Category Prednisone Taper

Response to: Elephant in the room' by Hartung et al

<h1>Response to: Elephant in the room' by Hartung et al</h1>

Response to: Elephant in the room’ by Hartung et al

We read the letter to the editor ‘Elephant in the room’ by Hartung et al in response to our open-label pilot clinical trial report on the use of repository corticotropin injection (RCI) in refractory polymyositis (PM) and dermatomyositis (DM). 1 2 First, the …

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IJERPH, Vol. 16, Pages 155: Corticosteroids in Moderate-To-Severe Graves’ Ophthalmopathy: Oral or Intravenous Therapy?

<h1>IJERPH, Vol. 16, Pages 155: Corticosteroids in Moderate-To-Severe Graves’ Ophthalmopathy: Oral or Intravenous Therapy?</h1>

IJERPH, Vol. 16, Pages 155: Corticosteroids in Moderate-To-Severe Graves’ Ophthalmopathy: Oral or Intravenous Therapy?

IJERPH, Vol. 16, Pages 155: Corticosteroids in Moderate-To-Severe Graves’ Ophthalmopathy: Oral or Intravenous Therapy?
International Journal of Environmental Research and Public Health doi: 10.3390/ijerph16010155
Authors: Laura Penta Giulia Muzi Marta Cofini Alberto Leonardi Lucia Lanciotti Susanna Esposito
Background: Ophthalmopathy is a rare extra-thyroid manifestation of Graves’ disease, in paediatrics. Intravenous corticosteroids are the main treatment of moderate-to-severe Graves’ orbitopathy. In this paper, we describe a moderate-to-severe active Graves’ ophthalmopathy in a child and the response to oral therapy with prednisone. Case presentation: A nine-year-old male child suffering for a few months, from palpitations, tremors, and paresthesia was hospitalized in our Pediatric Clinic. At admission, the thyroid function laboratory tests showed hyperthyroidism with elevated free thyroxine (FT4) and free triiodothyronine (FT3) levels and suppressed thyroid-stimulating hormone (TSH) levels. These findings, combined with the clinical conditions—an ophthalmologic evaluation (that showed the presence of exophthalmos without lagophthalmos and visual acuity deficiency), thyroid ultrasound, and TSH receptor antibody positivity—led to a diagnosis of Graves’ disease. Therefore, methimazole was administered at a dose of 0.4 mg/kg/day. After 4 months, thyroid function was clearly improved, with normal FT3 and FT4 values and increasing TSH values, without adverse effects. Nevertheless, an eye examination showed ophthalmopathy with signs of activity, an increase in the exophthalmos of the right eye with palpebral retraction, soft tissue involvement (succulent and oedematous eyelids, caruncle and conjunctival hyperaemia and oedema) and keratopathy, resulting from exposure. We began steroid therapy with oral administration of prednisone (1 mg/kg/day) for four weeks, followed by gradual tapering. After one week of therapy with prednisone, an eye assessment showed reduced retraction of the upper eyelid of the right eye, improvement of right eye exophthalmometry and reduction of conjunctival hyperaemia. After four weeks of therapy with prednisone, an eye assessment showed reduction of the right palpebral retraction without conjunctival hyperaemia and no other signs of inflammation of the anterior segment; after twelve weeks, an eye assessment showed a notable decrease in the right palpebral retraction and the absence of keratitis, despite persisting moderate conjunctival hyperaemia. No adverse event associated with steroid use was observed during the treatment period and no problem in compliance was reported. Conclusion: Prednisone seems a better choice than intravenous corticosteroids, for treating moderate-to-severe and active Graves’ ophthalmopathy, keeping in mind the importance of quality of life in pediatric patients.
http://bit.ly/2VCkkJW

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IJERPH, Vol. 16, Pages 155: Corticosteroids in Moderate-To-Severe Graves’ Ophthalmopathy: Oral or Intravenous Therapy?

<h1>IJERPH, Vol. 16, Pages 155: Corticosteroids in Moderate-To-Severe Graves’ Ophthalmopathy: Oral or Intravenous Therapy?</h1>

IJERPH, Vol. 16, Pages 155: Corticosteroids in Moderate-To-Severe Graves’ Ophthalmopathy: Oral or Intravenous Therapy?

IJERPH, Vol. 16, Pages 155: Corticosteroids in Moderate-To-Severe Graves’ Ophthalmopathy: Oral or Intravenous Therapy?
International Journal of Environmental Research and Public Health doi: 10.3390/ijerph16010155
Authors: Laura Penta Giulia Muzi Marta Cofini Alberto Leonardi Lucia Lanciotti Susanna Esposito
Background: Ophthalmopathy is a rare extra-thyroid manifestation of Graves’ disease, in paediatrics. Intravenous corticosteroids are the main treatment of moderate-to-severe Graves’ orbitopathy. In this paper, we describe a moderate-to-severe active Graves’ ophthalmopathy in a child and the response to oral therapy with prednisone. Case presentation: A nine-year-old male child suffering for a few months, from palpitations, tremors, and paresthesia was hospitalized in our Pediatric Clinic. At admission, the thyroid function laboratory tests showed hyperthyroidism with elevated free thyroxine (FT4) and free triiodothyronine (FT3) levels and suppressed thyroid-stimulating hormone (TSH) levels. These findings, combined with the clinical conditions—an ophthalmologic evaluation (that showed the presence of exophthalmos without lagophthalmos and visual acuity deficiency), thyroid ultrasound, and TSH receptor antibody positivity—led to a diagnosis of Graves’ disease. Therefore, methimazole was administered at a dose of 0.4 mg/kg/day. After 4 months, thyroid function was clearly improved, with normal FT3 and FT4 values and increasing TSH values, without adverse effects. Nevertheless, an eye examination showed ophthalmopathy with signs of activity, an increase in the exophthalmos of the right eye with palpebral retraction, soft tissue involvement (succulent and oedematous eyelids, caruncle and conjunctival hyperaemia and oedema) and keratopathy, resulting from exposure. We began steroid therapy with oral administration of prednisone (1 mg/kg/day) for four weeks, followed by gradual tapering. After one week of therapy with prednisone, an eye assessment showed reduced retraction of the upper eyelid of the right eye, improvement of right eye exophthalmometry and reduction of conjunctival hyperaemia. After four weeks of therapy with prednisone, an eye assessment showed reduction of the right palpebral retraction without conjunctival hyperaemia and no other signs of inflammation of the anterior segment; after twelve weeks, an eye assessment showed a notable decrease in the right palpebral retraction and the absence of keratitis, despite persisting moderate conjunctival hyperaemia. No adverse event associated with steroid use was observed during the treatment period and no problem in compliance was reported. Conclusion: Prednisone seems a better choice than intravenous corticosteroids, for treating moderate-to-severe and active Graves’ ophthalmopathy, keeping in mind the importance of quality of life in pediatric patients.
from Enviromental via alkiviadis.1961 on Inoreader http://bit.ly/2VCkkJW

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<h1></h1>

Yup, the doctor can increase the dosage or the frequency of Remicade. If your son has built up antibodies, there are other biologics. I recently switched from Remicade, after 20+ years, due to antibodies and am now on Humira. Best of luck to your son! diagnosed in 1997. meds: triamterene HCTZ, Humira, Lialda 1200mg 1x a day,Hyoscyamine sulfate odt 0.125 4-6 hours as needed,Omeprazole 40mg 1 capsule a day,Latanoprost op 0.005% 1 drop each eye, Potassium 90mg 1 x a day, Donnatal 1 x a day, 20 mg prednisone taper

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The Implications of Liver Biopsy Results in Patients with Myeloproliferative Neoplasms Being Treated with Ruxolitinib

<h1>The Implications of Liver Biopsy Results in Patients with Myeloproliferative Neoplasms Being Treated with Ruxolitinib</h1>

The Implications of Liver Biopsy Results in Patients with Myeloproliferative Neoplasms Being Treated with Ruxolitinib

