Asymptomatic Elevation Research Articles

Idiosyncratic drug-induced liver injury in patients: Detection, severity assessment, and regulatory implications.

Idiosyncratic Drug-Induced Liver Injury (IDILI) is a rare but potentially life-threatening event that is caused by drugs that, at usual therapeutic doses, do not cause any biochemical or clinical evidence of liver injury in the majority of treated patients. The most common clinical phenotypes of IDILI are "acute hepatitis," "mixed hepatocellular-cholestatic hepatitis," and "cholestatic hepatitis" and these are distinguished by clinical, biochemical and histologic characteristics. Anti-microbials, herbals and dietary supplements are now the agents most often implicated in the US Drug-Induced Liver Injury Network registry. There are several scales that have been used to characterize the severity of IDILI events. There are no reliable means to accurately predict the course of an IDILI event at presentation. In clinical trials, the "gold standard" liver safety signal is the occurrence of "Hy's Law Cases." Making the diagnosis of IDILI, and when a patient is taking multiple drugs, identifying the most likely culprit can be challenging, but many drugs cause IDILI with characteristic clinical and biochemical presentations, or "signatures." In a clinical trial, it is sometimes possible to identify an overlooked "signature" of IDILI by characterizing more minor, asymptomatic, and transient elevations in liver chemistries. This observation can be helpful in assessing causation in rare serious liver events occurring in the clinical trial, or first recognized post-marketing.

Clinicolaboratory profile of expanded dengue syndrome - Our experience in a teaching hospital.

Introduction:Classic dengue fever presentation has expanded its horizon by involving various organ systems and is named as expanded dengue syndrome. This changing presentation and rising burden across the globe may lead to delayed diagnosis and under reporting of this syndrome.Aim of Study:To analyze clinicolaboratory profile of patients with expanded dengue syndrome.Materials and Methods:About 520 cases of expanded dengue syndrome as per World Health Organization definition criteria 2012 were studied with their informed consent. Detailed history, thorough clinical examination, and relevant investigations were done. Their clinical and laboratory parameters were analyzed. Standard treatment guidelines were followed in all cases.Observation:About 301 patients were male and 219 were female with male-to-female ratio of 3:2. Their age varied from 12 to 76 years with the average age of 47.5 years. About 92% of cases presented with various gastro hepatic manifestations. The commonest gastrohepatic manifestation was transaminitis (57.5%) that is asymptomatic elevation of liver enzymes followed by acalculous cholecystitis (21%) and acute pancreatitis (13.9%). Twenty-nine patients presented with various neurological manifestations. Three patients presented with acute kidney injury and eight patients had coinfection with malaria. Fever with nausea and vomiting was the most common presentation. About 15% of patients presented with bleeding manifestations. About 40.6% of patients presenting as abdominal manifestations had platelet count <20,000/mm3 and needed platelet transfusion versus 9.8% with other system involvement (central nervous system, cardiovascular system (CVS), renal). Hepatomegaly was the most common ultrasonography (USG) finding being present in 57.5% of patients followed by acalculous cholecystitis in 21.3%. Total mortality was 1.9% in our series. We lost eight patients presenting with neurological manifestations and two patients with coinfection with malaria.Conclusion:Atypical presentations should prompt us to investigate for dengue especially during ongoing epidemics so that expanded dengue syndrome can be diagnosed and treated early.

Cardiac implications of thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a multisystem disorder that essentially can affect any organ in the human body. The hallmark of the pathogenesis in TTP is the large von Willebrand factor multimers on platelet-mediated micro-thrombi formation, leading to microvascular thrombosis. Autopsy studies showed that cardiac arrest and myocardial infarction are the most common immediate causes of death in these patients. Clinical manifestations of cardiac involvement in TTP vary dramatically, from asymptomatic elevation of cardiac biomarkers, to heart failure, MI and sudden cardiac death. There is limited knowledge about optimal cardiac evaluation and management in patients with TTP. The absence of typical cardiac symptoms, combined with complicated multi-organ involvement in TTP, may contribute to the under-utilization of cardiac evaluation and treatment. Prompt diagnosis and timely initiation of effective therapy could be critically important in selected cases. Based on our experience and this review of the literature, we developed several recommendations for focused cardiac evaluation for patients with acute TTP: (1) patients with suspected or confirmed TTP should be screened for the potential presence of cardiac involvement with detailed history and physical, electrocardiogram and cardiac enzymes; (2) clinical deterioration of TTP patients warrants immediate cardiac reevaluation; (3) TTP patients with clinical evidence of cardiac involvement should be monitored for telemetry, cardiac biomarkers and evaluated with transthoracic echocardiography. These patients require urgent targeted TTP treatment as well as cardiac-specific treatment. Aspirin therapy is indicated for all TTP patients. Since epicardial coronary artery involvement is rare, cardiac catheterization is usually not required, given the high risk for hemorrhage and kidney injury; (4) we recommend evidence-based medical therapy for ischemic symptoms and heart failure. TTP patients with evidence of cardiac involvement would also benefit from routine cardiology follow up during remission.

