ITI with high-dose FIX and combined immunosuppressive therapy in a patient with severe haemophilia B and inhibitor

2009 ◽  
Vol 29 (02) ◽  
pp. 155-157 ◽  
Author(s):  
H. Hauch ◽  
J. Rischewski ◽  
U. Kordes ◽  
J. Schneppenheim ◽  
R. Schneppenheim ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Immunosuppressive Agents ◽  
Tolerance Induction ◽  
Intravenous Immunoglobulins ◽  
Factor Ix ◽  
High Dose ◽  
Allergic Reactions ◽  
Success Rates ◽  
Serious Infections ◽  
History Of

SummaryInhibitor development is a rare but serious event in hemophilia B patients. Management is hampered by the frequent occurrence of allergic reactions to factor IX, low success rates of current inhibitor elimination protocols and the risk of development of nephrotic syndrome. Single cases of immune tolerance induction (ITI) including immunosuppressive agents like mycophenolat mofetil (MMF) or rituximab have been reported. We present a case of successful inhibitor elimination with a combined immune-modulating therapy and high-dose factor IX (FIX). This boy had developed a FIX inhibitor at the age of 5 years and had a history of allergic reactions to FIX and to FEIBA→. Under on-demand treatment with recombinant activated FVII the inhibitor became undetectable but the boy suffered from multiple joint and muscle bleeds. At the age of 11.5 years ITI was attempted with a combination of rituximab, MMF, dexamethasone, intravenous immunoglobulins and high-dose FIX. The inhibitor did not reappear and FIX half-life normalized. No allergic reaction, no signs of nephrotic syndrome and no serious infections were observed.

Successful second ITI with factor IX and combined immunosuppressive therapy

2014 ◽  
Vol 34 (S 01) ◽  
pp. S5-S8 ◽  
Author(s):  
R. Schneppenheim ◽  
J. Schrum ◽  
C. Bokemeyer ◽  
F. Langer ◽  
K. Holstein
Keyword(s):  
Nephrotic Syndrome ◽  
Immunosuppressive Therapy ◽  
Case Reports ◽  
Intravenous Immunoglobulins ◽  
Factor Ix ◽  
High Dose ◽  
Allergic Reactions ◽  
Success Rates ◽  
Skin Reactions ◽  
Haemophilia B

SummaryImmune tolerance induction (ITI) in patients with haemophilia B and inhibitors may be complicated by anaphylactic reactions and nephrotic syndrome with lower success rates than in haemophilia A (25% vs. 50–90%). According to case reports, immunosuppressive therapy in addition to high doses of factor IX (FIX) appears to be promising. We report an 18-year-old patient with severe haemophilia B and a FIX inhibitor with a maximum titre of 2.6 Bethesda units and allergic skin reactions to FIX infusions. At 5 years of age, this patient already had a FIX inhibitor with allergic reactions to FIX and activated prothrombin complex concentrate. ITI at 11 years of age with high-dose FIX, de-xamethasone, rituximab, mycophenolate mofetil and intravenous immunoglobulins had induced a sustained response until the current presentation.The patient was restarted on the same ITI regimen with aforementioned immunosup-pressants, which were initiated one week before high-dose FIX. No allergic reactions, nephrotic syndrome or serious infection occurred during ITI. The FIX inhibitor was unde-tectable after five weeks of treatment and remained so until 19 months of follow-up.

Oral Induction of Immunological Tolerance to Chromium in the Guinea Pig

1990 ◽  
Vol 69 (10) ◽  
pp. 1634-1639 ◽  
Author(s):  
K.J.J. Vreeburg ◽  
I.M.W. Van Hoogstraten ◽  
B.M.E. Von Blomberg ◽  
K. De Groot ◽  
R.J. Scheper
Keyword(s):  
Skin Testing ◽  
Tolerance Induction ◽  
Immunological Tolerance ◽  
Metal Alloys ◽  
High Dose ◽  
Allergic Reactions ◽  
Dose Frequency ◽  
Chromium Powder ◽  
Adverse Side Effects ◽  
Skin Contact