Case Series The Implications of Liver Biopsy Results in Patients with Myeloproliferative Neoplasms Being Treated with Ruxolitinib
1 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA 2 Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA 3 Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA 4 Department of Medicine, Division of Liver Diseases, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Correspondence should be addressed to John O. Mascarenhas ;
Received 13 September 2018; Accepted 9 December 2018; Published 6 January 2019
Academic Editor: Akimichi Ohsaka
Copyright © 2019 Douglas Tremblay et al. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract
Ruxolitinib is increasingly being utilized for the treatment of myelofibrosis and polycythemia vera, but the potential for hepatic toxicity is poorly understood. We performed a retrospective review of hepatic damage occurring in patients with myeloproliferative neoplasms receiving ruxolitinib. Relevant histologic images of liver biopsies were reviewed by an experienced liver pathologist and reported to a multidisciplinary team including hepatology and hematology. A variety of liver pathology was observed including extramedullary hematopoiesis, obliterative portal venopathy, and drug-induced liver injury. In all cases reviewed, the liver biopsy had significant treatment implications. We conclude that hepatology referral and liver biopsy in patients receiving ruxolitinib therapy with biochemical evidence of liver injury reveals a variety of etiologies which have significant treatment impact. Clinicians should be aware of the potential causes of liver damage in this population and initiate prompt referral and liver biopsy. 1. Introduction
Ruxolitinib is a JAK1/2 inhibitor and is the sole FDA-approved therapy for patients with intermediate-/high-risk myelofibrosis (MF), and it is also approved to treat patients with polycythemia vera (PV) that have previously failed therapy with hydroxyurea. Ruxolitinib treatment has been associated with transient mild aminotransferase elevations during preapproval clinical trials, with grade 1, by Common Terminology Criteria for Adverse Event (CTCAEs), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) elevations seen in 25.2% and 17.4% of patients, respectively [ 1 ]. Another estimate based on preapproval regulatory reviews cites the incidence of aminotransferase elevations as 18% in those receiving ruxolitinib [ 2 ]. No cases of acute hepatic failure have been reported to date.
MF itself is also associated with hepatic dysfunction. Examples include invasion of hepatic tissue with hematopoietic cells in the setting of extramedullary hematopoiesis (EMH), portal vein thrombosis, and obliterative portal venopathy (OPV) [ 3 ]. EMH in particular is important to identify as it is a disease manifestation that may respond favorably to ruxolitinib therapy [ 4 ]. With the increasingly widespread use of ruxolitinib in the treatment of MF and PV patients, clinicians may be faced with the dilemma as to whether ruxolitinib is the cause of hepatic enzyme elevations or is in fact beneficial for the treatment of hepatic dysfunction arising from EMH. Herein, we describe a series of patients without known liver disease or pathology receiving ruxolitinib who experienced hepatocellular damage and had a liver biopsy performed that assisted in their subsequent management. 2. Cases 2.1. Case 1
A 55-year-old male with a history of CALR -positive, low-risk MF by the Dynamic International Prognostic Scoring System (DIPSS) was initiated on 5 mg twice daily ruxolitinib treatment given progressive splenomegaly and worsening night sweats. He experienced an outstanding symptomatic response without significant improvement in splenomegaly. His aminotransferases, which were normal prior to ruxolitinib initiation, became mildly elevated, with ALT rising from 64 U/L at initiation to 232 U/L after 5 months of therapy. The patient was not on other hepatotoxic medications. A transjugular liver biopsy was obtained, which demonstrated significant EMH and diffuse sinusoidal infiltration with atypical appearing megakaryocytes, without evidence of steatohepatitis or drug-induced liver injury (DILI) (Figure 1 (A)). Given the finding of EMH, the ruxolitinib dose was increased to 10 mg twice daily with immediate and sustained improvement in ALT to 85 U/L. He is currently being evaluated for an allogeneic hematopoietic stem cell transplantation. Figure 1: (A) The liver biopsy specimen shows prominent extramedullary hematopoiesis in the sinusoids. Megakaryocytes are marked by the arrows. (B) An epithelioid granuloma (arrow) is noted in the portal tract. An adjacent area shows sinusoidal dilatation. (C) A portal tract with herniated portal veins(arrows). The findings are compatible with obliterative portal venopathy. 2.2. Case 2
A 66-year-old male with a history of PV was initiated on ruxolitinib 10 mg twice daily for worsening leukocytosis and massive splenomegaly. He experienced an excellent initial response with significant reduction in palpable splenomegaly by 50%. However, serum levels of alkaline phosphatase (ALP) began to rise from a baseline of 113 U/L to 311 U/L after 2 weeks of exposure to drug. The ALP peaked at 1286 U/L after approximately 8 months of ruxolitinib exposure. He did not start any other medications or supplements during this time. He was continued on a higher dose of ruxolitinib at 15 mg twice daily for presumed EMH. The ALP remained elevated at 334 U/L, so a liver biopsy was performed at that time, demonstrating granulomatous hepatitis with ductopenia (Figure 1 (B)), which was attributed to DILI. Shortly afterwards, he expired from hypoxemic respiratory failure in the setting of a lobar pneumonia. This represents a potential case of DILI due to ruxolitinib given the temporal relationship between ruxolitinib initiation and a grade 3 ALP rise, and further supported by the liver biopsy findings. 2.3. Case 3
A 74-year-old male with high-risk JAK2V617F-positive post-PV MF was initiated on ruxolitinib 10 mg twice daily to address worsening splenomegaly and debilitating fatigue. The patient experienced improvement in symptom burden and a decrease in palpable spleen size by 20%. However, he began to experience worsening ascites requiring large-volume paracentesis. Additionally, the ALP rose to 335 U/L from a baseline of around 180 U/L. Given the unknown cause of his liver dysfunction, he underwent a transjugular liver biopsy, demonstrating the presence of both EMH and OPV (Figure 1 (C)). Because of these findings, the ruxolitinib dose was increased to 20 mg twice daily with improvement in symptoms and ascites and decrease in ALP to 151 U/L within 5 months. 2.4. Case 4
A 49-year-old male with DIPSS intermediate-2 risk, JAK2V617F-positive post-PV MF, and a history of portal vein thrombosis was started on ruxolitinib at 10 mg twice daily for splenomegaly. He attained an excellent symptomatic response but was noted to have an increase in total bilirubin to 2.6 mg/dL (44.5  μ mol/L) from a normal baseline. During this time, no new medications were started. Although some hyperbilirubinemia can be attributed to hemolysis, he underwent a liver biopsy which demonstrated OPV with extensive EMH. He was continued on ruxolitinib 15 mg with improvement in total bilirubin to 1.3 mg/dL (22.23  μ mol/L). 3. Discussion
There is a significant but incompletely understood relationship between MPNs and liver disease. Noncirrhotic portal hypertension (NCPH), a broad category of diseases including OPV, has been described in the setting of MPNs with the sequela including ascites, esophageal and gastric varices, and subsequent variceal bleeding. The development of NCPH is at least in part a consequence of thrombotic disease; however, inappropriate endothelial cell activation associated with JAK2V617F expression has been implicated [ 5 ]. OPV involves variable obliteration of the portal vein, particularly in the terminal branches of the intrahepatic portal vein, and has been observed in patients with MPNs [ 3 ]. Finally, EMH can manifest as a focal hepatic nodule [ 6 ], diffuse hepatomegaly and portal hypertension [ 7 ], or laboratory manifestations as in the first, second, and fourth cases described in the current series [ 8 ].
As demonstrated in a retrospective study of 398 PMF patients, the most common hepatic laboratory derangement was an elevated ALP, which was CTCAE grade 1 in 40% of patients, grade 2 in 7%, and grade 3 or above in 1%. When grade 2 or above, an elevated ALP was associated with a higher leukocyte count and worse prognosis. AST elevations were also present in this population, with 9% having elevations which were mostly grade 1. No findings were reported for other liver chemistry tests such as ALT or bilirubin levels [ 9 ]. The pathological basis of these laboratory findings was not reported, nor were concomitant medications including ruxolitinib noted.
The cases described in the current series illustrate the variety of liver pathology seen in PV/MF patients with liver dysfunction. However, it is unclear the prevalence of liver pathology in MPN patients without liver dysfunction. We also report a possible case of ruxolitinib-associated DILI. There are no known mechanisms to explain possible hepatotoxicity with this agent. Ruxolitinib is metabolized by the liver through the CYP3A4 system, with metabolites mainly excreted in the urine. It is plausible that liver injury may be related to the production of a toxic intermediate [ 10 ]. If DILI is suspected with ruxolitinib exposure, discontinuation may be warranted. However, abrupt discontinuation of ruxolitinib in any context can lead to a serious and potentially life-threatening withdrawal syndrome characterized by worsening cytopenias and progressive splenomegaly, the most severe form of which can mimic septic shock with hemodynamic instability [ 11 ]. Therefore, when ruxolitinib is discontinued, it should be done as a taper under close supervision and in certain cases overlapped with prednisone to blunt the potential cytokine rebound phenomenon. Thus, utilizing a liver biopsy to diagnose DILI is of paramount importance before considering withdrawal of ruxolitinib.
Although some liver abnormalities can be attributed to ruxolitinib itself, the majority of patients in our series had abnormalities as a consequence of EMH. This series emphasizes that obtaining a liver biopsy is a crucial and necessary step for adaptive management in patients with evidence of hepatocellular damage receiving ruxolitinib treatment. The liver biopsy may be instrumental in determining if ruxolitinib therapy should be discontinued or continued. Conflicts of Interest
John Mascarenhas received research funding paid to the institution from Incyte, Janssen, Roche, Novartis, Merck, Promedior, and CTI Biopharma. Ronald Hoffman is a member of the advisory board for Janssen. The remaining authors have no conflicts of interest to disclose. References United States Food and Drug Administration, JAKAFI (Ruxolitinib) Label , USFDA, Silver Spring, MD, USA, 2011. R. R. Shah, J. Morganroth, and D. R. Shah, “Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives,” Drug Safety , vol. 36, no. 7, pp. 491–503, 2013. View at Publisher · View at Google Scholar · View at Scopus J. E. Mayer, T. D. Schiano, M. I. Fiel, R. Hoffman, and J. O. Mascarenhas, “An association of myeloproliferative neoplasms and obliterative portal venopathy,” Digestive Diseases and Sciences , vol. 59, no. 7, pp. 1638–1641, 2014. View at Publisher · View at Google Scholar · View at Scopus M. Maccaferri, G. Leonardi, R. Marasca et al., “Ruxolitinib for pulmonary extramedullary hematopoiesis in myelofibrosis,” Leukemia & Lymphoma , vol. 55, no. 9, pp. 2207-2208, 2014. View at Publisher · View at Google Scholar · View at Scopus S. Sozer, M. I. Fiel, T. Schiano, M. Xu, J. Mascarenhas, and R. Hoffman, “The presence of JAK2V617F mutation in the liver endothelial cells of patients with Budd-Chiari syndrome,” Blood , vol. 113, no. 21, pp. 5246–5249, 2009. View at Publisher · View at Google Scholar · View at Scopus F. S. Cardoso, J. V. Pires, J. S. Miranda, and J. M. Araujo, “Hepatic nodule: a case of primary myelofibrosis,” BMJ Case Reports , vol. 2011, Article ID bcr0520114220, 2011. View at Publisher · View at Google Scholar · View at Scopus P. Amarapurkar, S. Parekh, A. Amarapurkar, and D. Amarapurkar, “Portal hypertension and ascites in extramedullary hematopoiesis,” Journal of Clinical and Experimental Hepatology , vol. 2, no. 2, pp. 188–190, 2012. View at Publisher · View at Google Scholar · View at Scopus M. Yotsumoto, F. Ishida, T. Ito, M. Ueno, K. Kitano, and K. Kiyosawa, “Idiopathic myelofibrosis with refractory massive ascites,” Internal Medicine , vol. 42, no. 6, pp. 525–528, 2003. View at Publisher · View at Google Scholar · View at Scopus D. Barraco, M. Mudireddy, S. Shah et al., “Liver function test abnormalities and their clinical relevance in primary myelofibrosis,” Blood Cancer Journal , vol. 7, no. 4, p. e557, 2017. View at Publisher · View at Google Scholar · View at Scopus S. Galli, D. McLornan, and C. Harrison, “Safety evaluation of ruxolitinib for treating myelofibrosis,” Expert Opinion on Drug Safety , vol. 13, no. 7, pp. 967–976, 2014. View at Publisher · View at Google Scholar · View at Scopus A. Tefferi and A. Pardanani, “Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis,” Mayo Clinic Proceedings , vol. 86, no. 12, pp. 1188–1191, 2011. View at Publisher · View at Google Scholar · View at Scopus Follow Us