Real-World Lab Data in Natalizumab Treated Multiple Sclerosis Patients Up to 6 Years Long-Term Follow Up.

Natalizumab inhibits the transmigration of immune cells across the blood-brain barrier thus inhibiting inflammation in the central nervous system. Generally, this blockade at the blood-brain barrier has significant influence on the circulating lymphocytes. Up to date, only short-term data on peripheral blood parameters are available which are mostly from controlled clinical trials and not from real-world experience. Real-world lab data of 120 patients diagnosed with highly active disease course of relapsing-remitting multiple sclerosis (RRMS) were analyzed during natalizumab treatment. Patient sampling was performed by consecutive recruitment in the Multiple Sclerosis Center Dresden. Lab testing was performed before and at every third infusion up to 72 months follow-up. After first natalizumab infusion, absolute numbers of all major lymphocyte populations including CD4+ T-cells, CD8+ T-cells, CD19+ B-cells, and NK-cells significantly increased and remained stable during the whole observation period of 72 months. Upon lymphocyte subsets, CD19+ B-cells presented a disproportionate increase up to levels higher than normal level in most of the treated patients. Neutralizing antibodies to natalizumab abrogated the described changes. Intra-individual variation of lymphocytes and its subsets remained in a narrow range for the whole treatment period. CD4/CD8 ratio did not change compared to baseline measurement up to 6 years of natalizumab treatment. Monocytes, eosinophils, and basophils, but not neutrophils persistently increased during natalizumab treatment. Hematological parameters including erythrocyte, platelet count, hemoglobin, and hematocrit remained unchanged compared to baseline. Interestingly, immature precursor cells including erythroblasts were detectable in 36,8% of the treated patients during natalizumab therapy, but not in the pretreatment period. Asymptomatic elevations of liver enzymes were rare, mostly only transient and lower than 3x upper normal limit. Kidney function parameters remained stable within physiological ranges in most patients. CRP levels >20 mg/dl were recognized only in 10 patients during natalizumab therapy and were mostly linked to respiratory tract infections. In our present analysis, we report persistent, but stable increases of peripheral immune cell subtypes in natalizumab treated patients. Additional serological analyses confirm excellent tolerability and safety even 6 years after natalizumab initiation in post-marketing experience.

Drug-induced liver injury with skin reactions: Drugs and host risk factors, clinical phenotypes and prognosis.

While dermatologic manifestations of adverse drug reactions are frequent, drug-induced liver injury is rare. Numerous drugs are implicated in either Drug-Induced Liver Injury or Drug-Induced Skin Injury. However, concomitant Drug-Induced Liver Injury and Drug-Induced Skin Injury are uncommon, not well characterized and appear to be caused by a limited number of drugs. These are often associated with immuno-allergic or hypersensitivity features such as fever, skin rash, blisters or peeling of skin, eosinophilia, lymphadenopathy and mucositis. Liver injury can range from asymptomatic elevation of liver biochemical tests to severe hepatitis and acute liver failure needing liver transplantation. Severe cutaneous adverse reaction, particularly drug reaction with eosinophilia and systemic symptoms is commonly associated with internal organ involvement, the liver being the most frequently involved in approximately 90% of the cases. In Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis, abnormalities in liver biochemistry tests are common but severe liver disease is rare. There is a strong association of Human Leukocyte Antigen genotype with both drug reaction with eosinophilia and systemic symptoms and Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis. It is likely that the delayed immune-mediated reaction triggering skin reaction is also responsible for hepatitis. Drug-specific lymphocytes are found in the organs involved and also in circulating blood, which along with the cytokines and chemokines play a role in pathogenesis. Anti-epileptic drugs, allopurinol, sulfonamides, antibiotics and nevirapine are the top five causes of concomitant liver and skin injury. This review will focus on drug and host factors causing concomitant Drug-Induced Skin Injury and Drug-Induced Liver Injury and discuss the characteristics of liver involvement in patients with severe cutaneous adverse reaction.

