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Summary Background Baricitinib is an oral selective inhibitor of Janus kinase (JAK) 1 and JAK2, approved for the treatment of patients with active rheumatoid arthritis. Because baricitinib, like other disease-modifying antirheumatic drugs, is used chronically, continuous assessment of its long-term safety profile is important. Here we provide updated data supporting the existing safety profile of baricitinib in this patient population. Methods In this safety analysis, integrated data were included from nine phase 3, phase 2, and phase 1b clinical trials, and one long-term extension study with data up to 360 weeks, ending Feb 13, 2018. We analysed three integrated datasets, the largest of which was the all-bari-RA dataset, which includes patients who received any dose of baricitinib. We compared the safety of baricitinib with placebo on the basis of data from seven studies with baricitinib 4 mg and placebo and four studies with baricitinib 2 mg, including placebo to week 24 (placebo-controlled dataset). We did a dose-response assessment based on four studies with baricitinib 2 mg and 4 mg, including long-term extension data (2–4 mg extended dataset). We did an exploratory analysis of deaths and venous thromboembolic events in a subset of data from the all-bari-RA dataset that included patients who had ever taken baricitinib 2-mg or baricitinib 4-mg. We did an analysis for malignancies (excluding non-melanoma skin cancer) in the as-randomised population (patients not censored at rescue or dose change). Findings We collected data for 3770 patients who were given baricitinib for 10 127 patient-years of exposure in the all-bari-RA dataset (median 1115 days [IQR 426–1441], maximum 2520 days). The placebo-controlled dataset comprised 2836 patients, with 1215 in the placebo group, with 451 patient-years of exposure data; 479 in the baricitinib 2 mg group, with 186 patient-years of exposure data; and 1142 in the baricitinib 4 mg group, with 472 patient-years of exposure data. The 2–4 mg extended dataset comprised 958 patients, with 479 in both the 2 mg and 4 mg groups. No significant differences were seen for baricitinib 4 mg or 2 mg versus placebo, or for 4 mg versus 2 mg in the incidence of death, malignancy, serious infection, or major adverse cardiovascular events. Incidence of herpes zoster per 100 patient-years was higher for baricitinib (4 mg: 4·4 [95% CI 2·7–6·7]; 2 mg: 3·1 [1·1–6·8]) versus total placebo group (1·1 [0·4–2·5]), as were treatment-emergent infections (4 mg: 89·7 [81·3–98·6]; 2 mg: 84·0 [71·3–98·2] vs placebo 75·4 [67·6–83·9]). Consistent with previous reports, incidences in the all-bari-RA dataset for venous thromboembolic events was 0·5 (95% CI 0·4–0·6) per 100 patient-years, deep-vein thrombosis was 0·3 (0·2–0·5) per 100 patient-years, and pulmonary embolism was 0·2 (0·2–0·4) per 100 patient-years. Incidences of malignancy (excluding non-melanoma skin cancer) in the 2–4 mg extended dataset were 0·8 (0·4–1·5) per 100 patient-years for baricitinib 2 mg and 1·0 (0·5–1·7) per 100 patient-years for baricitinib 4 mg, without censoring patients who had dose changes or received rescue treatment. We found no indication of higher incidence of venous thromboembolic events in the baricitinib 4 mg group compared with the 2 mg group in the 2–4 mg extended dataset. Interpretation In this updated integrated analysis of patients with active rheumatoid arthritis exposed to baricitinib for a maximum of almost 7 years, baricitinib 2 mg and 4 mg maintained a similar safety profile to earlier analyses. No new safety signals were identified. Patients in the long-term extension study continue to be followed up to date. Funding Eli Lilly and Company, under license from Incyte Corporation.

