age ≥60 years (HR 1.7, 95% CI,1.1-2.8, p=0.02) and high risk HCT-comorbidity index (HCT-CI; HR 1.6, 95% CI,1.1-2.2, p=0.01). Similarly, mortality at 2 years was higher in HR GVHD (HR 1.7, 95% CI,1.2-2.4, p<0.01), high risk HCT-CI (HR 1.8, 95% CI,1.3-2.5, p<0.01), and recipients of URD grafts HR 1.9, 95% CI,1.1-3.1, p=0.01). Mortality was lower in early onset GVHD (HR 0.95, 95% CI,0.92-0.99, p=0.04). Two years after initiation of steroid therapy, 92 patients developed chronic GVHD for a cumulative incidence of 26% (95% CI 21-31%). No differences in the incidence of chronic GVHD were observed in those with SR and HR acute GVHD (28% vs 20%, p=0.54). Risks of chronic GVHD however were significantly lower in UCB recipients (HR 0.6, 95% CI,0.5-0.9, p=0.01) and in early onset GVHD (HR 0.95, 95% CI,0.92-0.98, p<0.01), but were higher in patients with high risk HCT-CI (HR 1.7, 95% CI,1.2-2.3, p<0.01).Conclusions: This analysis confirms that the Minnesota GVHD Risk Score is a valuable, immediately available bedside tool to define risk in patients with acute GVHD and predicts outcomes better than GVHD clinical grades. These results also demonstrate the importance of age, HCT-CI, graft source, and time to onset of GVHD on outcomes after GVHD therapy. Notably, UCB recipients have better responses to steroid therapy and lower subsequent risk for chronic GVHD than other donor sources. These data suggest that a tailored approach to upfront GVHD therapy based upon the Minnesota acute GVHD Risk Score and other risk factors should be considered in order to improve outcomes in patients with acute GVHD. Further studies are needed to explore why cord blood recipients with acute GVHD respond better than BM/PBSC recipients with a similar severity of GVHD. DisclosuresMacMillan:Angiocrine: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; Equillium: Consultancy. Holtan:Incyte: Consultancy. Brunstein:Gamidacell: Research Funding. Wagner:Magenta Therapeutics: Consultancy, Research Funding; Novartis: Research Funding. Blazar:Kadmon Corporation, LLC: Consultancy, Research Funding. Weisdorf:SL Behring: Consultancy; Equillium: Consultancy; FATE: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy.

Real-World Efficacy of Anti-Fungal Prophylaxis in Patients Treated for Acute Gastrointestinal Graft-Versus-host Disease (GI-GVHD)

AimAllogeneic progenitor cell transplant (HPCT) recipients who develop acute gastrointestinal graft-versus-host disease (GI-GVHD) are at increased risk of developing invasive fungal infections (IFI). Randomised control trial data supports the use of mould-active fungal prophylaxis in HPCT patients with grade II-IV GVHD (Ullman et al. 2007). We aimed to assess our unit's use of anti-fungal prophylaxis and describe the incidence and species of breakthrough IFI in patients with GI-GVHD.MethodWe conducted a retrospective audit of patients who underwent HPCT at our institution between 2011-2016 and identified those who were treated for acute GI-GVHD using a minimum of prednisone 1mg/kg or equivalent. For those patients the following details were collected: presence of any prior IFIs, anti-fungal prophylaxis before and after initiation of steroids, and the incidence of new IFIs within 6 months of commencing steroids.ResultOf the 551 HPCT performed during this period, 74 evaluable patients were treated for GI-GVHD. All patients received anti-fungal prophylaxis prior to steroid commencement (66.2% received fluconazole, 10.8% posaconazole, 20.2% voriconazole and 2.7% other). Post steroids 35.1% remained on fluconazole, 21.6% received posaconazole, 35.1% received voriconazole, and 8.1% received other anti-fungals. Of the 26 patients remaining on fluconazole, 9 were transitioned to mould-active prophylaxis at a later time.Twelve patients (16.2%) experienced a breakthrough IFI (6 definite and 6 probable). In the 42 patients receiving posaconazole or voriconazole, 7 (16.7%) experienced breakthrough IFI, compared with 3 (11.5%) in the fluconazole cohort. Two other cases occurred in patients who received caspofungin. Notably, patients receiving mould-active fungal prophylaxis developed mucormycosis, Fusarium and Scedosporium infections whereas fluconazole lead to invasive aspergillosis.ConclusionDespite anti-fungal prophylaxis, real-world GI-GVHD patients remain at particularly increased risk of developing IFI. Anti-mould prophylaxis is associated with lower incidence of invasive aspergillosis but higher incidence of non-Aspergillus mould. Further studies investigating optimal anti-mould strategies are warranted. DisclosuresNo relevant conflicts of interest to declare.