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Data on Use of Mallinckrodt’s H.P. Acthar® Gel (Repository Corticotropin Injection) in Patients with Rare Cause of Nephrotic Syndrome Published in Transplantation

<h1>Data on Use of Mallinckrodt’s H.P. Acthar® Gel (Repository Corticotropin Injection) in Patients with Rare Cause of Nephrotic Syndrome Published in Transplantation</h1>

Data on Use of Mallinckrodt’s H.P. Acthar® Gel (Repository Corticotropin Injection) in Patients with Rare Cause of Nephrotic Syndrome Published in Transplantation

STAINES-UPON-THAMES, United Kingdom , Jan. 3, 2019 /PRNewswire/ — Mallinckrodt plc (NYSE: MNK ), a leading global specialty pharmaceutical company, today announced publication of a retrospective analysis assessing the efficacy of H.P. Acthar ® Gel (repository corticotropin injection) in kidney transplant recipients with treatment-resistant focal segmental glomerular sclerosis (FSGS). FSGS is a rare disease that can cause nephrotic syndrome, a serious kidney disorder that may raise the risk of progression to end stage renal disease (ESRD).[2] Results from the analysis, which included data from patients treated at two large U.S. transplant centers between April 2012 and December 2016 , were published in the January issue of Transplantation .
“This is the first study of H.P Acthar Gel treatment in renal transplant patients who were previously treated with conventional therapy for FSGS, a rare and serious kidney disease with few available treatments,” said Steven Romano , M.D., Executive Vice President and Chief Scientific Officer at Mallinckrodt . “We are pleased to share these valuable insights to better understand the potential applications of Acthar in treating patients who develop FSGS after their kidney transplant.”
H.P. Acthar Gel is U.S. Food and Drug Administration (FDA)-approved to induce a diuresis or a remission of proteinuria (excess protein in the urine) in nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus. Clinical experience has shown reduction in proteinuria in multiple glomerular nephropathies, including FSGS.[3]
H.P. Acthar Gel in Resistant Focal Segmental Glomerulosclerosis after Kidney Transplantation[1] This retrospective study evaluated 20 kidney transplant patients (mean age of 49 years; range 22-80 years) who received H.P. Acthar Gel for the treatment of proteinuria due to new or recurrent post-transplant FSGS. Subjects had previously received conventional FSGS treatment with therapeutic plasma exchange (TPE) and/or rituximab and developed FSGS approximately three months after their transplant (median interquartile range [IQR] of three months; range 0.75-7.5 months).
Forty percent of patients (8/20) received rituximab within 24 hours of the transplant surgery and twenty percent (4/20) received TPE before transplantation. Seventy-five percent of patients (15/20) were treated with TPE at the time of post-transplant FSGS; 50 percent (10/20) received rituximab as well which was started before the use of H.P Acthar Gel. Eighty percent (16/20) were treated with TPE and/or rituximab prior to initiating H.P. Acthar Gel therapy. All 20 patients in the study received thymoglobulin induction therapy (an immunosuppressive used in kidney transplantation). All patients were maintained on triple immunosuppression antirejection therapy of a calcineurin inhibitor (CNI), mycophenolate mofetil and prednisone. Tacrolimus (CNI) was used in 85 percent (17/20) of patients and cyclosporine (CNI) in 15 percent (3/20). One patient (5 percent) was switched from a CNI to belatacept because of CNI nephrotoxicity. Subjects took H.P. Acthar Gel twice a week for approximately six months (median IQR of 24 weeks; range 8-32 weeks) and were evaluated for treatment response using the urine protein to creatinine ratio to determine complete or partial remission of proteinuria. Complete remission (CR) was defined as a decrease of proteinuria ≤1g/g with stable kidney function (creatinine within 30 percent from baseline after H.P. Acthar Gel treatment), and partial remission (PR) was defined as a decrease of proteinuria between 1 and ≤3.5 g/g with stable kidney function (creatinine within 30 percent from baseline after H.P. Acthar Gel treatment).
Key Findings
The analysis found significant improvement in proteinuria after treatment with H.P. Acthar Gel from a mean ± Standard Deviation (SD) of 8.6 ± 7.6 g/g at baseline to a mean± SD of 3.3 ± 2.3 g/g at about six months (P=0.004). Fifty percent of patients (10/20) who received H.P. Acthar Gel had a complete or partial remission of proteinuria (four patients achieved CR and six patients achieved PR). The use of H.P. Acthar Gel did not significantly change mean serum creatinine levels (3.3 ± 2.7 vs. 2.8 ± 1.67 mg/dL, P=0.42) or estimated glomerular filtration rate (eGFR) (30.7 ± 19.3 vs. 34.4 ± 20 mL/min/1.73 m2, P=0.56). Three patients died, one during treatment and two in the post-treatment follow-up period. Additional Observations
During the observation period, 40 percent (8/20) of patients had transplant failure, with five cases attributed to new or recurring FSGS, while 60 percent of patients (12/20) reported no transplant failure. The analysis also assessed if patients on TPE (10/20) could discontinue therapy. Six patients were weaned off TPE. The remaining four were reported to require TPE less frequently. Study Limitations
This was a retrospective study with no control group. Not all patients were treated similarly; this included some subjects who received initial prophylactic TPE or rituximab as a preventative measure at their treatment center. A variety of factors may have influenced the improvement in proteinuria including TPE given with H.P. Acthar Gel. The analysis was supported, in part, through the Mallinckrodt Investigator-Initiated Research program.
“The incidence of recurrent FSGS after kidney transplant has been reported between 20 percent to 50 percent but may exceed 80 percent in patients with a history of transplant failure from a prior FSGS recurrence. Further, transplant recipients with recurrent FSGS are two to five times more likely to have transplant loss compared to those with no recurrence. The goal of treatment is to reduce patients’ disease activity or, ideally, achieve remission, but there are no real standards of care and challenges exist with current approaches,” said Tarek Alhamad , MD, MS, FACP, FASN, Assistant Professor of Medicine, Medical Director of Transplant Nephrology at the Washington University School of Medicine in St. Louis , and the study’s lead author. “This retrospective analysis – the first retrospective cohort review to date – provides data insights regarding H.P. Acthar Gel for physicians treating patients with post-transplant FSGS.”
About Nephrotic Syndrome Nephrotic syndrome (NS) is a collection of symptoms that occur when the blood vessels in the kidney begin to leak excess protein in the urine, a condition called proteinuria. A variety of diseases and underlying disorders may damage the kidneys and cause proteinuria in people with NS. These etiologies can include glomerular diseases such as: idiopathic membranous nephropathy, focal segmental glomerulosclerosis, minimal change disease, membranoproliferative glomerulonephritis, lupus nephritis, and IgA nephropathy. In these and other related disorders, the glomeruli, or small blood vessels that work as the kidney’s filtering system, are damaged.
Proteinuria is one of the most important adverse prognostic factors for progression to end stage renal failure in patients with glomerular disease. One of the goals of treating nephrotic syndrome includes reducing or eliminating proteinuria.[4]