Carfilzomib Cardiovascular Disease: Use of the Atherosclerotic Cardiovascular Disease Score to Predict Cardiovascular Events in Multiple Myeloma Patients Treated with Carfilzomib

Introduction: In the ASPIRE and ENDEAVOR trials, multiple myeloma (MM) patients treated with carfilzomib (K) had significantly improved progression‐free survival and overall survival compared with standard of care. The incidence of all-grade adverse cardiovascular events (ACVE) was 26.6% and 24.5% in the K treated groups in ASPIRE and ENDEAVOR respectively. The atherosclerotic cardiovascular disease (ASCVD) score is a risk stratification tool used by cardiologists to classify patients with a score ≥7.5% as high risk for the incidence of ASCVD events. To date, there are no clinically relevant models that predict the likelihood of ACVE in MM patients treated with K nor are we aware of any protective factors against ACVE. Our study aims to identify factors which can predict and mitigate the incidence of ACVE.Methods: A retrospective chart review of 372 MM patients who were treated with K between 2011 and 2018 at our institution was performed.Data were summarized using descriptive statistics; Chi-square tests of association and Kruskal-Wallis tests were employed to test for differences across groups, where appropriate. Logistic regression was performed to examine the risk factors associated with ACVE.Results: Of the 372 patients, 243 (65%) were Durie-Salmon Stage (DSS) III, 70 (19%) were International Staging System (ISS) III; 186 (50%) were men. There were a total of 102 (27%) ACVE and 33 (9%) ≥grade 3 events. The most common ACVE were congestive heart failure (29%), asymptomatic elevations in pulmonary arterial systolic pressure (PASP) (27%), and hypertension (HTN) (16%). Sixty-eight (66%) Caucasians, 14 (14%) African Americans and 17 (17%) Hispanics developed ACVE. Aspirin (ASA) (64%), beta blockers (BB) (51%), calcium channel blockers (CCB) (43%) and statins (37%) were the most common cardiac medications patients were taking at the time of K initiation. Regardless of cardiac history, patients who were taking a CCB had higher odds of experiencing an ACVE compared to patients who were not taking a CCB (CCB + Cardiac history: OR=1.9; CI=1.0-3.7; CCB, no Cardiac history: OR=6.3; CI= 2.1-18.4) (Table 1).Patients with an ASCVD score ≥7.5% did not have an increased incidence of ACVE but did have an increased incidence of ≥grade 3 vs. grade 1-2 ACVE (100% vs. 78%, p=0.092). Prior cardiac history, including history of HTN, was common (59%) but not associated with incidence or severity of ACVE. Those with type 2 diabetes had a higher rate of ≥grade 3 vs. grade 1-2 ACVE (33% vs. 10%, p=0.004).Patients on certain CV medications while receiving K-based treatment had a higher incidence of ACVE compared to those not on these medications, including BB (51% vs. 34%, p=0.002), CCB (43% vs. 26%, p=0.002), aldosterone antagonists (AA) (8% vs. 3%, p=0.024) and statins (37% vs. 25%, p=0.022). Patients on ASA were more likely to experience ≥grade 3 compared to grade 1-2 ACVE (78% vs. 53%, p=0.016). ACE inhibitors or angiotensin receptor blockers (ACE/ARB) were not associated with increased incidence or severity of ACVE.The use of K in relapsed, as opposed to induction setting, was associated with a higher incidence of ACVE (31% vs. 20%, p=0.035). Maximum dose and number of K doses were not associated with ACVE. There was no relationship between PASP elevation and age >75, use of BB, CCB, AA, ACE/ARB, number of K treatments or maximum dose of K.Factors that were associated with increased odds of ACVE in multivariate analysis included patients who received K in the relapsed setting (OR= 1.7; CI=0.94-3.0) and use of an AA (OR= 4.5; CI=1.4-14.1) (Table 1).Conclusion: In line with prior studies, 28% of MM patients treated with K at our institution developed an ACVE, with 9% grade 3 or above. Use of CCB and AA were particularly associated with increased risk of ACVE, while use of ACE/ARB were not. ASCVD score ≥7.5% was associated with an increased incidence of ≥grade 3 ACVE in K-treated patients and should perhaps be evaluated as a predictive tool in prospective studies. [Display omitted] DisclosuresSiegel:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Speakers Bureau. Biran:Merck: Research Funding; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; BMS: Research Funding.