Metal alloys used in dentistry may elicit adverse side-effects. Contact allergic reactions to metals released from such alloys are among the most frequently encountered problems. In an earlier study, we observed that oral contacts with nickel or chromium salts did not sensitize, but rather decreased the risk of subsequent sensitization to these metals. In the present study, we focused on chromium allergy and extended our earlier observations by further dose-response studies. In addition, we compared different chromium valencies as to their potential oral tolerogenic effects. Development of immunological tolerance in chromium-fed guinea pigs was demonstrated by their inability to develop chromium hypersensitivity after a subsequent immunization attempt. For these studies, the techniques of immunization and skin testing were first improved. One feeding with a high dose of K2Cr2O7, (containing hexavalent chromium) was effective in full tolerance induction. In contrast, trivalent chromium (CrCl3) induced a distinctly lower degree of tolerance, whereas metallic chromium powder was not detectably tolerogenic after a limited number of feedings. Dose-frequency-response studies with K2Cr2O 7, showed that full tolerance could also be induced by an increase in the number of feedings with sub-optimal tolerogenic doses. The present results therefore support our hypothesis that long-lasting oral contact with chromium-releasing metal alloys may ultimately result in strong immune tolerance to this metal in subjects without previous skin contact with it. This view is further supported by recent insights into the unique tolerogenicity of oral, as compared with gastro-intestinal, allergenic contacts.

scholarly journals Noncoagulation inhibitory factor VIII antibodies after induction of tolerance to factor VIII in hemophilia A patients

Blood ◽  
1990 ◽  
Vol 75 (2) ◽  
pp. 378-383 ◽  
Author(s):  
IM Nilsson ◽  
E Berntorp ◽  
O Zettervall ◽  
B Dahlback
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Protein A ◽  
Gel Filtration ◽  
Tolerance Induction ◽  
Factor Ix ◽  
High Dose ◽  
Void Fractions ◽  
Igg4 Antibody ◽  
Induction Of Tolerance

Abstract We recently described tolerance induction with factor VIII/IX, cyclophosphamide, and high-dose intravenous IgG in hemophilia A or B patients with coagulation inhibitory antibodies. Circulating noninhibitory antibodies complexed with factor IX have been demonstrated in tolerant hemophilia B patients. Similar findings are now described in six tolerant hemophilia A patients. Complexes between factor VIII and the ‘tolerant’ antibody were demonstrated by subjecting plasma to gel filtration chromatography, void fractions containing factor VIII/vWF complexes being collected and adsorbed to protein A. Using 125I-labeled F(ab')2 fragments against IgG subclass and factor VIII antigen, complexes between an IgG4 antibody and factor VIII were found to adsorb to protein A. After infusion of factor VIII to tolerant patients, all factor VIII circulated in complex with IgG4 antibody. In three of the patients, the ‘tolerant’ antibodies inhibited an ELISA specific for factor VIII light chain but, unlike the pretolerant antibodies, did not bind radiolabeled factor VIII heavy chain. Although after induction of tolerance the patients still have circulating IgG4 antibodies against factor VIII, the antibodies differ in specificity, lack coagulation inhibitory activity, and do not enhance the rate of elimination of factor VIII.

Novel Treatment Approaches in Combination with Rituximab for Immune Tolerance Induction in Severe Hemophilia B.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3975-3975 ◽  
Author(s):  
Amanda M. Brandow ◽  
Rowena C. Punzalan ◽  
Karen Stephany ◽  
Craig Helsell ◽  
Joan C. Gill
Keyword(s):  
Immune Tolerance ◽  
High Titer ◽  
Tolerance Induction ◽  
Factor Ix ◽  
Hemophilia B ◽  
High Dose ◽  
Subdural Hemorrhage ◽  
Severe Hemophilia ◽  
Immune Tolerance Induction ◽  
Novel Approaches