H.P. Acthar Gel (repository corticotropin injection) Indications H.P. Acthar Gel is an injectable drug approved by the FDA for the treatment of 19 indications. Of these, today the majority of Acthar use is in these indications:
Adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy) Monotherapy for the treatment of infantile spasms in infants and children under 2 years of age Treatment during an exacerbation or as maintenance therapy in selected cases of systemic lupus erythematosus The treatment of acute exacerbations of multiple sclerosis in adults. Controlled clinical trials have shown H.P. Acthar Gel to be effective in speeding the resolution of acute exacerbations of multiple sclerosis. However, there is no evidence that it affects the ultimate outcome or natural history of the disease Inducing a diuresis or a remission of proteinuria in nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus Treatment during an exacerbation or as maintenance therapy in selected cases of systemic dermatomyositis (polymyositis) The treatment of symptomatic sarcoidosis Treatment of severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: keratitis, iritis, iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, chorioretinitis, anterior segment inflammation IMPORTANT SAFETY INFORMATION
Contraindications
Acthar should never be administered intravenously Administration of live or live attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of Acthar Acthar is contraindicated where congenital infections are suspected in infants Acthar is contraindicated in patients with scleroderma, osteoporosis, systemic fungal infections, ocular herpes simplex, recent surgery, history of or the presence of a peptic ulcer, congestive heart failure, uncontrolled hypertension, primary adrenocortical insufficiency, adrenocortical hyperfunction or sensitivity to proteins of porcine origins Warnings and Precautions
The adverse effects of Acthar are related primarily to its steroidogenic effects Acthar may increase susceptibility to new infection or reactivation of latent infections Suppression of the hypothalamic-pituitary-axis (HPA) may occur following prolonged therapy with the potential for adrenal insufficiency after withdrawal of the medication. Adrenal insufficiency may be minimized by tapering of the dose when discontinuing treatment. During recovery of the adrenal gland patients should be protected from the stress (e.g. trauma or surgery) by the use of corticosteroids. Monitor patients for effects of HPA suppression after stopping treatment Cushing’s syndrome may occur during therapy but generally resolves after therapy is stopped. Monitor patients for signs and symptoms Acthar can cause elevation of blood pressure, salt and water retention, and hypokalemia. Blood pressure, sodium and potassium levels may need to be monitored Acthar often acts by masking symptoms of other diseases/disorders. Monitor patients carefully during and for a period following discontinuation of therapy Acthar can cause GI bleeding and gastric ulcer. There is also an increased risk for perforation in patients with certain gastrointestinal disorders. Monitor for signs of bleeding Acthar may be associated with central nervous system effects ranging from euphoria, insomnia, irritability, mood swings, personality changes, and severe depression, and psychosis. Existing conditions may be aggravated Patients with comorbid disease may have that disease worsened. Caution should be used when prescribing Acthar in patients with diabetes and myasthenia gravis Prolonged use of Acthar may produce cataracts, glaucoma and secondary ocular infections. Monitor for signs and symptoms Acthar is immunogenic and prolonged administration of Acthar may increase the risk of hypersensitivity reactions. Neutralizing antibodies with chronic administration may lead to loss of endogenous ACTH activity There is an enhanced effect in patients with hypothyroidism and in those with cirrhosis of the liver Long-term use may have negative effects on growth and physical development in children. Monitor pediatric patients Decrease in bone density may occur. Bone density should be monitored for patients on long-term therapy Pregnancy Class C: Acthar has been shown to have an embryocidal effect and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus Adverse Reactions
Common adverse reactions for Acthar are similar to those of corticosteroids and include fluid retention, alteration in glucose tolerance, elevation in blood pressure, behavioral and mood changes, increased appetite and weight gain Specific adverse reactions reported in IS clinical trials in infants and children under 2 years of age included: infection, hypertension, irritability, Cushingoid symptoms, constipation, diarrhea, vomiting, pyrexia, weight gain, increased appetite, decreased appetite, nasal congestion, acne, rash, and cardiac hypertrophy. Convulsions were also reported, but these may actually be occurring because some IS patients progress to other forms of seizures and IS sometimes mask other seizures, which become visible once the clinical spasms from IS resolve Other adverse events reported are included in the full Prescribing Information. Please see full Prescribing Information .
ABOUT MALLINCKRODT Mallinckrodt is a global business that develops, manufactures, markets and distributes specialty pharmaceutical products and therapies. Areas of focus include autoimmune and rare diseases in specialty areas like neurology, rheumatology, nephrology, pulmonology and ophthalmology; immunotherapy and neonatal respiratory critical care therapies; analgesics and gastrointestinal products. To learn more about Mallinckrodt, visit www.mallinckrodt.com .
Mallinckrodt uses its website as a channel of distribution of important company information, such as press releases, investor presentations and other financial information. It also uses its website to expedite public access to time-critical information regarding the company in advance of or in lieu of distributing a press release or a filing with the U.S. Securities and Exchange Commission (SEC) disclosing the same information. Therefore, investors should look to the Investor Relations page of the website for important and time-critical information. Visitors to the website can also register to receive automatic e-mail and other notifications alerting them when new information is made available on the Investor Relations page of the website.
CONTACTS
For Trade Media Inquiries Caren Begun Green Room Communications 201-396-8551 caren@greenroompr.com
For Financial/Dailies Media Inquiries Daniel Yunger Kekst CNC 212-521-4879 mallinckrodt@kekstcnc.com
Investor Relations Daniel J. Speciale , CPA Investor Relations and Strategy Officer 314-654-3638 daniel.speciale@mnk.com
Mallinckrodt , the “M” brand mark and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company. Other brands are trademarks of a Mallinckrodt company or their respective owners. © 2019 Mallinckrodt . US-1900004 1/19
[1] Alhamad T, Dieck JM, Younus U, et al. ACTH gel in resistant focal segmental glomerulosclerosis after kidney transplantation. Transplantation . 2019;103: 202–209. [2] Korbet SM. Clinical picture and outcome of primary focal segmental glomerulosclerosis. Nephrol Dial Transplant. 1999;14 Suppl 3:68-73. [3] H.P. Acthar ® Gel (repository corticotropin injection) [prescribing information]. Mallinckrodt ARD, Inc. [4] Troyanov et al. J Am Soc Nephrol. 2005;16(4):1061–1068.
SOURCE Mallinckrodt plc
Related Links www.mallinckrodt.com
releases/data-on-use-of-mallinckrodts-hp-acthar-gel-repository-corticotropin-injection-in-patients-with-rare-cause-of-nephrotic-syndrome-published-in-transplantation-300772221.html