Objective To assess the frequency of cardiovascular and venous thromboembolic events in clinical studies of baricitinib, an oral, selective JAK1 and JAK2 inhibitor approved in more than 50 countries for the treatment of moderately‐to‐severely active rheumatoid arthritis (RA). Methods Data were pooled from 9 RA studies. Placebo comparison up to 24 weeks included data from 6 studies. Randomized dose comparison between baricitinib doses of 2 mg and 4 mg used data from 4 studies and from the associated long‐term extension study. The data analysis set designated “All‐bari‐RA” included all baricitinib exposures at any dose. Results Overall, 3,492 RA patients received baricitinib (7,860 patient‐years of exposure). No imbalance compared to the placebo group was seen in the incidence of major adverse cardiovascular events (MACE) (incidence rates [IRs] of 0.5 per 100 patient‐years for placebo and 0.8 per 100 patient‐years for 4 mg baricitinib), arterial thrombotic events (ATE) (IRs of 0.5 per 100 patient‐years for placebo and 0.5 per 100 patient‐years for 4 mg baricitinib), or congestive heart failure (CHF) broad term (IRs of 4.3 per 100 patient‐years for placebo and 2.4 per 100 patient‐years for 4 mg baricitinib). Deep vein thrombosis (DVT)/pulmonary embolism (PE) were reported in 0 of 1,070 patients treated with placebo and 6 of 997 patients treated with 4 mg baricitinib during the placebo‐controlled period; these events were serious in 2 of 6 patients, while all 6 had risk factors and 1 patient developed DVT/PE after discontinuation of the study drug. In the 2 mg–4 mg‐extended data analysis set, IRs of DVT/PE were comparable between the doses across event types (IRs of 0.5 per 100 patient‐years in those receiving 2 mg baricitinib and 0.6 per 100 patient‐years in those receiving 4 mg baricitinib). In the All‐bari‐RA data analysis set, the rates were stable over time, with an IR of DVT/PE of 0.5 per 100 patient‐years. Conclusions In RA clinical trials, no association was found between baricitinib treatment and the incidence of MACE, ATE, or CHF. With regard to incidence of DVT/PE, 6 events occurred in patients treated with 4 mg baricitinib, but no cases of DVT/PE were reported in the placebo group. During longer‐term evaluation, the incidence of DVT/PE was similar between the baricitinib dose groups, with consistent IR values over time, and this was similar to the rates previously reported in patients with RA.

ObjectiveTo characterise changes in selected haematological parameters following once-daily oral baricitinib dosing.MethodsData were pooled from eight randomised clinical trials (four phase 3, three phase 2, one phase 1b) and one long-term extension. Changes in haematological parameters were evaluated up to 128 weeks (N=2387); overall safety of baricitinib was assessed up to 6 years (N=3492).ResultsMean absolute neutrophil counts decreased (−1.36×109/L) within 1 month, followed by stabilisation within the normal reference range through week 128. The incidence of serious infections was not elevated in patients with neutropenia during the 24-week placebo-controlled period. Mean lymphocyte counts increased (+0.30×109/L) within 1 month, then decreased to baseline (weeks 12–24). Mean platelet counts increased at week 2 (+51×109/L), then decreased towards baseline. Overall, mean haemoglobin concentrations decreased (−0.12 mmol/L), then returned to baseline; however, reduced baseline haemoglobin concentrations observed in the highest baseline high-sensitivity C reactive protein quartile increased over time. Permanent drug discontinuation occurred due to laboratory abnormalities related to neutrophil count in 8 (0.2%), lymphocyte counts in 6 (0.2%), platelet counts in 8 (0.2%), and haemoglobin levels in 16 (0.5%) of all baricitinib-treated patients (N=3492 with 7993 total person-years of exposure).ConclusionsModerate decreases in neutrophils were seen during baricitinib treatment; however, serious infection was uncommon in patients with neutropenia. Transient increases were observed in lymphocytes and platelets, which returned to baseline over time. Changes in haemoglobin concentration were generally small. Haematological abnormalities seldom led to drug discontinuation.

Objectives: Baricitinib is a selective oral inhibitor of JAK1/JAK2 for patients with moderately-to-severely active rheumatoid arthritis (RA). Baricitinib’s safety profile in Japanese patients was evaluated using six studies (five Ph2/Ph3 trials, one long-term extension study through 01 September 2016) from an integrated database (nine RA studies). Methods: Incidence rates (IRs) or exposure-adjusted IRs (EAIRs) of adverse events (AEs) per 100 patient-years (PY) were calculated using data which included RA patients exposed to any baricitinib dose. Results: Five hundred and fourteen Japanese patients received baricitinib for 851.5 total PY of exposure (median 1.7 years, maximum 3.2). The EAIR of treatment-emergent AEs was 57.4/100PY. There were no deaths; 31 patients had serious infections (IR: 3.6/100PY), 55 herpes zoster (6.5), 0 tuberculosis, 10 malignancies (1.1) including two lymphomas, two major cardiovascular AEs (0.3), one gastrointestinal perforation (0.1), and four deep vein thrombosis (0.5). In Japanese patients, herpes zoster was more frequent than that of patients overall in the integrated database, but the events were considered manageable. Conclusion: In this analysis, baricitinib had acceptable safety profile in Japanese RA patients in the context of demonstrated efficacy. Aside from herpes zoster, baricitinib safety was not notably different between Japanese RA patients and those RA patients in the integrated database. Trial registration: NCT01185353, NCT00902486, NCT01469013, NCT01710358, NCT01721044, NCT01721057, NCT01711359, and NCT01885078 at https://clinicaltrials.gov/