Conservative Management of Idiopathic Hemophagocytic Lymphohistiocytosis (HLH) Achieving Complete Remission

IntroductionHemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by overwhelming activation of the immune system. The disease can affect patients of all ages and many times it goes under recognized for long periods of time, thus increasing its mortality due to organ failure. It mainly affects infants, nonetheless, adults can suffer from the disease as well, with catastrophic consequences. HLH etiology subsumes sporadic and familial presentations. Of the former, the two more common causes are infectious and neoplastic conditions. Clinical presentation includes nonspecific findings such as jaundice, hepatosplenomegaly, fever, fatigue, neurologic deficits. Laboratory findings display a spectrum of cytopenias, hemolysis, elevated ferritin, elevated IL-2, hypertriglyceridemia. Early initiation of treatment accounts for a great deal of the patient's recovery. Treatment consists of immunosuppressive therapy such as the HLH94 protocol - includes etoposide and dexamethasone -, or other combination immunosuppressive regimens. Using steroids alone is not typically a standard approach for the management of patients with HLH. Here we present a case of a patient with HLH with likely infectious etiology, successfully treated with steroids alone.Case PresentationA 34-year-old male patient presented to the emergency room (ER) complaining of jaundice, abdominal distention, fatigue, weakness, and fevers to 102 F. Vital signs were stable except for tachycardia hear rate 119 /min. Physical exam disclosed the presence of hepatosplenomegaly, palpable edge of liver, spleen palpable 6 cm below left costal margin, skin with jaundice. Blood work showed signs of cytopenias and hemolysis. WBC 2.2 /uL, hemoglobin 6.1 gr/dL, platelet count 114,000 /uL, neutrophil percentage 35%. On his peripheral smear review he had excessive monocytosis of 18%, atypical lymphocytes 31%, and 4% basophils. Reticulocyte count 1.3%. INR 1.2. AST elevated at 305 U/L, ALT 230 U/L, LDH 1063 U/L, Albumin 3.0 , total bilirubin 25.9, direct bilirubin 19.69, sodium 129. Haptoglobin less than 8. Coombs direct positive IgG subtype. Differential diagnosis included warm autoimmune hemolytic anemia. CT scan of the abdomen with contrast showed splenomegaly, 19.4 cm coronal view (fig 1), hepatomegaly as well, 21 cm in the mid hepatic craniocaudal diameter, steatosis. The patient was started on prednisone 1 mg/kg with rapid improvement on his laboratory parameters within the first 48 hours. A ferritin level on the third day of hospitalization was elevated at 2184. This finding along with unexplained transaminitis and hepatosplenomegaly raised suspicion for HLH. The patient met 6 out of the 8 criteria for diagnosis: Cytopenias (nadir ANC less than 1000, thrombocytopenia nadir 112,000, anemia), fever, splenomegaly, soluble CD25 (IL-2) elevated at 1803 pg/mL (normal values less than 1033 pg/mL), triglycerides 309 mg/dL, ferritin level 2184. Thus, the following workup was conducted. A. Bone marrow aspiration and biopsy showed hypercellular marrow with erythroid hyperplasia, negative for lymphoma or leukemia, adequate trilineage hematopoiesis (fig 2). B. Flow cytometry from peripheral blood was negative for paroxysmal nocturnal hemoglobinuria. C. PET-CT scan done negative for malignancy. D. Brain MRI: normal. E. Extensive infectious workup: the patient was found to have positive PCR, less than 2000 copies/mL, for Epstein-Barr virus. E. HLH gene panel was sent out showing negative results. F. Liver biopsy demonstrated extramedullary hematopoiesis. G. Reduced natural killer T cell cytotoxicity; reduced perforin levels. The patients' hemolysis, cytopenias and hepatosplenomegaly rapidly improve after initiation of steroids. The patient continued on steroid regimen during 6 months on a taper.ConclusionHLH is a devastating disease that potentially culminates in multisystem organ failure if not appropriately treated. At the time of clinical suspicion of HLH, approximately 3 days after the patient's admission, his clinical condition had improved on high dose steroids alone, therefore additional immunosuppression was not initiated. The patient might have had EBV that precipitated his HLH, however at the time of diagnosis his viral load was less than 2000 copies/mL and antiviral therapy was not considered necessary. He continues to be in remission, asymptomatic, 9 months after original diagnosis. DisclosuresNo relevant conflicts of interest to declare.