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Data on Use of Mallinckrodt's H.P. Acthar® Gel (Repository Corticotropin Injection) in Patients with Rare Cause of Nephrotic Syndrome Published in Transplantation

<h1>Data on Use of Mallinckrodt's H.P. Acthar® Gel (Repository Corticotropin Injection) in Patients with Rare Cause of Nephrotic Syndrome Published in Transplantation</h1>

Data on Use of Mallinckrodt’s H.P. Acthar® Gel (Repository Corticotropin Injection) in Patients with Rare Cause of Nephrotic Syndrome Published in Transplantation

Teilen Drucken STAINES-UPON-THAMES, United Kingdom , Jan. 3, 2019 /PRNewswire/ — (NYSE: MNK), a leading global specialty pharmaceutical company, today announced publication of a retrospective analysis assessing the efficacy of H.P. Acthar ® Gel (repository corticotropin injection) in kidney transplant recipients with treatment-resistant focal segmental glomerular sclerosis (FSGS). FSGS is a rare disease that can cause nephrotic syndrome, a serious kidney disorder that may raise the risk of progression to end stage renal disease (ESRD).[2] Results from the analysis, which included data from patients treated at two large U.S. transplant centers between April 2012 and December 2016 , were published in the January issue of Transplantation . “This is the first study of H.P Acthar Gel treatment in renal transplant patients who were previously treated with conventional therapy for FSGS, a rare and serious kidney disease with few available treatments,” said Steven Romano , M.D., Executive Vice President and Chief Scientific Officer at Mallinckrodt . “We are pleased to share these valuable insights to better understand the potential applications of Acthar in treating patients who develop FSGS after their kidney transplant.” H.P. Acthar Gel is U.S. Food and Drug Administration (FDA)-approved to induce a diuresis or a remission of proteinuria (excess protein in the urine) in nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus. Clinical experience has shown reduction in proteinuria in multiple glomerular nephropathies, including FSGS.[3] H.P. Acthar Gel in Resistant Focal Segmental Glomerulosclerosis after Kidney Transplantation[1] This retrospective study evaluated 20 kidney transplant patients (mean age of 49 years; range 22-80 years) who received H.P. Acthar Gel for the treatment of proteinuria due to new or recurrent post-transplant FSGS. Subjects had previously received conventional FSGS treatment with therapeutic plasma exchange (TPE) and/or rituximab and developed FSGS approximately three months after their transplant (median interquartile range [IQR] of three months; range 0.75-7.5 months). Forty percent of patients (8/20) received rituximab within 24 hours of the transplant surgery and twenty percent (4/20) received TPE before transplantation. Seventy-five percent of patients (15/20) were treated with TPE at the time of post-transplant FSGS; 50 percent (10/20) received rituximab as well which was started before the use of H.P Acthar Gel. Eighty percent (16/20) were treated with TPE and/or rituximab prior to initiating H.P. Acthar Gel therapy. All 20 patients in the study received thymoglobulin induction therapy (an immunosuppressive used in kidney transplantation). All patients were maintained on triple immunosuppression antirejection therapy of a calcineurin inhibitor (CNI), mycophenolate mofetil and prednisone. Tacrolimus (CNI) was used in 85 percent (17/20) of patients and cyclosporine (CNI) in 15 percent (3/20). One patient (5 percent) was switched from a CNI to belatacept because of CNI nephrotoxicity. Subjects took H.P. Acthar Gel twice a week for approximately six months (median IQR of 24 weeks; range 8-32 weeks) and were evaluated for treatment response using the urine protein to creatinine ratio to determine complete or partial remission of proteinuria. Complete remission (CR) was defined as a decrease of proteinuria ≤1g/g with stable kidney function (creatinine within 30 percent from baseline after H.P. Acthar Gel treatment), and partial remission (PR) was defined as a decrease of proteinuria between 1 and ≤3.5 g/g with stable kidney function (creatinine within 30 percent from baseline after H.P. Acthar Gel treatment). Key Findings The analysis found significant improvement in proteinuria after treatment with H.P. Acthar Gel from a mean ± Standard Deviation (SD) of 8.6 ± 7.6 g/g at baseline to a mean± SD of 3.3 ± 2.3 g/g at about six months (P=0.004). Fifty percent of patients (10/20) who received H.P. Acthar Gel had a complete or partial remission of proteinuria (four patients achieved CR and six patients achieved PR). The use of H.P. Acthar Gel did not significantly change mean serum creatinine levels (3.3 ± 2.7 vs. 2.8 ± 1.67 mg/dL, P=0.42) or estimated glomerular filtration rate (eGFR) (30.7 ± 19.3 vs. 34.4 ± 20 mL/min/1.73 m2, P=0.56). Three patients died, one during treatment and two in the post-treatment follow-up period. Additional Observations During the observation period, 40 percent (8/20) of patients had transplant failure, with five cases attributed to new or recurring FSGS, while 60 percent of patients (12/20) reported no transplant failure. The analysis also assessed if patients on TPE (10/20) could discontinue therapy. Six patients were weaned off TPE. The remaining four were reported to require TPE less frequently. Study Limitations This was a retrospective study with no control group. Not all patients were treated similarly; this included some subjects who received initial prophylactic TPE or rituximab as a preventative measure at their treatment center. A variety of factors may have influenced the improvement in proteinuria including TPE given with H.P. Acthar Gel. The analysis was supported, in part, through the Mallinckrodt Investigator-Initiated Research program. “The incidence of recurrent FSGS after kidney transplant has been reported between 20 percent to 50 percent but may exceed 80 percent in patients with a history of transplant failure from a prior FSGS recurrence. Further, transplant recipients with recurrent FSGS are two to five times more likely to have transplant loss compared to those with no recurrence. The goal of treatment is to reduce patients’ disease activity or, ideally, achieve remission, but there are no real standards of care and challenges exist with current approaches,” said Tarek Alhamad , MD, MS, FACP, FASN, Assistant Professor of Medicine, Medical Director of Transplant Nephrology at the Washington University School of Medicine in St. Louis , and the study’s lead author. “This retrospective analysis – the first retrospective cohort review to date – provides data insights regarding H.P. Acthar Gel for physicians treating patients with post-transplant FSGS.” About Nephrotic Syndrome Nephrotic syndrome (NS) is a collection of symptoms that occur when the blood vessels in the kidney begin to leak excess protein in the urine, a condition called proteinuria. A variety of diseases and underlying disorders may damage the kidneys and cause proteinuria in people with NS. These etiologies can include glomerular diseases such as: idiopathic membranous nephropathy, focal segmental glomerulosclerosis, minimal change disease, membranoproliferative glomerulonephritis, lupus nephritis, and IgA nephropathy. In these and other related disorders, the glomeruli, or small blood vessels that work as the kidney’s filtering system, are damaged. Proteinuria is one of the most important adverse prognostic factors for progression to end stage renal failure in patients with glomerular disease. One of the goals of treating nephrotic syndrome includes reducing or eliminating proteinuria.[4] H.P. Acthar Gel (repository corticotropin injection) Indications H.P. Acthar Gel is an injectable drug approved by the FDA for the treatment of 19 indications. Of these, today the majority of Acthar use is in these indications: Adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy) Monotherapy for the treatment of infantile spasms in infants and children under 2 years of age Treatment during an exacerbation or as maintenance therapy in selected cases of systemic lupus erythematosus The treatment of acute exacerbations of multiple sclerosis in adults. Controlled clinical trials have shown H.P. Acthar Gel to be effective in speeding the resolution of acute exacerbations of multiple sclerosis. However, there is no evidence that it affects the ultimate outcome or natural history of the disease Inducing a diuresis or a remission of proteinuria in nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus Treatment during an exacerbation or as maintenance therapy in selected cases of systemic dermatomyositis (polymyositis) The treatment of symptomatic sarcoidosis Treatment of severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: keratitis, iritis, iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, chorioretinitis, anterior segment inflammation IMPORTANT SAFETY INFORMATION Contraindications Acthar should never be administered intravenously Administration of live or live attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of Acthar Acthar is contraindicated where congenital infections are suspected in infants Acthar is contraindicated in patients with scleroderma, osteoporosis, systemic fungal infections, ocular herpes simplex, recent surgery, history of or the presence of a peptic ulcer, congestive heart failure, uncontrolled hypertension, primary adrenocortical insufficiency, adrenocortical hyperfunction or sensitivity to proteins of porcine origins Warnings and Precautions The adverse effects of Acthar are related primarily to its steroidogenic effects Acthar may increase susceptibility to new infection or reactivation of latent infections Suppression of the hypothalamic-pituitary-axis (HPA) may occur following prolonged therapy with the potential for adrenal insufficiency after withdrawal of the medication. Adrenal insufficiency may be minimized by tapering of the dose when discontinuing treatment. During recovery of the adrenal gland patients should be protected from the stress (e.g. trauma or surgery) by the use of corticosteroids. Monitor patients for effects of HPA suppression after stopping treatment Cushing’s syndrome may occur during therapy but generally resolves after therapy is stopped. Monitor patients for signs and symptoms Acthar can cause elevation of blood pressure, salt and water retention, and hypokalemia. Blood pressure, sodium and potassium levels may need to be monitored Acthar often acts by masking symptoms of other diseases/disorders. Monitor patients carefully during and for a period following discontinuation of therapy Acthar can cause GI bleeding and gastric ulcer. There is also an increased risk for perforation in patients with certain gastrointestinal disorders. Monitor for signs of bleeding Acthar may be associated with central nervous system effects ranging from euphoria, insomnia, irritability, mood swings, personality changes, and severe depression, and psychosis. Existing conditions may be aggravated Patients with comorbid disease may have that disease worsened. Caution should be used when prescribing Acthar in patients with diabetes and myasthenia gravis Prolonged use of Acthar may produce cataracts, glaucoma and secondary ocular infections. Monitor for signs and symptoms Acthar is immunogenic and prolonged administration of Acthar may increase the risk of hypersensitivity reactions. Neutralizing antibodies with chronic administration may lead to loss of endogenous ACTH activity There is an enhanced effect in patients with hypothyroidism and in those with cirrhosis of the liver Long-term use may have negative effects on growth and physical development in children. Monitor pediatric patients Decrease in bone density may occur. Bone density should be monitored for patients on long-term therapy Pregnancy Class C: Acthar has been shown to have an embryocidal effect and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus Adverse Reactions Common adverse reactions for Acthar are similar to those of corticosteroids and include fluid retention, alteration in glucose tolerance, elevation in blood pressure, behavioral and mood changes, increased appetite and weight gain Specific adverse reactions reported in IS clinical trials in infants and children under 2 years of age included: infection, hypertension, irritability, Cushingoid symptoms, constipation, diarrhea, vomiting, pyrexia, weight gain, increased appetite, decreased appetite, nasal congestion, acne, rash, and cardiac hypertrophy. Convulsions were also reported, but these may actually be occurring because some IS patients progress to other forms of seizures and IS sometimes mask other seizures, which become visible once the clinical spasms from IS resolve Other adverse events reported are included in the full Prescribing Information.Please see full . ABOUT MALLINCKRODT Mallinckrodt is a global business that develops, manufactures, markets and distributes specialty pharmaceutical products and therapies. Areas of focus include autoimmune and rare diseases in specialty areas like neurology, rheumatology, nephrology, pulmonology and ophthalmology; immunotherapy and neonatal respiratory critical care therapies; analgesics and gastrointestinal products. To learn more about Mallinckrodt, visit . Mallinckrodt uses its website as a channel of distribution of important company information, such as press releases, investor presentations and other financial information. It also uses its website to expedite public access to time-critical information regarding the company in advance of or in lieu of distributing a press release or a filing with the U.S. Securities and Exchange Commission (SEC) disclosing the same information. Therefore, investors should look to the Investor Relations page of the website for important and time-critical information. Visitors to the website can also register to receive automatic e-mail and other notifications alerting them when new information is made available on the Investor Relations page of the website. CONTACTS For Trade Media Inquiries

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Mallinckrodt : Data on Use of Mallinckrodt's H.P. Acthar® Gel (Repository Corticotropin Injection) in Patients with Rare Cause of Nephrotic Syndrome Published in Transplantation | MarketScreener

<h1>Mallinckrodt : Data on Use of Mallinckrodt's H.P. Acthar® Gel (Repository Corticotropin Injection) in Patients with Rare Cause of Nephrotic Syndrome Published in Transplantation | MarketScreener</h1>

Mallinckrodt : Data on Use of Mallinckrodt’s H.P. Acthar® Gel (Repository Corticotropin Injection) in Patients with Rare Cause of Nephrotic Syndrome Published in Transplantation | MarketScreener