Abstract Although only 4–5% of patients with severe Hemophilia B (HB) develop factor IX (FIX) antibodies that cause inactivation of transfused FIX concentrate (conc), about 1/3 of these are associated with life-threatening anaphylactic reactions; immune tolerance induction (ITI) with high-dose FIX conc is often unsuccessful. We present individualized novel approaches to ITI in 2 boys with severe HB and high-responding inhibitors. ELISA assays utilizing recombinant FIX (rFIX) to capture patient IgG followed by detection with subclass specific monoclonal antibodies were developed to evaluate the characteristics of the factor IX inhibitors before, during and following ITI. Patient 1, a 2 yo boy, presented with a subdural hemorrhage; his inhibitor titer was 14 BU. He was treated with recombinant VIIa (rVIIa), 200 mcg/kg followed by 100 mcg/kg q2 hours plus rFIX conc (BeneFix), 1000 U/kg prior to and post subdural hematoma evacuation; a continuous infusion, 40U/kg/hour rFIX conc was started. FIX:C was >100%, so rVIIa was discontinued and the rFIX infusion was continued to maintain FIX:C levels above 50%. Rituximab (375 mg/m2 q week x 4) was started. On the 6th day, he developed anamnesis; plasma FIX:C dropped to the 20% range in spite of increases in his rFIX conc drip to 68 u/kg/hour. Investigation of right leg edema revealed a large thrombus involving the popliteal, iliac and inferior vena cava with pulmonary embolism. In order to remove the inhibitor antibody and achieve plasma FIX levels that would allow safe anticoagulation with heparin, plasmapheresis with an immunoadsorption Protein A sepharose column (Fresenius) was undertaken. FIX:C levels were unexpectedly lower immediately following each cycle. Investigation of FIX: Ag and anti-FIX IgG, IgG1 and IgG4 by ELISA assays before and after each cycle revealed the presence of FIX: Ag and specific anti-FIX IgG in the column eluates. After the 5th cycle, increasing FIX:C levels allowed weaning of the rFIX conc; the thromboses completely resolved. The patient currently is on standard prophylactic doses of rFIX conc with expected recoveries with no evidence of inhibitor. Patient 2 was a 9 year old boy with a high responding anaphylactoid inhibitor; he had severe and frequent hemarthroses treated with rVIIa with variable success resulting in significant hemophilic arthropathy. He had previously received 2 courses of rituximab with recurrence of inhibitor 3 weeks post-therapy. Therefore, in order to suppress T-cell as well as B-cell immune responses, after desensitization with increasing infusions of rFIX conc, he was treated with cyclophosphamide (10 mg/kg IV on days 2, 3 and PO on days 4 and 5) a standard course of rituximab (375 mg/m2 on days 1, 8, 15, 22), IVIG (100 mg/kg on days 2–5) initially, and high dose rFIX conc, 100U/kg/day. He is now maintained on every-other monthly doses of rituximab and replacement doses of IVIG. As FIX levels rose during ITI, rFIX conc was weaned; eight months after initiation of ITI, he has expected recoveries of FIX: C on standard prophylactic doses of rFIX conc. Investigation of the nature of the patient’s inhibitors revealed that both patients had high titer IgG1 and IgG 4 anti-factor IX antibodies that disappeared after ITI. Unlike the persistence of non-inhibitory IgG4 factor VIII antibodies reported in some patients with hemophilia A, in these two patients, there was no detectable FIX-specific pan-IgG, IgG1 or IgG4 following ITI. We conclude that novel approaches to ITI can be successfully undertaken in severe HB patients with high titer factor IX inhibitors.

scholarly journals Noncoagulation inhibitory factor VIII antibodies after induction of tolerance to factor VIII in hemophilia A patients

Blood ◽  
1990 ◽  
Vol 75 (2) ◽  
pp. 378-383
Author(s):  
IM Nilsson ◽  
E Berntorp ◽  
O Zettervall ◽  
B Dahlback
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Protein A ◽  
Gel Filtration ◽  
Tolerance Induction ◽  
Factor Ix ◽  
High Dose ◽  
Void Fractions ◽  
Igg4 Antibody ◽  
Induction Of Tolerance