Background: Baricitinib (bari), is an oral, selective inhibitor of Janus kinase (JAK) 1/JAK 2, to treat moderately to severely active RA in adults. Objectives: To update bari’s safety profile with data from an additional Phase (Ph) 3 trial and on-going long-term extension (LTE) study. Methods: Long-term safety of once-daily bari was evaluated in the All-Bari-RA dataset: all patients (pts) exposed to any bari dose from 9 randomized trials (5 Ph3, 3 Ph2, 1 Ph 1b) and 1 LTE (data to 13-Feb-2018). Placebo (PBO) comparisons were evaluated to Week 24 from 7 Ph2/3 trials: pts randomized to PBO, bari 2-mg or 4-mg, with censoring at rescue/treatment switch. Dose responses were evaluated in the 2-mg/4-mg extended dataset from 4 Ph2/3 trials: pts randomized to 2- or 4-mg, LTE data included; data censored at rescue/dose change (as-treated analysis) and, due to latent period for malignancy, analyzed without censoring (as-randomized analysis). Incidence rates (IR) per 100 patient-years (PY) were calculated. Results: 3770 pts received bari (10127 PYs); maximum exposure was 7 yrs (Table). No significant differences were seen for bari 4-mg vs PBO in adverse events leading to permanent drug discontinuation, death, malignancy, serious infection, or major adverse cardiovascular events. Herpes zoster IR was significantly higher for bari 4-mg vs PBO (3.8 vs 0.9) and numerically higher for bari 2-mg (3.1). IRs for deep vein thrombosis/pulmonary embolism were numerically higher in bari 4-mg vs PBO; IRs were similar by dose in 2-mg/4-mg-extended dataset. Malignancy (excluding non-melanoma skin cancer) IRs were 0.8 (2-mg) and 1.0 (4-mg; as-randomized analysis). Fewer than 1% of pts discontinued due to abnormal laboratory results. Conclusion: In this updated integrated analysis of pts with active RA exposed to bari for up to 7 yrs, across safety topics, bari maintained a safety profile similar to that previously reported1 and acceptable in the context of demonstrated efficacy. Reference: [1] Smolen JS, et al. J Rheumatol. 2019;46:7-18. Disclosure of Interests: Mark C. Genovese Grant/research support from: Sanofi/Genzyme, Genentech/Roche, RPharm, Consultant for: Sanofi/Genzyme, Genentech/Roche, RPharm, Josef S. Smolen Grant/research support from: AbbVie, Eli Lilly, Janssen, MSD, Pfizer Inc, Roche, Consultant for: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Eli Lilly, GlaxoSmithKline, ILTOO, Janssen, Medimmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, UCB, Speakers bureau: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Eli Lilly, GlaxoSmithKline, ILTOO, Janssen, Medimmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, UCB, Tsutomu Takeuchi Grant/research support from: Astellas Pharma Inc, Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., AbbVie GK, Asahikasei Pharma Corp., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Eisai Co., Ltd., AYUMI Pharmaceutical Corporation, Nipponkayaku Co. Ltd., Novartis Pharma K.K., Grant/research support from: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Grant/research support from: Astellas Pharma Inc., Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahi Kasei Pharma Corp., Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd., Janssen Pharmaceutical K.K., Celltrion Inc., Nipponkayaku Co. Ltd., and UCB Japan, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Abbivie GK, Nipponkayaku Co.Ltd, Janssen Pharmaceutical K.K., Astellas Pharma Inc., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Taisho Toyama Pharmaceutical Co. Ltd., GlaxoSmithKline K.K., UCB Japan Co. Ltd., Consultant for: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Asahi Kasei Medical K.K., AbbVie GK, Daiichi Sankyo Co., Ltd., Bristol Myers Squibb, and Nipponkayaku Co. Ltd., Speakers bureau: Astellas Pharma Inc., Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahi Kasei Pharma Corp., Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd., Janssen Pharmaceutical K.K., Celltrion Inc., Nipponkayaku Co. Ltd., and UCB Japan, Speakers bureau: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Speakers bureau: AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Astellas Pharma Inc, Diaichi Sankyo Co. Ltd., Eisai Co. Ltd., Sanofi K.K., Teijin Pharma Ltd., Takeda Pharmaceutical Co. Ltd., Novartis Pharma K.K., Gerd Rudiger Burmester Consultant for: Roche, Sanofi-Genzyme, Speakers bureau: Roche, Sanofi-Genzyme, Dennis Brinker Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Terence Rooney Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Jinglin Zhong Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Daojun Mo Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Chadi Saifan Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Anabela Cardoso Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Maher Issa Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Wen-Shuo Wu Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Kevin Winthrop Consultant for: Gilead, Galapagos, Eli Lilly and Company, Abbvie, Pfizer, GSK