STAINES-UPON-THAMES, United Kingdom , Jan. 3, 2019 /PRNewswire/ — Mallinckrodt plc (NYSE: MNK), a leading global specialty pharmaceutical company, today announced publication of a retrospective analysis assessing the efficacy of H.P. Acthar ® Gel (repository corticotropin injection) in kidney transplant recipients with treatment-resistant focal segmental glomerular sclerosis (FSGS). FSGS is a rare disease that can cause nephrotic syndrome, a serious kidney disorder that may raise the risk of progression to end stage renal disease (ESRD).[2] Results from the analysis, which included data from patients treated at two large U.S. transplant centers between April 2012 and December 2016 , were published in the January issue of Transplantation .
“This is the first study of H.P Acthar Gel treatment in renal transplant patients who were previously treated with conventional therapy for FSGS, a rare and serious kidney disease with few available treatments,” said Steven Romano , M.D., Executive Vice President and Chief Scientific Officer at Mallinckrodt . “We are pleased to share these valuable insights to better understand the potential applications of Acthar in treating patients who develop FSGS after their kidney transplant.”
H.P. Acthar Gel is U.S. Food and Drug Administration (FDA)-approved to induce a diuresis or a remission of proteinuria (excess protein in the urine) in nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus. Clinical experience has shown reduction in proteinuria in multiple glomerular nephropathies, including FSGS.[3]
H.P. Acthar Gel in Resistant Focal Segmental Glomerulosclerosis after Kidney Transplantation[1]
This retrospective study evaluated 20 kidney transplant patients (mean age of 49 years; range 22-80 years) who received H.P. Acthar Gel for the treatment of proteinuria due to new or recurrent post-transplant FSGS. Subjects had previously received conventional FSGS treatment with therapeutic plasma exchange (TPE) and/or rituximab and developed FSGS approximately three months after their transplant (median interquartile range [IQR] of three months; range 0.75-7.5 months).
Forty percent of patients (8/20) received rituximab within 24 hours of the transplant surgery and twenty percent (4/20) received TPE before transplantation. Seventy-five percent of patients (15/20) were treated with TPE at the time of post-transplant FSGS; 50 percent (10/20) received rituximab as well which was started before the use of H.P Acthar Gel. Eighty percent (16/20) were treated with TPE and/or rituximab prior to initiating H.P. Acthar Gel therapy. All 20 patients in the study received thymoglobulin induction therapy (an immunosuppressive used in kidney transplantation). All patients were maintained on triple immunosuppression antirejection therapy of a calcineurin inhibitor (CNI), mycophenolate mofetil and prednisone. Tacrolimus (CNI) was used in 85 percent (17/20) of patients and cyclosporine (CNI) in 15 percent (3/20). One patient (5 percent) was switched from a CNI to belatacept because of CNI nephrotoxicity. Subjects took H.P. Acthar Gel twice a week for approximately six months (median IQR of 24 weeks; range 8-32 weeks) and were evaluated for treatment response using the urine protein to creatinine ratio to determine complete or partial remission of proteinuria. Complete remission (CR) was defined as a decrease of proteinuria ≤1g/g with stable kidney function (creatinine within 30 percent from baseline after H.P. Acthar Gel treatment), and partial remission (PR) was defined as a decrease of proteinuria between 1 and ≤3.5 g/g with stable kidney function (creatinine within 30 percent from baseline after H.P. Acthar Gel treatment).
Key Findings
The analysis found significant improvement in proteinuria after treatment with H.P. Acthar Gel from a mean ± Standard Deviation (SD) of 8.6 ± 7.6 g/g at baseline to a mean± SD of 3.3 ± 2.3 g/g at about six months (P=0.004). Fifty percent of patients (10/20) who received H.P. Acthar Gel had a complete or partial remission of proteinuria (four patients achieved CR and six patients achieved PR). The use of H.P. Acthar Gel did not significantly change mean serum creatinine levels (3.3 ± 2.7 vs. 2.8 ± 1.67 mg/dL, P=0.42) or estimated glomerular filtration rate (eGFR) (30.7 ± 19.3 vs. 34.4 ± 20 mL/min/1.73 m2, P=0.56). Three patients died, one during treatment and two in the post-treatment follow-up period. Additional Observations
During the observation period, 40 percent (8/20) of patients had transplant failure, with five cases attributed to new or recurring FSGS, while 60 percent of patients (12/20) reported no transplant failure. The analysis also assessed if patients on TPE (10/20) could discontinue therapy. Six patients were weaned off TPE. The remaining four were reported to require TPE less frequently. Study Limitations
This was a retrospective study with no control group. Not all patients were treated similarly; this included some subjects who received initial prophylactic TPE or rituximab as a preventative measure at their treatment center. A variety of factors may have influenced the improvement in proteinuria including TPE given with H.P. Acthar Gel. The analysis was supported, in part, through the Mallinckrodt Investigator-Initiated Research program.
“The incidence of recurrent FSGS after kidney transplant has been reported between 20 percent to 50 percent but may exceed 80 percent in patients with a history of transplant failure from a prior FSGS recurrence. Further, transplant recipients with recurrent FSGS are two to five times more likely to have transplant loss compared to those with no recurrence. The goal of treatment is to reduce patients’ disease activity or, ideally, achieve remission, but there are no real standards of care and challenges exist with current approaches,” said Tarek Alhamad , MD, MS, FACP, FASN, Assistant Professor of Medicine, Medical Director of Transplant Nephrology at the Washington University School of Medicine in St. Louis , and the study’s lead author. “This retrospective analysis – the first retrospective cohort review to date – provides data insights regarding H.P. Acthar Gel for physicians treating patients with post-transplant FSGS.”
About Nephrotic Syndrome
Nephrotic syndrome (NS) is a collection of symptoms that occur when the blood vessels in the kidney begin to leak excess protein in the urine, a condition called proteinuria. A variety of diseases and underlying disorders may damage the kidneys and cause proteinuria in people with NS. These etiologies can include glomerular diseases such as: idiopathic membranous nephropathy, focal segmental glomerulosclerosis, minimal change disease, membranoproliferative glomerulonephritis, lupus nephritis, and IgA nephropathy. In these and other related disorders, the glomeruli, or small blood vessels that work as the kidney’s filtering system, are damaged.
Proteinuria is one of the most important adverse prognostic factors for progression to end stage renal failure in patients with glomerular disease. One of the goals of treating nephrotic syndrome includes reducing or eliminating proteinuria.[4]
H.P. Acthar Gel (repository corticotropin injection) Indications
H.P. Acthar Gel is an injectable drug approved by the FDA for the treatment of 19 indications. Of these, today the majority of Acthar use is in these indications:
Adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy) Monotherapy for the treatment of infantile spasms in infants and children under 2 years of age Treatment during an exacerbation or as maintenance therapy in selected cases of systemic lupus erythematosus The treatment of acute exacerbations of multiple sclerosis in adults. Controlled clinical trials have shown H.P. Acthar Gel to be effective in speeding the resolution of acute exacerbations of multiple sclerosis. However, there is no evidence that it affects the ultimate outcome or natural history of the disease Inducing a diuresis or a remission of proteinuria in nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus Treatment during an exacerbation or as maintenance therapy in selected cases of systemic dermatomyositis (polymyositis) The treatment of symptomatic sarcoidosis Treatment of severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: keratitis, iritis, iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, chorioretinitis, anterior segment inflammation IMPORTANT SAFETY INFORMATION
Contraindications
Acthar should never be administered intravenously Administration of live or live attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of Acthar Acthar is contraindicated where congenital infections are suspected in infants Acthar is contraindicated in patients with scleroderma, osteoporosis, systemic fungal infections, ocular herpes simplex, recent surgery, history of or the presence of a peptic ulcer, congestive heart failure, uncontrolled hypertension, primary adrenocortical insufficiency, adrenocortical hyperfunction or sensitivity to proteins of porcine origins Warnings and Precautions
The adverse effects of Acthar are related primarily to its steroidogenic effects Acthar may increase susceptibility to new infection or reactivation of latent infections Suppression of the hypothalamic-pituitary-axis (HPA) may occur following prolonged therapy with the potential for adrenal insufficiency after withdrawal of the medication. Adrenal insufficiency may be minimized by tapering of the dose when discontinuing treatment. During recovery of the adrenal gland patients should be protected from the stress (e.g. trauma or surgery) by the use of corticosteroids. Monitor patients for effects of HPA suppression after stopping treatment Cushing’s syndrome may occur during therapy but generally resolves after therapy is stopped. Monitor patients for signs and symptoms Acthar can cause elevation of blood pressure, salt and water retention, and hypokalemia. Blood pressure, sodium and potassium levels may need to be monitored Acthar often acts by masking symptoms of other diseases/disorders. Monitor patients carefully during and for a period following discontinuation of therapy Acthar can cause GI bleeding and gastric ulcer. There is also an increased risk for perforation in patients with certain gastrointestinal disorders. Monitor for signs of bleeding Acthar may be associated with central nervous system effects ranging from euphoria, insomnia, irritability, mood swings, personality changes, and severe depression, and psychosis. Existing conditions may be aggravated Patients with comorbid disease may have that disease worsened. Caution should be used when prescribing Acthar in patients with diabetes and myasthenia gravis Prolonged use of Acthar may produce cataracts, glaucoma and secondary ocular infections. Monitor for signs and symptoms Acthar is immunogenic and prolonged administration of Acthar may increase the risk of hypersensitivity reactions. Neutralizing antibodies with chronic administration may lead to loss of endogenous ACTH activity There is an enhanced effect in patients with hypothyroidism and in those with cirrhosis of the liver Long-term use may have negative effects on growth and physical development in children. Monitor pediatric patients Decrease in bone density may occur. Bone density should be monitored for patients on long-term therapy Pregnancy Class C: Acthar has been shown to have an embryocidal effect and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus Adverse Reactions
Common adverse reactions for Acthar are similar to those of corticosteroids and include fluid retention, alteration in glucose tolerance, elevation in blood pressure, behavioral and mood changes, increased appetite and weight gain Specific adverse reactions reported in IS clinical trials in infants and children under 2 years of age included: infection, hypertension, irritability, Cushingoid symptoms, constipation, diarrhea, vomiting, pyrexia, weight gain, increased appetite, decreased appetite, nasal congestion, acne, rash, and cardiac hypertrophy. Convulsions were also reported, but these may actually be occurring because some IS patients progress to other forms of seizures and IS sometimes mask other seizures, which become visible once the clinical spasms from IS resolve Other adverse events reported are included in the full Prescribing Information.
Please see full Prescribing Information .
ABOUT MALLINCKRODT
Mallinckrodt is a global business that develops, manufactures, markets and distributes specialty pharmaceutical products and therapies. Areas of focus include autoimmune and rare diseases in specialty areas like neurology, rheumatology, nephrology, pulmonology and ophthalmology; immunotherapy and neonatal respiratory critical care therapies; analgesics and gastrointestinal products. To learn more about Mallinckrodt, visit www.mallinckrodt.com .
Mallinckrodt uses its website as a channel of distribution of important company information, such as press releases, investor presentations and other financial information. It also uses its website to expedite public access to time-critical information regarding the company in advance of or in lieu of distributing a press release or a filing with the U.S. Securities and Exchange Commission (SEC) disclosing the same information. Therefore, investors should look to the Investor Relations page of the website for important and time-critical information. Visitors to the website can also register to receive automatic e-mail and other notifications alerting them when new information is made available on the Investor Relations page of the website.
CONTACTS
For Trade Media Inquiries
Caren Begun
Green Room Communications
201-396-8551
caren@greenroompr.com
For Financial/Dailies Media Inquiries
Daniel Yunger
Kekst CNC
212-521-4879
mallinckrodt@kekstcnc.com
Investor Relations
Daniel J. Speciale , CPA
Investor Relations and Strategy Officer
314-654-3638
daniel.speciale@mnk.com
Mallinckrodt , the “M” brand mark and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company. Other brands are trademarks of a Mallinckrodt company or their respective owners. © 2019 Mallinckrodt . US-1900004 1/19
[1] Alhamad T, Dieck JM, Younus U, et al. ACTH gel in resistant focal segmental glomerulosclerosis after kidney transplantation. Transplantation . 2019;103: 202–209.
[2] Korbet SM. Clinical picture and outcome of primary focal segmental glomerulosclerosis. Nephrol Dial Transplant. 1999;14 Suppl 3:68-73.
[3] H.P. Acthar ® Gel (repository corticotropin injection) [prescribing information]. Mallinckrodt ARD, Inc.
[4] Troyanov et al. J Am Soc Nephrol. 2005;16(4):1061–1068.
View original content to download multimedia: http://www.prnewswire.com/news-releases/data-on-use-of-mallinckrodts-hp-acthar-gel-repository-corticotropin-injection-in-patients-with-rare-cause-of-nephrotic-syndrome-published-in-transplantation-300772221.html
SOURCE Mallinckrodt plc