A Phase 1/2 Trial of Investigational Spk-8011 in Hemophilia a Demonstrates Durable Expression and Prevention of Bleeds

A Phase 1/2 Trial of Investigational Spk-8011 in Hemophilia a Demonstrates Durable Expression and Prevention of Bleeds

Lenalidomide Induced Hemorrhagic Colitis in Multiple Myeloma

Lenalidomide is an immunomodulating drug of the thalidomide class which has significantly improved survival in patients with multiple myeloma. Its toxicity has limited its availability, but it continues to be a treatment option in the United States given its noteworthy life-altering outcomes in patients with myeloma. The known complications included venous thromboembolism, hepatotoxicity, and myelosuppression. Its effect on the gastrointestinal system is less known. We present the first reported case of Lenalidomide induced hemorrhagic colitis. A 59 year old woman with a history of multiple myeloma on Lenalidomide 10mg daily (week 10) presented with four days of nausea, abdominal pain, and loose bloody bowel movements. Vital signs were stable. Labs revealed normocytic anemia (Hb 10.5 g/dL from 12.0 g/dL) and normal platelet count (201 k/uL). Computed tomography of the abdomen showed thickened ascending and transverse colon with mucosal hyperemia and surrounding inflammatory change concerning for colitis. Clostridium difficile and stool ova/parasites were negative. Upper endoscopy was unremarkable. Colonoscopy revealed erythematous, granular, hemorrhagic, inflamed, ulcerated, and vascular pattern decreased mucosa in the entire colon. Biopsies were obtained, which revealed colonic mucosa with superficial mucosal necrosis, erosion, focal hyalinization of the lamina propria, and atrophic crypts. The examined portion of the ileum was normal. Lenalidomide was discontinued and the patient was started on prednisone. She made symptomatic improvement and was discharged home. Follow up colonoscopy six weeks later revealed normal appearing mucosa and biopsies. This is the first reported case of Lenalidomide induced hemorrhagic colitis. Lenalidomide is an immunomodulating drug that is used to treat myelodysplastic syndromes, multiple myeloma, and mantle cell lymphoma. It does this through tumor cell apoptosis, inhibition of bone barrow stromal cell support, anti-angiogenic and anti-osteoclastogenic effects. There has been one other case of Lenalidomide induced colitis, but it was ischemic. Bleeding that occurs while on this immunomodulator is typically attributed to its myelosuppressive properties and resultant thrombocytopenia. However, our case demonstrates hemorrhagic colitis that is independent from thrombocytopenia. Withdrawal of the drug and initiation of steroids resulted in complete resolution.1652 Figure 1 No Caption available.

DUCHENNE MUSCULAR DYSTROPHY - PHYSIOTHERAPY: P.316Utility of ACTIVE workspace volume as a clinically meaningful measure of functional capacity in individuals with neuromuscular disease

ACTIVE, a custom video game, uses a skeletal tracking algorithm to quantify the worskpace volume (WSV) with which a person can interact by reaching and leaning in three dimensions to squish spiders or dig for jewels. ACTIVE evaluates a combination of upper-extremity and proximal muscle function, making it an ideal tool to identify and track impairment across a spectrum of abilities in individuals with neuromuscular disease. This study explored the validity and functional relevance of ACTIVE across a variety of neuromuscular disorders and its ability to measure change as a result of treatment. Three hundred and thirty five individuals with neuromuscular disease including Duchenne muscular dystrophy (n=119), Becker muscular dystrophy (n=41), limb girdle muscular dystrophies (n=113) performed ACTIVE, other traditional assessments of upper extremity and lower extremity function, and self- and parent-reports of function as appropriate at regularly scheduled clinic visits. ACTIVE demonstrated validity by significantly correlating to disease-specific validated outcome measures (Rho= 0.5 - 0.9, p<0.001). ACTIVE also reduced the ceiling and floor effects when compared to traditional scales as ACTIVE measures function on a continuous scale. We explored the minimum clinically important difference in ACTIVE score, drew comparisons to patient reports of function for individual activities of daily living (ADL), and formulated minimal WSV requirements for each ADL. Additionally, ACTIVE was responsive to intervention in a sub-cohort of the DMD group that performed ACTIVE pre and post steroid initiation. ACTIVE is able to quantify functional abilities in patients across ages and diagnoses on a single continuous scale and is responsive to intervention in neuromuscular disease.

Tocilizumab for the treatment of severe steroid-refractory acute graft-versus-host disease of the lower gastrointestinal tract.