Single Institutional Experience with Nivolumab in Relapsed/Refractory Classic Hodgkin

Objectives: One of the newly discovered mechanisms to escape the immune response in classic Hodgkin lymphoma (cHL) is to induce immune tolerance through interaction of program cell death 1 (PD-1) on activated T cells and PD ligand-1 (PD-L1) on tumor cells. Tissue of patients with cHL was recently found to overexpress PD-L1. Nivolumab is a novel checkpoint inhibitor designed to block PD-1 and inhibits interaction between PD-1 and PD-L1. Unlike many available antibodies and chemotherapies, nivolumab itself is not cytotoxic but rather inhibits the tolerance of tumor cells through activation of the immune system.Patients and methods: We report on ten patients with relapsed/refractory cHL who were treated between 05/2016 and 03/2018 with single agent nivolumab in a tertiary care hospital. Follow-up was performed after 4 cycles with positron emission tomography (PET). Patients' files were retrospectively analyzed.Results:Mean age was 26.2 year (range 15-40). Prior to nivolumab 3/10 and 5/10 patients failed ASCT and brentuximab vedotin respectively. Mean follow-up time was 12.3 months (range 5-32). Average of prior lines was 6.3. After 4 cycles of nivolumab response rate was 80% with complete metabolic (CR) and partial remission rates of 70% and 10% respectively. In one case PET showed stable disease and another patient experienced progressive disease. Three deaths occurred after 5, 9 and 32 months of nivolumab's initiation.One patients experienced pneumonitis grade 2 which was manageable by oral steroids. Another patient had an asymptomatic TSH elevation. Two patients had grade 2 neutropenia. No serious adverse events (grade ≥3) were observed. All patients experienced a remarkable improvement of quality of life. On treatment start, two patients had performance status ECOG 3 and 4 which were attributed to refractory Hodgkin lymphoma. They recovered dramatically each to ECOG 2 within 7 days and 10 days after nivolumab start respectively.Conclusion: The CR rate seen in our cohort supports the high sensitivity of relapsed/refractory cHL to checkpoint inhibition seen in Checkmate 205. Nivolumab induces impressive clinical and radiological responses with excellent tolerance. The drug enriches our treatments armamentarium in treating cHL. Further controlled studies are needed to determine the effectiveness on a large patients' cohort and its role in earlier lines. 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

Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors

AimTo characterise clinical presentation, laboratory and histopathologic characteristics and assess the treatment and outcome of neuromuscular side-effects of checkpoint therapy. MethodsThe side-effect registry and the institutional database from ten skin cancer centres were queried for reports on myositis and neuromuscular side-effects induced by checkpoint inhibitors. In total, 38 patients treated with ipilimumab, tremelimumab, nivolumab and pembrolizumab for metastatic skin cancer were evaluated and characterised. ResultsMyositis was the most frequent neuromuscular adverse event. In 32% of cases, myositis was complicated by concomitant myocarditis. Furthermore, cases of isolated myocarditis, myasthenia gravis, polymyalgia rheumatica, radiculoneuropathy and asymptomatic creatine kinase elevation were reported. The onset of side-effects ranged from the first week of treatment to 115 weeks after the start of therapy. Most of the cases were severe (49% grade III–IV Common Terminology Criteria for Adverse Events), and there were two fatalities (5%) due to myositis and myositis with concomitant myocarditis. Only half of the cases (50%) completely resolved, whereas the rest was either ongoing or had sequelae. Steroids were given in 80% of the resolved cases and in 40% of the unresolved cases. ConclusionImmune-mediated neuromuscular side-effects of checkpoint inhibitors greatly vary in presentation and differ from their idiopathic counterparts. These side-effects can be life threatening and may result in permanent sequelae. Occurrence of these side-effects must be taken into consideration for patient information, especially when considering adjuvant immunotherapy with anti–programmed cell-death protein 1 (PD-1) antibodies and monitoring, which should include regular surveillance of creatine kinase.

Selective coronary angiography, percutaneous coronary intervention and asymptomatic peri-procedural myocardial injury.