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<h1></h1>

I was on prednisone twice last year, and every time I would try to taper, my symptoms came back. Also, I had a lot of trouble sleeping and night sweat too. I eventually started Remicade and it has been a lifesaver for me.

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Intravenous Cyclophosphamide Therapy for Anti-IFN-Gamma Autoantibody-Associated Mycobacterium abscessus Infection

<h1>Intravenous Cyclophosphamide Therapy for Anti-IFN-Gamma Autoantibody-Associated Mycobacterium abscessus Infection</h1>

Intravenous Cyclophosphamide Therapy for Anti-IFN-Gamma Autoantibody-Associated Mycobacterium abscessus Infection

Research Article Intravenous Cyclophosphamide Therapy for Anti-IFN-Gamma Autoantibody-Associated Mycobacterium abscessus Infection
1 Division of Infectious Diseases and Tropical Medicine, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand 2 Division of Rheumatology, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand 3 Cellular and Molecular Immunology Unit, Centre for Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
Correspondence should be addressed to Ploenchan Chetchotisakd ;
Received 14 August 2018; Accepted 7 November 2018; Published 30 December 2018
Academic Editor: Theresa Hautz
Copyright © 2018 Ploenchan Chetchotisakd et al. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract
Introduction . Anti-interferon-gamma (IFN- γ ) autoantibodies are increasingly recognized as a cause of adult-onset immunodeficiency (AOID) worldwide. These patients are susceptible to various intracellular pathogens especially nontuberculous mycobacteria. Most of the patients have a refractory clinical course. Herein, we report the use of immunotherapy with pulse intravenous cyclophosphamide (IVCY) in patients who had progressive, refractory Mycobacterium abscessus infection. Method . We included patients, seen at Srinagarind Hospital, Thailand, infected with M. abscessus , who had received ≥3 courses of parenteral antibiotics within the last 12 months and who received pulse IVCY with a tapering dose of prednisolone. Results . There were 8 AOID patients who met the criteria and received pulse IVCY between January 2011 and December 2015. One patient was lost to follow-up after 5 courses of IVCY: he had died at home 3 months later. Five patients had favorable outcomes: 2 were able to discontinue NTM therapy, and 3 had stable disease and were on NTM treatment without hospitalization for parenteral antibiotics. Two patients relapsed and needed hospitalization. The IFN- γ Ab titers among the 7 patients were significantly decreased during treatment, and the median initial antibody titer started at 200,000 and then decreased to 5,000 after 2 years of treatment ( ). The antibody titer reduction among responsive vs. nonresponsive patient was significantly different after 6 months of treatment: the median antibody titer was 5,000 and 100,000, respectively ( ). Conclusion . IVCY therapy might be an alternative treatment for AOID patients infected with M. abscessus and refractory to antimycobacterial therapy. 1. Introduction
Anti-interferon- γ (IFN- γ ) autoantibodies are increasingly recognized as a cause of adult-onset immunodeficiency (AOID) worldwide [ 1 – 19 ]. These patients are susceptible to various intracellular pathogens especially nontuberculous mycobacteria (NTM). The majority of patients have a persistent NTM infection and require long-term antimycobacterial therapy [ 20 ]. Some patients infected with rapidly growing mycobacteria (RGM) have recurrent disease despite continuous oral antimycobacterial treatment and need hospitalization for parenteral imipenem. Various adjunctive therapies have been used to treat patients with anti-IFN- γ autoantibodies [ 3 , 4 , 21 – 25 ], including B cell depletion therapy with rituximab which has attracted much attention. Owing to economic constraints, rituximab is not accessible through the Thai National Health Insurance program for off-label treatment.
Cyclophosphamide is an alkylating agent affecting depletion of both B and T cells, hence reducing the production of pathogenic autoantibodies. Intravenous cyclophosphamide (IVCY) has been used successfully as an induction therapy for severe lupus nephritis, either 6 monthly pulses of IVCY (NIH regimen) [ 26 ] or 6 pulses of lower-dose IVCY every 2 weeks (Euro-Lupus Nephritis Trail) [ 27 ]. The low-dose regimen was found to be associated with half as many severe infections as compared to the high-dose regimen, and long-term outcomes did not differ at the 10-year follow-up [ 28 ]. Currently, IVCY has been used as a standard regimen particularly for severe autoimmune and autoinflammatory diseases such as systemic lupus erythematosus (SLE) [ 29 – 32 ], active alveolitis from systemic sclerosis [ 33 – 35 ], antineutrophil cytoplasmic antibodies- (ANCA-) associated primary vasculitis syndrome [ 36 – 38 ], and other autoimmune diseases [ 39 – 44 ].
Plasmapheresis followed by pulse cyclophosphamide has been successfully treated in an AOID patient with recurrent MAC infection [ 21 ]. Herein, we report the use of immunotherapy with intravenous cyclophosphamide (IVCY) in 8 AOID patients with a high titer of anti-IFN- γ autoantibodies who had progressive refractory M. abscessus infection needing frequent hospitalization for parenteral antibiotics. 2. Methods
This study is a retrospective study and has been approved by our ethics committee (HE601199). 2.2. Patients and Immunotherapy
All patients were seen at Srinagarind Hospital, a tertiary care university hospital. The standard regimen for treating AOID patients infected with RGM is a combination of oral antimycobacterial agents, mostly macrolides and fluoroquinolones. If they have progressive disease—despite being continuously on oral antimycobacterial treatment—they will be hospitalized for parenteral antibiotic treatment (i.e., particularly imipenem for 2–4 weeks).
We included patients who received ≥3 courses of parenteral antibiotics within 12 months and who received pulse IVCY. The regimen consists of methylprednisolone 1,000 mg intravenous on the last day of parenteral antibiotics followed by oral prednisolone 30 mg/day and IVCY 400 mg every 2 weeks for 6 cycles, then IVCY 400 mg every 4–6 weeks for 3 cycles plus oral prednisolone 15 mg/day, then IVCY 400 mg every 8–12 weeks for 3 cycles and oral prednisolone 10 mg/day, and then IVCY 400 mg every 12 weeks and oral prednisolone 5 mg/day until 2 years of therapy was completed. All patients received a combination of oral antimycobacterial treatment continuously. 2.3. Clinical Monitoring
Patients underwent routine safety monitoring during the IVCY therapy, including complete blood count with differentials, urine analysis, and renal and hepatic function chemistries. We also monitored their anti-IFN- γ titer. Disease activity was assessed by observing clinical signs and evidence of active infection on computed tomography, pathology, culture, or smear as indicated. Treatment and clinical data were collected by review of chart records. 2.4. Determination of IFN- γ Autoantibody Titers
A method for determining anti-IFN- γ autoantibody titer was previously described [ 20 , 45 ]. Briefly, a 96-well polystyrene plate (Nunc) was precoated with 100  μ l of anti-human IFN- γ capture antibody (BD Biosciences) overnight at 4°C. On the day of the experiment, the precoated plate was washed 3 times with 0.05% Tween20 in phosphate-buffered saline (PBS) and then blocked with 200  μ l of 10% fetal bovine serum in PBS for 2 h at room temperature. Meanwhile, plasma samples were diluted with 300 pg/ml of recombinant human IFN- γ at 1 : 100, 1 : 1,000, 1 : 5,000, 1 : 10,000, 1 : 50,000, 1 : 100,000, 1 : 200,000, 1 : 400,000, 1 : 800,000, and 1 : 1,600,000 before being incubated at 37°C for 1 h. The preincubated diluted plasma samples (100  μ l) were added to the plate and incubated at room temperature for 1 h. After washing 5 times with 0.05% Tween20-PBS, a 100  μ l mixture of horseradish peroxidase (HRP), tagged streptavidin, and biotinylated anti-human IFN- γ detection antibody (BD Biosciences) was added to the plate and incubated at room temperature for 1 h. The plate was washed 7 times before adding 100  μ l of tetramethylbenzidine (TMB) substrate (BD Biosciences), which was incubated at room temperature for 15 min. The reaction was stopped by adding 25  μ l of 2 N H 2 SO 4 . Absorbance was measured at 450/570 nm by spectrophotometry.
The level of detectable human IFN- γ was calculated according to the standard curve from each plate. The percentage of neutralizing IFN- γ from each diluted plasma sample was calculated according to the equation below. The highest plasma dilution that resulted in ≥50% neutralization of the IFN- γ was considered a positive titer.
GraphPad Prism version 6 (GraphPad) was used for the statistical analysis. Statistical significance was determined using ANOVA with Dunnett’s multiple comparisons test.
All the data used to support the findings of this study are included within the article. 3. Results 3.1. Patients
There were 8 AOID patients who met the criteria and received pulse IVCY between January 2011 and December 2015. All of the patients had M. abscessus lymphadenitis along with other organ involvements. All but two patients were coinfected with other opportunistic infections. All of the patients had had progressive mycobacterial infection for over 10–48 months. The median NTM infection was 17 months before IVCY therapy. The patients received 3-6 courses of parenteral antimicrobial (mostly imipenem) within 12 months prior to the IVCY.