ObjectivesLipid profiles are altered by active disease in patients with rheumatoid arthritis (RA) and may be further modified by treatment with Janus kinase inhibitors and other disease-modifying antirheumatic drugs.MethodsLipid data were analysed from phase II and III studies of 4 mg (n=997) and 2 mg (n=479) oral baricitinib administered once daily in patients with moderate-to-severe active RA. Lipoprotein particle size and number and GlycA were evaluated with nuclear magnetic resonance in one phase III study. The effect of statin therapy on lipid levels was evaluated in patients on statins at baseline and in patients who initiated statins during the study.ResultsTreatment with baricitinib was associated with increased levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides, but no significant change in LDL-C:HDL-C ratio. Lipid levels plateaued after 12 weeks of treatment. Baricitinib treatment increased large LDL and decreased small, dense LDL particle numbers and GlycA. Lipid changes from baseline were not significantly different between baseline statin users and non-users. In patients who initiated statin therapy during the study, LDL-C, triglycerides (baricitinib 4 mg only) and apolipoprotein B decreased to pre-baricitinib levels; HDL-C and apolipoprotein A-I levels remained elevated.ConclusionsBaricitinib was associated with increased LDL-C, HDL-C and triglyceride levels, but did not alter the LDL-C:HDL-C ratio. Evaluation of cardiovascular event rates during long-term treatment is warranted to further characterise these findings and their possible clinical implications.Trial registration numberNCT00902486, NCT01469013, NCT01185353, NCT01721044, NCT01721057, NCT01711359, NCT01710358, NCT01885078.

Background: Hemodialysis patients are exposed to blood and blood products more than the general population and are also at higher risk for hepatitis B (HB) contamination. For these reasons, it is highly recommended that this patient population gets the HB vaccine. The efficacy of the vaccine is measured by measuring titers of antibody in the serum of the patient. A minimum titer of 10 mIU/mL is considered to be a response. The conversion rate in hemodialysis patients ranges from 50% to 80%, as compared to the general population where the conversion rate is over 95%. As opposed to the general population, end-stage renal patients on hemodialysis do not always respond to the vaccine. The main objective in this study was to try to identify factors that may hinder the response. Correction of these factors in the future may help non-responders. Methods: This was a retrospective chart review at a single hemodialysis center to compare the laboratory and clinical differences between responders and non-responders. Inclusion criteria are hemodialysis patients who received the HB vaccine and patients with concomitant hepatitis C. Exclusion criteria are patients who refused the vaccine and patients who did not complete the vaccine course. Results: There are a total of 108 subjects included in the study, out of which 44 (42.3%) are responders to the HB vaccine. A multivariate logistic regression was performed using the statistically significant risk factors as identified by the univariate logistic regression, including age range, albumin, hemodialysis vintage, vascular access and diabetes status. The results from the multivariate logistic regression show that advanced age (P = 0.005) and diabetes status (P = 0.003) are found to be strong independent risk factors of responder status. The type of vascular access (AVF or other types) is also marginally statistically significant (P = 0.05). Conclusions: In this retrospective chart review comparing HB vaccine in responders versus non-responders, we found that advanced age and a history of diabetes are independent risk factors in predicting responder status. J Clin Med Res. 2015;7(5):315-318 doi: http://dx.doi.org/10.14740/jocmr1999w

Background Rheumatoid arthritis (RA) is associated with increased neutrophil levels1 and platelet2 counts and decreased lymphocyte levels.1,3 Baricitinib (bari) is a selective and reversible Janus kinase (JAK)1/JAK2 inhibitor in development for patients (pts) with moderate to severe RA.4 Objectives To characterize changes in absolute neutrophil counts (ANC), absolute leukocyte counts (ALC), and platelet counts following once daily oral administration of bari. Methods Data were pooled from 6 placebo-controlled phase 2 and 3 studies of bari (2 and 4 mg). Changes in ANC, ALC, and platelets were evaluated for up to 52 weeks (wks) including data from a long-term extension study. Reversibility was evaluated in a subgroup of pts who discontinued treatment by wk 24. Results Mean ANC decreased within 1 month of administration of bari, followed by stabilization and an increase to baseline after treatment discontinuation (Figure 1). ANC Mean ALC increased within 1 month of bari administration and then decreased to baseline level in wks 12 to 24 (Figure 1). Lymphopenia appeared to be associated with slightly higher rate of overall infections (Table 1). Mean platelet counts increased to peak at wk 2, returned towards baseline, stabilized over time, and returned to baseline after treatment discontinuation (Figure 1). Permanent study drug discontinuations from thrombocytosis occurred in 2 bari-treated pts (0.1%). No clear association between platelet increase and thromboembolic events was observed. Conclusions Treatment with bari was associated with a decrease in ANC and an increase in ALC and platelets, which stabilized over time and returned to baseline with prolonged treatment (ALC) or treatment discontinuation (ANC and platelets). No associations between ANC decrease and infections or between thrombocytosis and thromboembolic events were observed. References Schulze-Koops H et al. Rheumatology. 2017;56(1):46–57. Farr M et al. Ann Rheum Dis. 1983;42(5):545–549. Symmons DP et al. J R Soc Med. 1989;82:462–463. Fridman JS et al. J Immunol. 2010;184:5298–5307. Disclosure of Interest J. Kremer Grant/research support from: Abbvie, Genentech, Eli Lilly and Company, Novartis, Pfizer, Consultant for: Abbvie, Amgen, BMS, Genentech, GSK, Eli Lilly and Company, Novartis, Pfizer, Employee of: Corrona, Speakers bureau: Genentech (non-promotional), T. W. J. Huizinga Grant/research support from: Eli Lilly and Company, Pfizer, Consultant for: Eli Lilly and Company, Pfizer, Speakers bureau: Eli Lilly and Company, Pfizer, L. Chen Employee of: Eli Lilly and Company, C. Saifan Employee of: Eli Lilly and Company, M. Issa Employee of: Eli Lilly and Company, S. Witt Employee of: Eli Lilly and Company, C. Walls Employee of: Eli Lilly and Company, I. de la Torre Employee of: Eli Lilly and Company