While there have been a number of studies reporting the incidence and implications of elevated troponin levels after percutaneous coronary intervention (PCI), the body of information about the incidence, associations, and implications of elevated troponin levels following coronary angiography (CAG) is limited. A total of 220 consecutive patients with stable coronary artery disease or intermediate or low-risk acute coronary syndrome without persistent ST-segment elevation (NSTE-ACS) were included in our study. High-sensitivity cardiac troponin I (hs-cTnI) levels were measured before and after coronary angiography (CAG) in patients with or without PCI and correlated with a number of clinical variables. Hs-cTnI elevations above the 99th percentile upper reference limit (URL), or above 20% of the initially positive, yet already declining values, were found in 60 (37.2%) patients after CAG and in 45 (76.2%) patients undergoing PCI. Significant correlations of hs-cTnI elevation were found with the following variables: volume of contrast, fluoroscopy time, dose-area product, amount of contrast agent injected directly into the coronary arteries, total time of balloon dilation and the number and total length of implanted stents (P<0.001 for all). While an asymptomatic elevation of hs-cTnI is a common finding after PCI, it does occur, quite surprisingly, also after CAG. Despite contradictory views regarding the clinical relevance of asymptomatic post-procedural elevated hs-cTnI levels, it is generally believed that a mild elevation is not associated with an increased risk. Still, it may pose a diagnostic quandary following a successful interventional procedure and even more so after an uncomplicated CAG. Clinicaltrials.gov - NCT02960321.

Wilson's disease or hepatolenticular degeneration

Wilson's disease or hepatolenticular degeneration Abstract. Wilson's disease, or hepatolenticular degeneration, is a rare inherited disorder of copper metabolism. The most common clinical presentations are liver disease and / or neuro-psychiatric manifestations. Pathophysiologically, Wilson's disease is caused by mutations in the ATP7B gene, which lead to defective biliary excretion of copper and subsequent accumulation of copper in the liver and in other organs. Its prevalence is approximately 1:30 000, however its penetrance, clinical presentation and disease severity vary widely, ranging from asymptomatic elevation of liver enzymes to cirrhosis or acute liver failure with or without neuro-psychiatric symptoms. For this reason, Wilson's disease should be suspected and ruled out in cases of indeterminate liver disease or neuropsychiatric disturbances. The diagnostic algorithms are complex and involve clinical tests, ophthalmologic examination (Kayser-Fleischer rings in split-lamp examination), blood and urine tests, genetic testing, imaging and histology. In compensated liver disease, treatment of Wilson's disease by copper depletion (chelators, zinc) is usually effective. In case of liver failure liver transplantation may be needed, which corrects the underlying error of copper metabolism. New drugs with improved efficacy and tolerability are in clinical development.

Necrotizing Autoimmune myopathy: A case report on statin induced rhabdomyolysis requiring immunosuppressive therapy

Statins can cause a wide spectrum of muscular adverse effects ranging from asymptomatic elevation of Creatine Kinase (CK), myalgia and exercise intolerance to rhabdomyolysis. Most of these effects generally resolve on stopping the medication. However, statins can be associated with a unique autoimmune myopathy wherein symptoms persist or even progress after statin discontinuation and require immunosuppressive therapy. The case presented is a 60-year-old woman who was on statin treatment for a period of 2 years. She developed muscle weakness with a limb girdle distribution. She had persistent elevation of CK even after discontinuation of statin therapy. EMG done revealed irritable myopathy and muscle biopsy showed necrosis without inflammation. She subsequently tested positive for anti-3-hydroxy-3-methylglutaryl-coenzyme A (anti-HMG CoA) antibody which is found to be present in patients with statin-associated necrotizing autoimmune myopathy. Patient was started on steroid without much improvement in her symptoms. After a month of follow up, her upper extremity strength was back but lower extremity continued to be weak which prompted us to start her on Methotrexate and Azathioprine. Like our patient, there are rare subgroup of patients with an immune-mediated necrotizing myopathy that does not improve after discontinuation of the drug and requires aggressive treatment with immunosuppressive agents. Awareness and early recognition of this disease is very important in patients who continue to have CK elevation and weakness after discontinuation of statin therapy.

Liver Injury Associated with Sporting Activities.