Table 1 summarizes the clinical data and outcomes of disseminated M. abscessus -infected patients treated with IVCY. Patients received 5–25 cycles of IVCY (median, 17 cycles). There were no serious laboratory test results related to cyclophosphamide during the IVCY therapy. Patient #1 received 5 courses of IVCY and then was lost to follow-up: he had died at home some 3 months after we lost contact with him. (Patient #1 was censored from the analysis.) Among the 7 evaluable cases, 5 had favorable outcomes: 2 (patients #2 and #3) had complete remission and were able to discontinue the NTM therapy while 3 (patients #4, #5, and #6) had stable disease but remained on NTM treatment without the need of hospitalization for parenteral antibiotics. Two (patients #7 and #8) relapsed and needed hospitalization. Patient #7 had enlarged lymph nodes after 12 cycles of IVCY and needed hospitalization for imipenem; after which, he resumed IVCY for another 3 cycles but developed Herpes zoster ophthalmicus which required admission for administration of parenteral acyclovir. He had a persistent enlarged epitrochlear lymph node after 25 cycles of IVCY. Patient #8 had 2 relapses requiring hospitalization for parenteral imipenem. Table 1: Clinical data and outcomes among disseminated M. abscessus -infected patients treated with intravenous cyclophosphamide (IVCY). 3.2. Anti-IFN- γ Autoantibody Titers
The anti-IFN- γ Ab titers among the 7 evaluable patients were significantly decreased during treatment. The median initial antibody titer starting at 200,000 then was decreased to 5,000 after 2 years of treatment ( ). The median antibody titers started to be significantly reduced 1 month after receiving IVCY (Figure 1 ). Antibody titer reduction among responsive patients ( ) vs. nonresponsive patients ( ) was significantly different after 6 months of treatment (median antibody titer was 5,000 and 100,000, respectively) ( ). Antibody titer among the responsive patients started at between 100,000 and 200,000 and was reduced to around 5,000 (range, 1,000–10,000). The antibody titer of nonresponsive patients started at between 200,000 and 400,000 and was reduced to between 10,000 and 200,000 after the first year of treatment and to 100,000 after the second year of treatment. Figure 1: Anti-IFN- γ autoantibody titer changes in plasma from responsive patients ( , close circle (●)) and nonresponsive patients ( , open circle (○)) at different time points after receiving intravenous cyclophosphamide (IVCY) pulse therapy. (a) Align dot plot with bar graph represents the median anti-IFN- γ autoantibody titer changing dynamic at each time point in all 7 cases. (b) Scatter dot plot with bar graph compares the median titer between responsive and nonresponsive patients. Statistical significance was determined using ANOVA with Dunnett’s multiple comparisons test; ns: nonsignificant; and .
Among the 5 responsive patients, their anti-IFN- γ autoantibody titers were followed for 1 year after completing the IVCY pulse therapy (Figure 2 ). The median anti-IFN- γ autoantibody titer had increased from 5,000 to 10,000 three months after discontinuation of treatment, albeit the difference was not statistically significant. The median titers remained stable for up to 12 months. Figure 2: Anti-IFN- γ autoantibody titers of responsive patients after stopping IVCY pulse therapy. Median anti-IFN- γ autoantibody titers in plasma from responsive patients ( ) were followed for 1 year at different time points after stopping IVCY pulse therapy. Statistical significance was determined using ANOVA with Dunnett’s multiple comparisons test; ns: nonsignificant. 4. Discussion
Our patients had extensive disease as a result of M. abscessus infection, which progressed over the years: the median duration of infection was 17 months. All of the patients had lymphadenitis along with other sites of M. abscessus infection (Table 1 ). All but two had coinfection with other opportunistic infections. The patients were refractory to antimycobacterial treatment, so we sought an adjunctive immunotherapy. Rituximab has been used in AOID patients associated with mycobacterial infection with clinical improvement [ 22 – 25 ]; among 7 patients reported, they received 4-18 cycles of rituximab over 1-5 years of treatment. Since rituximab is not accessible in our setting, we tried to treat our AOID patients with an available immunosuppressant drug. We used an IVCY regimen resembling the Euro-Lupus protocol for lupus nephritis in combination with a single pulse of methyl prednisolone followed by a moderate dose of prednisolone for the first 3 months and maintenance with low-dose corticosteroid until the end of study. We treated only patients who had a protracted clinical course, defined as having received ≥3 courses of parenteral antibiotic within 12 months. We started the IVCY treatment regimen at the end of the parenteral therapy after the disease was controlled.
Among the 7 evaluable cases, 5 had a clinical response. To date, in two of our patients, the M. abscessus infection was cleared, and the patients were able to discontinue NTM treatment. Three of the remaining patients had stable disease and continued treatment for M. abscessus without needing to be hospitalized for parenteral therapy. Only 2 patients did not respond; they relapsed and needed hospitalization for imipenem therapy.
We demonstrated that IVCY reduced IFN- γ Ab titers significantly. Among the 7 patients studied, the median initial titers decreased after 2 years of treatment ( ) and the titers started to decline within one month of receiving IVCY (Figure 1(a) ). Comparing between responders and nonresponders, the reduction in Ab titers among responders was significantly greater than that among nonresponders after 6 months of therapy throughout the end of 2 years of therapy (Figure 1(b) ). The IFN- γ titers among responders at the end of treatment ranged between 1,000 and 5,000 while for nonresponders’ titers, they averaged 50,000. Our findings suggest that IFN- γ Ab titers are correlated to clinical response; thus, an early drop in IFN- γ titer is a predictor of a good outcome of IVCY treatment. The use of Ab titers to monitor disease activity or to determine when to discontinue antimycobacterial treatment needs further investigation.
Patients #7 and #8 received an extended course of IVCY (25 and 20 cycles, respectively). The lack of clinical improvement suggests that extension of IVCY treatment does not help nonresponders to reduce Ab titers to the level of a responsive titer. Among IVCY nonresponders, switching to other immunosuppressive drugs (i.e., mycophenolate mofetil, azathioprine, or calcineurin inhibitor) may be considered. Importantly, Ab titers among responders were stable up to one year after stopping IVCY therapy.
The present study had some limitations. First, it was a retrospective study, so some information might have been lost. Second, the study had a small sample size but that is partly because AOID is uncommon, and not all cases of anti-IFN- γ autoantibody-mediated disseminated NTM require immunotherapy. Third, we did not identify the isolates of M. abscessus to subspecies level nor identify an inducible macrolide resistance gene which might have effect on the treatment outcomes. Fourth, we did not perform plasma-mediated inhibition of IFN- γ -stimulated STAT-1 phosphorylation; notwithstanding, we previously demonstrated that plasma specimens containing anti-interferon- γ autoantibodies inhibited interferon- γ -induced STAT1 phosphorylation [ 1 ]. The Ab titers were correlated to clinical response; thus, we hypothesize that the IFN- γ antibodies in our patients were functioning. Despite these limitations, our results offer valuable clinical information vis-à-vis patients with anti-IFN- γ autoantibody-associated M. abscessus infection who had refractory disease in a resource-limited setting.
In conclusion, IVCY therapy might be an alternative adjunctive immunotherapy for AOID patients infected with M. abscessus and refractory to antimycobacterial treatment since it improved clinical outcomes and reduced the titer of anti-IFN- γ autoantibodies. A rapid decline in the titer of anti-IFN- γ antibody after 6 months of immunosuppressive treatment predicted a good outcome. In cases of a persistently high anti-IFN- γ antibody titer, rather than extending the use of IVCY, the clinician should consider switching to other immunosuppressive drug(s) with different target(s) of action. To avoid serious infection related to the use of long-term cyclophosphamide, a better outcome may be achieved by using a less toxic immunosuppressive drug. Data Availability
The data used to support the findings of this study are included within the article. Disclosure
This study has been presented as conference abstract in 28th ECCMID according to the following link: https://www.escmid.org/escmid_publications/escmid_elibrary/material/?mid=64583 . Conflicts of Interest
None of the authors declared conflict of interests relevant for the present work. Acknowledgments
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