Chadi Saifan, Elie El-Charabaty, Suzanne El-SayeghStaten Island University Hospital, Staten Island, NY, USABackground: Elevated total plasma homocysteine is an independent risk factor for arterial and venous thrombosis in patients with normal renal function. Patients on hemodialysis have a high prevalence of mild to moderate hyperhomocysteinemia. Conflicting retrospective analyses and prospective studies have been reported regarding the association between total homocysteine levels and hemodialysis vascular thrombosis. The purpose of this retrospective study was to investigate the relationship between hyperhomocysteinemia and vascular access thrombosis (VAT) in patients on hemodialysis.Methods: One hundred and twenty-five patients undergoing dialysis were selected as subjects. The experimental group participants were identified as those having one or more VAT during the previous 13 months and the control group participants had no access thrombosis during the same period. Additional subgroup analysis included the presence of hypertension, diabetes, low-density lipoprotein levels, sex, and use of aspirin.Results: No statistically significant difference was found in total homocysteine levels between the two groups (P = 0.27). No association was found between VAT and sex (P = 0.09), VAT and hypertension (P = 0.96), VAT and diabetes (P = 0.49), nor VAT and low-density lipoprotein level (P = 0.04). A lower rate of VAT was associated with aspirin intake (P = 0.04).Conclusion: This study did not demonstrate a relationship between total homocysteine concentrations and risk of VAT in patients with end-stage renal disease on hemodialysis. There were no significant differences in the number of VAT across additional variables of sex and previous morbidity. Aspirin intake was associated with a lower incidence of VAT.Keywords: hyperhomocysteinemia, vascular access thrombosis, hemodialysis

Chadi Saifan, Mark Samarneh, Norbert Shtaynberg, Rabih Nasr, Elie El-Charabaty, Suzanne El-Sayegh Division of Nephrology, Staten Island University Hospital, Staten Island, NY, USA Background: Vitamin B12 deficiency may have deleterious effects on end stage renal disease (ESRD) patients on maintenance hemodialysis, and may increase erythropoietin stimulating agent (ESA) resistance, yet little is known about its prevalence in this population. Methods: Serum Vitamin B12 and methylmalonic acid (MMA) levels were drawn from ESRD patients prior to hemodialysis. All patients with MMA levels greater than 800 nmol/L had peripheral smears evaluated for B12 deficiency. Those with confirmatory smears were considered to be deficient and received intramuscular vitamin B12 injections for 4 months. Post-treatment MMA levels and smears were obtained. Erythropoietin dosages were monitored throughout the treatment period. Results: There was a 58% (60/103) prevalence of vitamin B12 deficiency as defined by a positive MMA level and a positive blood smear. Out of 52 patients with positive smears, 36 (69.2%) were negative on repeat analysis after B12 treatment. Mean Epogen® (EPO) dosages significantly decreased by 16,572 ± 41,902 units per month from baseline to the post-B12 treatment period (P = 0.0082, Wilcoxon signed-rank test). Three months prior to treatment, the mean monthly EPO dose was 82,067 ± 47,906 and post, the mean EPO usage was 65,495 ± 39,691. Post treatment hemoglobin levels were not significantly different from baseline. Conclusion: Vitamin B12 supplementation was associated with a decrease in the mean dose of ESA administration while maintaining a stable hemoglobin level. Maintaining serum vitamin B12 levels improves functionality, and may allow a decrease in the use of ESA’s, avoiding their toxicities and significant costs. Keywords: ESRD, end stage renal disease, chronic kidney disease, anemia, vitamin deficiency, erythropoietin, dialysis