Exertional heat stroke most commonly develops following prolonged levels of aerobic activity in a warm or humid environment. Hypoperfusion of the vital organs along with activation of the inflammasome can lead to progressive and potentially fatal multiorgan failure including acute liver failure. In the United States, herbal and dietary supplements that are marketed to improve performance, strength, and weight loss are increasingly being used by both amateur and professional athletes. Consumption of bodybuilding supplements that contain androgenic anabolic steroids can lead to adverse hepatic effects ranging from asymptomatic serum aminotransferase elevations to severe cholestatic hepatitis with prolonged jaundice. Various non-bodybuilding nutritional supplements that contain a mixture of botanicals, caffeine, and chemicals have also been associated with idiosyncratic hepatotoxicity. In particular, green tea extract derivatives that contain epigallocatechin gallate are hepatotoxic in animal models and have been associated with severe acute hepatocellular injury in humans.

Unmasking and aggravation of polycythemia vera by canagliflozin

Sodium-glucose co-transporter-2 inhibitors are novel antidiabetes drugs that act via inhibition of renal glucose reabsorption. This action causes osmotic diuresis, reduces intravascular volume and is associated with various adverse effects. In the present paper, we describe the first report on the unmasking of underlying polycythemia vera by canagliflozin in a person with Type 2 diabetes mellitus, which was temporally related to the use of the drug. A 51-year-old obese man with Type 2 diabetes was prescribed canagliflozin 100 mg for control of his glycaemia. He presented 6 months later with asymptomatic elevation of his haemogram measurements (haemoglobin: 16.9 g/dl; haematocrit: 55%; red cell number: 8.1 million/mm3 ; total leukocytes: 23010/mm3 ; platelet count: 9.7 *106 /mm3 ). He had no history of smoking, exposure to high altitude or other drugs. Subsequent investigations revealed myeloproliferative neoplasm (polycythemia vera) on trephine biopsy of bone marrow, normal erythropoietin level and JAK2V617F positivity. Because of the possibility that the underlying condition had been unmasked by canagliflozin, the latter was stopped. This led to a remarkable improvement in the man's haematological profile, with no other significant intervention. The man subsequently restarted the drug of his own accord, causing his haematological profile to worsen again and thereby posing a challenge in monitoring of both polycythemia vera as well as diabetes mellitus. This report brings to light unmasking of a new adverse effect of sodium-glucose co-transporter-2 inhibitors in clinical practice caused by volume loss, apart from hypotension and falls.

Disease Modification in Multiple Sclerosis by Flupirtine-Results of a Randomized Placebo Controlled Phase II Trial.

Central nervous system inflammation and neurodegeneration are the pathophysiological hallmarks of multiple sclerosis (MS). While inflammation can readily be targeted by current disease modifying drugs, neurodegeneration is by far less accessible to treatment. Based on suggested additional neuroprotective capacities of the orally available non-opioid and centrally acting analgesic drug flupirtine maleate we hypothesized that treatment with flupirtine maleate might be beneficial in MS patients. The flupirtine as oral treatment in multiple sclerosis (FLORIMS) study was a multi-center, randomized and stratified, placebo-controlled double-blind phase II trial to investigate safety and efficacy in terms of clinical and radiographical activity of flupirtine maleate (300 mg per day) given orally for 12 months, add-on to interferon beta 1b subcutaneously in patients with relapsing remitting MS. Due to a substantial delay in recruitment, enrolment of patients was prematurely terminated after randomization of only 30 of the originally planned 80 patients. Of these, 24 regularly terminated study after 12 months of treatment. Data were analyzed as originally planned. Treatment with flupirtine maleate was overall well tolerated. We observed moderate and asymptomatic elevations of liver enzymes in several cases but no overt hepatotoxicity. Neither the intention to treat nor the per protocol analysis revealed any significant treatment effects of flupirtine maleate with respect to occurrence of MS relapses, disability progression, or development of new lesions on cranial MRI. However, substantial methodological limitations need to be considered when interpreting these results. In conclusion, the results of the FLORIMS study neither add further evidence to nor argue against the hypothesized neuroprotective or disease modifying effects of flupirtine maleate in MS.