Steroid-refractory (SR) acute gastrointestinal (GI) graft-versus-host disease (GVHD) is associated with significant mortality in allogeneic hematopoietic cell transplantation recipients. We retrospectively evaluated the efficacy of tocilizumab for the treatment of SR biopsy-proven acute lower GI GVHD in 16 consecutive adult transplant recipients between October 2015 and July 2016. Tocilizumab 8 mg/kg was administered every 2 weeks until achievement of complete response, defined as resolution of all manifestations of GI GVHD, or until patients had progression or initiation of other therapy. Ten of 16 patients (62.5%; 95% CI, 0.39-82) achieved a complete response after a median time of 11 days (range, 2-28 days) from tocilizumab initiation. The median time to response onset (improvement in stage by at least 1) was 1 day (range, 1-4 days). Tocilizumab was administered at a median of 9 days (range, 3-75 days) from GVHD diagnosis and 10 days (range, 3-75 days) from initiation of high-dose steroids. At a median follow-up of 7.6 months (range, 0.8-27.7 months) from initiation of tocilizumab, 6/16 (37.5%) patients are alive and free of their underlying hematologic malignancy. Tocilizumab appears to be a highly active agent for the treatment of severe SR lower GI acute GVHD.

Sensorineural hearing loss after spine surgery treated with hyperbaric oxygen therapy: two case reports

Acute idiopathic sudden sensorineural hearing loss (ISSNHL) following lumbar spinal surgery is an exceedingly rare phenomenon. This paper presents a case of ISSNHL presenting acutely after lumbar spine decompression and fusion treated with transtympanic steroids and hyperbaric oxygen (HBO₂) therapy. It also presents the ironic case of SSNHL secondary to presumed viral pathology sustained by the patient's operative surgeon who was treated with transtympanic steroids and HBO₂ as well. Proposed etiologies of the patient's ISSNHL include: hypotension, prone operative position, malfitted/malpositioned headrest, microemboli from a cell-saver, and nitrous oxide anesthesia. The role of systemic hypotension as an etiology of ISSNHL is discussed given the fact that there are no reported cases of ISSNHL in orthopedic procedures performed with permissive hypotension. The initiation of steroids and HBO₂ therapy has been shown to be an effective treatment for ISSNHL when started within 14 days of symptom onset. HBO₂ and transtympanic steroids were initiated 10 days earlier in the operative surgeon, which showed to be a better treatment modality compared to the postoperative patient. ISSNHL in the acute postoperative period of lumbar spinal fusion surgery presents a unique treatment dilemma because systemic steroids are routinely avoided over concerns of pseudarthrosis. Of the seven documented cases of ISSNHL following lumbar spine surgery, none underwent HBO₂ as a treatment modality.

Steroid-Induced Diabetic Ketoacidosis in a Patient with Type 2 Diabetes Mellitus

ABSTRACT Objective: Diabetic ketoacidosis (DKA) is usually associated with type 1 diabetes mellitus; however, it is increasingly being recognized in patients with type 2 diabetes mellitus (T2DM). Triggering factors usually involve infections and poor medication adherence. Other potential triggers are myocardial infarction, antipsychotic drug usage, malignancy, and cerebrovascular accidents. No case of steroid-induced DKA in a patient with T2DM has been reported in the literature. Methods: Clinical and laboratory data are presented. Results: We present a case of a middle-aged patient with a history of well-controlled T2DM via metformin. The patient was started on oral prednisone for lumbar disc herniation, and then presented with acute DKA. No other trigger for DKA but steroid initiation was found. Conclusion: We conclude that patients with diabetes who receive glucocorticoids should be monitored carefully, as steroids can precipitate DKA. This may occur in the absence of any other triggering factor, and e...

The mortality of very low birth weight infants: the benefit and relative impact of changes in population and therapeutic variables

Objective: Very low birth weight (VLBW, ≤1500 g) infants’ mortality rates have decreased markedly. We aimed to quantify the relative contribution of changes in the distribution of population characteristics and changes in specific mortality rates on the decline in mortality rates of VLBW infants.Study design: A population-based observational study of the Israel national VLBW infant database. The study population comprised singleton VLBW infants of 24–32 weeks’ gestation born during the epochs 1995–2000 (n = 3728) and 2006–2010 (n = 3246). The Kitagawa methodology was applied to determine the contribution of changes in demographic and perinatal characteristics and changes in specific mortality rates on the decline in mortality between the periods.Results: During the study epochs, VLBW infant mortality rates decreased from 19.7 to 13.8%. Of the 5.9% decrease in mortality, 60.6% was attributed to the decrease in specific mortality rates and 39.4% to changes in the proportions of population characteristics and therapies, predominantly early initiation of prenatal care (8.1%), antenatal steroids (25.1%), and cesarean delivery (8.1%). For most of the demographic and perinatal categories considered the relative contribution of changes in their proportions was <3%, whereas >97% could be attributed to changes in the specific mortality rates for these characteristics.Conclusions: The decrease in preterm VLBW infant mortality was attributable predominantly to changes in variable specific mortality rates whereas changes in the proportions of demographic, perinatal risk factors, and therapies had a limited impact on VLBW infant mortality. Future assessment of determinants of VLBW infant mortality data should be dissected by discriminatory models.