Diabetes Insipidus (DI) is either due to deficient secretion of arginine vasopressin (central) or to tubular unresponsiveness (nephrogenic). Drug induced DI is a well-known entity with an extensive list of medications. Polyuria is generally defined as urine output exceeding 3 liters per day in adults. It is crucial to identify the cause of diabetes insipidus and to implement therapy as early as possible to prevent the electrolyte disturbances and the associated mortality and morbidity. It is very rare to have an idiosyncratic effect after a short use of a medication, and physicians should be aware of such a complication to avoid volume depletion. The diagnosis of diabetes insipidus is very challenging because it relies on laboratory values, urine output, and the physical examination of the patient. A high clinical suspicion of diabetes insipidus should be enough to initiate treatment. The complications related to DI are mostly related to the electrolyte imbalance that can affect the normal physiology of different organ systems.

Background.Sudden sensorineural hearing loss (SSHL) caused by opiate abuse or overuse has been well documented in the medical literature. Most documented case reports have involved either heroin or hydrocodone/acetaminophen. Recently, case reposts of methadone induced SSHL have been published.Case Report.We present the case of a 31-year-old man who developed SSHL after a methadone overdose induced stupor. He was subsequently restarted on methadone at his regular dose. On follow-up audiometry exams, he displayed persistent moderately severe sensorineural hearing loss bilaterally.Discussion.This case is notable because unlike all but one previously reported case, the patient—who was restated on methadone—did not make a complete recovery.Conclusion. Methadone overuse in rare cases causes SSHL.

A continuous dosing schedule of aerosolized ribavirin has been used for respiratory syncytial virus (RSV) upper respiratory tract infection and lower respiratory tract infection (LRTI) but is associated with high cost and inconvenient administration. We conducted an adaptive randomized trial to evaluate the effectiveness of an intermittent dosing schedule of ribavirin versus that of a continuous dosing schedule of ribavirin in preventing RSV LRTIs in 50 hematopoietic stem cell transplant recipients or patients with hematologic malignancies. LRTI occurred in 3 patients (9%) receiving the intermittent schedule and in 4 (22%) receiving the continuous schedule, with a 0.889 posterior probability. Because the intermittent schedule is easy to administer and has a higher efficacy than the continuous schedule, we recommend the intermittent schedule for patients who are at risk for RSV LRTI. Clinical Trials Registration. NCT00500578.

Adalimumab is a fully human monoclonal anti-TNF-alpha antibody. Reported adverse effects have raised a number of safety concerns associated with their prolonged use. A case of granulomatous pneumonitis and hemidiaphragm paresis associated with adalimumab therapy for rheumatoid arthritis is described. In May 2012, a 57 year old male presented with dry cough, dyspnea and orthopnea after 4 months of treatment with adalimumab for rheumatoid arthritis. The patient received adalimumab from November 2011 to February 2012. A right hemidiaphragm elevation was shown on chest radiograph. A right hemidiaphragm paresis was shown on chest fluoroscopy. Bilateral lower lobe interstitial disease was shown on the chest HRCT scan. Open lung biopsy of the right lower lobe showed subacute granulomatous pneumonitis. In July 2013, the patient's respiratory symptoms and the previous restrictive pattern on PFTs resolved. In a same patient, a rare association of hemidiaphragm paresis and granulomatous pneumonitis with adalimumab treatment is herein reported.

Rabih Nasr,1 Chadi Saifan,1 Iskandar Barakat,2 Yorg Al Azzi,2 Ali Naboush,2 Marc Saad,2 Suzanne El Sayegh1 1Department of Nephrology, Staten Island University Hospital, Staten Island, NY, USA; 2Department of Medicine, Staten Island University Hospital, Staten Island, NY, USA Background: One factor associated with poor outcomes in hemodialysis patients is exposure to a foreign membrane. Older membranes are very bioincompatible and increase complement activation, cause leukocytosis by activating circulating factors, which sequesters leukocytes in the lungs, and activates platelets. Recently, newer membranes have been developed that were designed to be more biocompatible. We tested if the different “optiflux” hemodialysis membranes had different effects on platelet levels. Methods: Ninety-nine maintenance hemodialysis patients with no known systemic or hematologic diseases affecting their platelets had blood drawn immediately prior to, 90 minutes into, and immediately following their first hemodialysis session of the week. All patients were dialyzed using a Fresenius Medical Care Optiflux polysulfone membrane F160, F180, or F200 (polysulfone synthetic dialyzer membranes, 1.6 m2, 1.8 m2, and 2.0 m2 surface area, respectively, electron beam sterilized). Platelet counts were measured from each sample by analysis using a CBC analyzer. Results: The average age of the patients was 62.7 years; 36 were female and 63 were male. The mean platelet count pre, mid, and post dialysis was 193 (standard deviation ±74.86), 191 (standard deviation ±74.67), and 197 (standard deviation ±79.34) thousand/mm3, respectively, with no statistical differences. Conclusion: Newer membranes have no significant effect on platelet count. This suggests that they are, in fact, more biocompatible than their predecessors and may explain their association with increased survival. Keywords: platelet count, polysulfone membranes, complement activation, electron beam sterilized, cellulosic membranes, bioincompatible events