Ciprofloxacin—Induced Cholestatic Jaundice in Setting of Chronic Liver Disease

Ciprofloxacin is a frequently prescribed fluoroquinolone antibiotic for its broad—spectrum coverage. It is commonly used for spontaneous bacterial peritonitis (SBP) prophylaxis in patients with cirrhosis. Severe adverse effects associated with its use include tendon rupture, Stevens—Johnson syndrome, interstitial nephritis, and liver injury. Liver injury associated with ciprofloxacin can cause mild asymptomatic elevation of liver enzymes, although rarely it can cause acute liver injury or cholestatic jaundice. We present a case of a 69 year—old male with a past medical history of alcoholic liver cirrhosis diagnosed in 1995, (has been sober since then with stable liver function) who was admitted for evaluation of hyperbilirubinemia reaching 27.4 mg/dl from 0.9 mg/dl in the time span of 5 weeks. 5 weeks back the patient had presented with small bowel obstruction managed by bowel resection and diverting ileostomy, which was complicated by him developing a pelvic abscess. CT scan showed minimal ascites. The abscess was drained by Interventional Radiology, treated with levofloxacin and metronidazole. The patient was discharged on ciprofloxacin daily for spontaneous bacterial peritonitis prophylaxis. Extensive viral and autoimmune panels were negative. Ceruloplasmin levels, transferrin saturation, and a—1 anti—trypsin level were normal. ERCP was unremarkable. Liver biopsy showed established cirrhosis and hepatocytes showed marked intracellular and intracanalicular cholestasis with proliferation along with scattered eosinophils suggesting drug—induced liver injury (DILI). Ciprofloxacin—induced cholestasis was suspected by exclusion, and ciprofloxacin was discontinued with gradual improvement of the bilirubin to 14 mg/dl over a period of 4 weeks. This case demonstrates the potential for cholestasis from ciprofloxacin use. The gradual resolution of liver function after the withdrawal of ciprofloxacin supports the diagnosis. We aim to highlight the increased risk of cholestasis and worsening liver function in patients with chronic liver disease with ciprofloxacin use. Chronic liver disease patients should be closely monitored when prescribed ciprofloxacin, and should be discontinued promptly at the first signs of liver injury.3044_A.tif Figure 1: No Caption available.3044_B.tif Figure 2: High Power showing eosinophils indicating Drug induced Liver Injury.3044_C.tif Figure 3: No Caption available.

Liver injury with drugs used for multiple sclerosis: A contemporary analysis of the FDA Adverse Event Reporting System

Background: Drug-induced liver injury (DILI) has been observed in patients with multiple sclerosis (MS), raising concerns on the liver safety of MS drugs. Objective: To describe DILI events with MS drugs by analyzing the FDA Adverse Event Reporting System. Methods: DILI reports were extracted and classified in overall liver injury (OLI), including asymptomatic elevation of liver enzymes, and severe liver injury (SLI). We performed disproportionality analysis by calculating adjusted reporting odds ratios (RORs) with 95% confidence interval (CI) and case-by-case evaluation for concomitant drugs with hepatotoxic potential. Results: Fampridine showed statistically significant ROR for both OLI and SLI, whereas teriflunomide and fingolimod generated solid disproportionality (ROR > 2) only for OLI (ROR, 2.31; 95% CI, 2.12–2.52; and 2.53; 2.40–2.66, respectively). Among monoclonal antibodies, only alemtuzumab generated higher-than-expected ROR for OLI (1.34; 1.09–1.65). We also detected the expected hepatotoxic potential of beta interferon and mitoxantrone. Concomitant reporting of hepatotoxic drugs ranged from 26% (dimethyl fumarate) to 90% (mitoxantrone). Conclusion: These real-world pharmacovigilance findings suggest that DILI might be a common feature of MS drugs and call for (1) formal population-based study to verify the risk of fampridine and (2) awareness by clinicians, who should assess the possible responsibility of MS drugs when they diagnose DILI.

Prognostic Significance of Asymptomatic Brain Natriuretic Peptide Elevation at Nephrology Referral in Patients with Chronic Kidney Disease

Background: It is unclear whether asymptomatic elevation of brain natriuretic peptide (BNP) is associated with cardiovascular events (CVEs) or heart failure (HF) in predialysis chronic kidney disease (CKD) patients. Methods: We measured BNP in 482 asymptomatic predialysis patients with CKD stages 2–5 at nephrology referral between August 2004 and October 2010, and followed them prospectively to investigate the prognostic significance of BNP using Cox models and receiver operating characteristic (ROC) analyses. The primary composite end point was the time to death or the first nonfatal CVEs. Secondary end points included CVEs including sudden death, HF and all-cause death. Results: The median age was 67 years (male, 67.4%; diabetic nephropathy, 33.4%), and estimated glomerular filtration rate was 20.1 mL/min/1.73 m². The primary end point occurred in 92 patients. CVEs including sudden death, HF and all-cause death occurred in 66, 35, and 54 patients, respectively during a median follow-up period of 37.7 months. Multivariate analyses showed that BNP level was significantly associated with the primary end point (hazard ratio [HR] 1.241; 95% CI 1.020–1.511; p = 0.031), CVEs (HR 1.337; 95% CI 1.067–1.675; p = 0.012) and HF (HR 1.489; 95% CI 1.059–2.091; p = 0.022), but not associated with all-cause death (HR 1.081; 95% CI 0.829–1.410; p = 0.565). The ROC curves showed that the optimal predictive BNP levels for the primary end point, CVEs and HF were 92.5, 127.0, and 274.6 (pg/mL) respectively. Conclusion: Asymptomatic elevation of BNP is strongly predictive for CVEs and HF, which might help to integrate cardio-renal risk stratification in predialysis CKD patients.

NEXT GENERATION SEQUENCING AND EXPERIMENTAL MYOLOGY: P.372Next generation sequencing: new phenotype-genotype correlations

Congenital myopathies and muscular dystrophies are clinically and genetically heterogeneous diseases with broadly overlapping features. Next generation sequencing (NGS) techniques represent a powerful tool to identify genetic variants in these disorders in contrast to classic time consuming gene by gene approach. We describe the results obtained in an extensive study of 150 genetically undiagnosed patients. The patients were classified, according to their clinical phenotype, as affected by congenital myopathy (CM), congenital muscular dystrophy (CMD), limb girdle muscle dystrophy (LGMD), distal myopathies (DM) and exercise intolerance. All the patients were followed at the French South-West Reference Center of neuromuscular disorders. The causing gene mutations could be identified in 46% of the patients. In most of the cases the variants were localized in genes classically implicated in each phenotype group (RYR1, ACTA1, NEB mutations in congenital myopathy group for example). However, one key finding from our study was the identification of new phenotype-genotype correlations in 10% of the cases. Two FLNC gene mutations in patients with congenital myopathy and severe cardiopathy; NEB variants in three patients with adult onset pure distal myopathy; ACTA1 neomutation in a patient with asymptomatic elevation of creatin kinase; 11 GCG repeats expansions in PABPN1 in a patient with predominant axial myopathy without ptosis. Of special interest is the emerging role of TTN gene mutations in muscular disease. We found clear pathogenic variants (compound heterozygous or homozygous stop codon, frameshift or splicing) in seven patients with quite heterogeneous clinical picture from congenital centronuclear myopathy to congenital distal arthrogryposis or limb girdle muscular weakness with cardiopathy The aim of the work is to present the global results of the study and more particularly the new phenotype-genotype correlations.

Rhabdomyolysis as a rare but fatal complication of bariatric surgery: A case report.

Rhabdomyolysis after bariatric surgery is a quite rare occurrence with low recognition. Due to the breakdown of the striated muscle fibers, creatine kinase and myoglobin are released into the systemic circulation with variable effects on the renal filtration functions. Herein we present the case of a patient who developed rhabdomyolysis following revision bariatric surgery. A 34-year-old male patient was admitted for bariatric surgery. He had undergone a gastric band surgery approximately 6 years ago, with weight regain starting 1 year postoperatively gradually reaching the previous weight level. Consequently, the gastric band was removed with open surgery 3 years ago. The patient had a body mass index of 69 kg/m2 and an incisional hernia due to the previous surgery. Although initially, laparoscopic sleeve gastrectomy was planned, a switch to open surgery was made due to the presence of diffuse intra-abdominal adhesions and a giant incisional hernia precluding a laparoscopic intervention. The total duration of surgery was 420 min. Postoperative laboratory work-up showed elevated blood creatine kinase levels (25837 U/L). Upon the failure of fluid replacement and diuretics, hemodialysis was initiated on postoperative day 1. Despite daily sessions of hemodialysis, the patient's acidosis did not improve; his general status worsened, and he died on postoperative day 14. Rhabdomyolysis is a severe and potentially life-threatening complication of bariatric surgery. Its severity may vary from asymptomatic elevation in creatine kinase levels to death. Postoperative creatine kinase levels should be routinely monitored in high-risk patients as a practical and inexpensive laboratory modality for early diagnosis.