Elie El-Charabaty, Chadi Saifan, Mokhtar Abdallah, Ali Naboush, Daniel Glass, Georges Azzi, Yorg Azzi, Ahsan Khan, Hassan Baydoun, Chetana Rondla, Ninad Parekh, Suzanne El-SayeghDepartment of Medicine, Staten Island University Hospital, Staten Island, NY, USAAbstract: Several case reports have been written regarding the relationship between the use of proton pump inhibitors (PPI) and hypomagnesemia. Some of these reported cases have electrocardiogram abnormalities where electrolytes deficiencies were the contributing factor for these events. This study investigates the correlation between different arrhythmias and the use of PPI and hypomagnesaemia incidence. Four-hundred and twenty-one patients admitted to the critical care unit with unstable angina, non-ST elevation myocardial infarction, and ST-elevation myocardial infarction were included in this study. One-hundred and eighty-four patients (43.8%) received PPI and 237 patients (51.16%) did not, magnesium levels were low (

Background. Alport's syndrome is an X-linked hereditary disorder affecting the glomerular basement membrane associated with ocular and hearing defects. In women, the disease is much less severe compared to that in men. However, women with Alport's syndrome can have an accelerated form of their disease during pregnancy with worsening of kidney function and can also develop preeclampsia. There are only four described cases of Alport's syndrome in pregnancy.Case Presentation. 20-year-old woman with a history of Alport's syndrome, which during pregnancy worsened resulting in hypertension, proteinuria, and acute kidney injury. Fortunately, there was complete resolution of the proteinuria and kidney injury with delivery, and the patient did not require any renal replacement therapy.Conclusion. One of the four reported cases had an accelerated form of the disease during pregnancy with rapid progression of kidney injury and end-stage renal disease. There are no definite guidelines to monitor these patients during pregnancy. Further studies are required to understand the exact pathophysiology of kidney damage that occurs in pregnant women with Alport's syndrome. This may give us some insight into the prognostic predictors, so that we can monitor these women more thoroughly and prevent adverse outcomes.

Marc Saad,1 Boutros Karam,1 Geovani Faddoul,2 Youssef El Douaihy,1 Harout Yacoub,1 Hassan Baydoun,3 Christine Boumitri,1 Iskandar Barakat,1 Chadi Saifan,4 Elie El-Charabaty,4 Suzanne El Sayegh4 1Department of Internal Medicine, Staten Island University Hospital, Staten Island, 2Department of Nephrology, Icahn School of Medicine, New York, NY, 3Department of Cardiology, Tulane University Medical Center, New Orleans, LA, 4Department of Nephrology, Staten Island University Hospital, Staten Island, NY, USA Abstract: Patients with chronic kidney disease (CKD) are three times more likely to have myocardial infarction (MI) and suffer from increased morbidity and higher mortality. Traditional and unique risk factors are prevalent and constitute challenges for the standard of care. However, CKD patients have been largely excluded from clinical trials and little evidence is available to guide evidence-based treatment of coronary artery disease in patients with CKD. Our objective was to assess whether a difference exists in the management of MI (ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction) among patients with normal kidney function, CKD stage III–V, and end-stage renal disease (ESRD) patients. We conducted a retrospective cohort study on patients admitted to Staten Island University Hospital for the diagnosis of MI between January 2005 and December 2012. Patients were assigned to one of three groups according to their kidney function: Data collected on the medical management and the use of statins, platelet inhibitors, beta-blockers, and angiotensin converting enzyme inhibitors/angiotensin receptor blockers were compared among the three cohorts, as well as medical interventions including: catheterization and coronary artery bypass graft (CABG) when indicated. Chi-square test was used to compare the proportions between nominal variables. Binary logistic analysis was used in order to determine associations between treatment modalities and comorbidities, and to account for possible confounding factors. Three hundred and thirty-four patients (mean age 67.2±13.9 years) were included. In terms of management, medical treatment was not different among the three groups. However, cardiac catheterization was performed less in ESRD when compared with no CKD and CKD stage III–V (45.6% vs 74% and 93.9%) (P

Background Hyperglycemia is an independent predictor of adverse outcomes during hospitalization. In patients who have pneumonia, significant hyperglycemia is associated with poor outcomes. This study evaluates the interaction of the degree of hyperglycemia and complication rates stratified by age in non-critically ill patients admitted to the hospital for care of community-acquired pneumonia. Methods Retrospective review of patient records coded for pneumonia. Analysis included 501 non-critically ill patients admitted to a tertiary care hospital in New York City. Data were stratified by diabetes status, age (less than 65 and 65 and over), and fasting blood glucose (FBG) within the first 24 hours of hospitalization. Among patients with no history of diabetes, FBG was stratified as "normal" [FBG ≤100 mg/dl (5.6 mmol/l)], "mild-hyperglycemia" [101-125 mg/dl (5.7-6.9 mmol/l)], and "severe-hyperglycemia" [≥126 mg/dl (7 mmol/l)]. The diabetic group included known diabetics regardless of FBG. The Pneumonia Severity Index (PSI) was calculated for all patients. Complications rates, hospital length of stay and mortality were compared among the groups. Results In patients age 65 and older, complication rates were 16.7% in normoglycemics, 27.5% in the "mild-hyperglycemia" group, 28.6% in the "severe hyperglycemia" group, and 25.5% in those with known diabetes. The mild and severe-hyperglycemics had similar complication rates (p = 0.94). Compared to the normal group, mild and severe groups had higher rates of complications, p = 0.05 and p = 0.03, respectively. PSI tended to be higher in those over the age of 65. PSI was not significantly different when the normal, mild, severe, and known diabetes groups were compared. PSI did not predict complications for new hyperglycemia (normals' mean score 87, mild 84.7, severe 93.9, diabetics 100). Hospital mortality did not differ among groups. Length of stay was longer (p = 0.05) among mild-hyperglycemics (days = 8.4 s.e. 14.3) vs. normals (days = 6.2 s.e.6.5). Conclusion This study shows that FBS between 101-125 mg/dl (5.7-6.9 mmol/l) on hospital admission increases pneumonia complication rates among the elderly with no previous diagnosis of diabetes.

Calciphylaxis is a challenging complication of end-stage renal disease, with an unknown underlying mechanism. Several risk factors have been identified, such as hyperphosphatemia, hypercalcemia, hyperparathyroidism, low serum albumin levels, and history of warfarin therapy. This article presents a case of calciphylaxis provoked by reintroduction of warfarin therapy, introducing the possibility of direct induction.

Chadi Saifan, Elie El-Charabaty, Morton Kleiner, Suzanne El-SayeghDepartment of Medicine, Division of Nephrology, Staten Island University Hospital, Staten Island, NY, USABackground: Erythropoietin is a hormone that regulates erythropoiesis and is mainly produced by the kidneys. Several animal studies as well as a few case reports and case series have demonstrated that regenerating hepatic tissue can produce more erythropoietin than normal hepatic tissue. The purpose of the study was to examine the difference in hemoglobin and hematocrit levels as well as epoetin dosage in patients on hemodialysis with and without hepatitis C (HCV).Methods: A retrospective chart review was performed. Seventy-six patients were included in the study (19 with HCV and 57 without HCV) at a ratio of 1:3. Exclusion criteria were a history of gastrointestinal bleeding or blood transfusion over the previous six months, polycystic kidney disease, and pregnancy. Variables examined included gender, age, duration of hemodialysis, hemoglobin, hematocrit, epoetin dose, aspartate transaminase, and ferritin levels over a three-month period.Results: The patients were divided into two groups. The first consisted of patients with HCV on hemodialysis and the second of patients on hemodialysis without HCV. Mean hemoglobin was 12.6 ± 1.2 g/dL for the HCV-positive group and 11.9 ± 1.1 g/dL for the HCV-negative group. The difference was statistically significant (P = 0.03). Mean hematocrit was higher in the HCV-positive group, but was not significantly different at 39.08% ± 4.06% versus 37.43% ± 3.4% in the HCV-negative group (t-test, P = 0.11). Further, the HCV-positive group required less epoetin, but this was not significantly different from that required in the HCV-negative group at 6258 ± 5208 IU versus 7596 ± 7056 IU, respectively (t-test, P = 0.38).Conclusion: In our study, patients with HCV infection were found to have higher hemoglobin and hematocrit levels and lower epoetin requirements than those without HCV. Although the findings were not statistically significant, the computed values between these two groups of patients did follow a general trend. Further investigation with more patients, a longer duration of follow-up, and incorporation of additional medical variables is needed to clarify the role of HCV on erythropoiesis in hemodialysis patients.Keywords: hepatitis C virus, erythropoiesis, hemodialysis, hematocrit, epoetin