We recently described tolerance induction with factor VIII/IX, cyclophosphamide, and high-dose intravenous IgG in hemophilia A or B patients with coagulation inhibitory antibodies. Circulating noninhibitory antibodies complexed with factor IX have been demonstrated in tolerant hemophilia B patients. Similar findings are now described in six tolerant hemophilia A patients. Complexes between factor VIII and the ‘tolerant’ antibody were demonstrated by subjecting plasma to gel filtration chromatography, void fractions containing factor VIII/vWF complexes being collected and adsorbed to protein A. Using 125I-labeled F(ab')2 fragments against IgG subclass and factor VIII antigen, complexes between an IgG4 antibody and factor VIII were found to adsorb to protein A. After infusion of factor VIII to tolerant patients, all factor VIII circulated in complex with IgG4 antibody. In three of the patients, the ‘tolerant’ antibodies inhibited an ELISA specific for factor VIII light chain but, unlike the pretolerant antibodies, did not bind radiolabeled factor VIII heavy chain. Although after induction of tolerance the patients still have circulating IgG4 antibodies against factor VIII, the antibodies differ in specificity, lack coagulation inhibitory activity, and do not enhance the rate of elimination of factor VIII.

scholarly journals Immune Tolerance Induction for FIX Inhibitors Using Combined B and T Cell Immune Modulation Therapy in Severe Hemophilia B

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1193-1193 ◽  
Author(s):  
Yasmina L. Abajas ◽  
Paul Edward Monahan ◽  
Brenda Nielsen ◽  
Pia Petrini ◽  
Susanna Ranta ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Median Time ◽  
Immune Tolerance ◽  
Research Funding ◽  
Immune Modulation ◽  
Tolerance Induction ◽  
Factor Ix ◽  
Hemophilia B ◽  
Inhibitor Titer

Abstract Introduction Development of an inhibitor to Factor IX is a potentially life-threatening complication that occurs in 2-4% of severe hemophilia B patients. Attempt to eradicate these neutralizing alloantibodies with immune tolerance induction (ITI) regimens using prolonged repeated exposure to FIX fails to induce tolerance in ~70% of cases, and is limited by severe complications including FIX hypersensitivity and nephrotic syndrome. Cases of FIX ITI with immunosuppressive drugs have been reported infrequently. In light of increased understanding of the role of active T lymphocyte regulation of clotting factor-directed B lymphocyte-mediated humoral immunity, an approach combining immune modulating agents and frequent FIX infusions was reported by Beutel, et al (Haemostaseologie, 2009; 2014). We report a multi-institutional retrospective experience with combination immune modulation therapy (CIT), including B cell suppression with anti-CD20 monoclonal antibody Rituximab and T cell modulation using mycophenylate mofetil (MMF) with FIX ITI in 11 males with severe congenital hemophilia B. Methods The originally published regimen of Beutel, et al involves a 50 day course including FIX 100 IU/kg twice daily, rituximab 375 mg/m2 x 4 doses, mycophenolate (MMF) 300 mg/m2/dose daily, dexamethasone 6 mg/m2/dose pulses and IVIG 1 g/kg x 6 doses. Following individual Institutional Review Board approval, data on 11 patients was contributed by the INPH investigators and via outreach internationally and collected retrospectively using a uniform data collection form. Cases were included in the CIT series if the combination of FIX, rituximab and MMF was used. Approaches varied in the concomitant use of IVIG and pulse corticosteroids (dexamethasone or prednisone). Results CIT was the first immune tolerance therapy for 9/11 patients. Patients were 14-222 months of age at time of CIT, with a median time from inhibitor diagnosis to CIT 20 (range 0-207) months. Median historical peak inhibitor titer prior to initiation of CIT was 3.2 (range 1-42) BU/ml. Inhibitor titers at the initiation of CIT ranged from undetectable to 7 BU/ml. Eighty-onepercent of patients had a history of FIX hypersensitivity reaction. Prior to initiation of therapy, 27% of the patients underwent FIX desensitization during the initial course. The patients received FIX BID (9/11 patients) or QD (2/11 patients), 4 doses of rituximab 375 mg/m2, MMF for a minimum of 49 days (varying duration from 49-1247 days). IVIG was infused in 10/11 patients, with most receiving 3-7 doses during each course of CIT. 6/11 patients received between 2-10 courses of pulse corticosteroids during a CIT course. Each course of CIT achieved disappearance of the titer of FIX inhibitor at a median time of 1 month (range 1-41 months) Hypersensitivity reactions did not limit the courses of CIT, but did recur with inhibitor recurrence in 1 patient. Recurrence occurred in 6/11 patients at a median time of 11 months from time of CIT, in some cases soon after documented B cell recovery with a median inhibitor titer of 1.8 (range 0.7-7) BU/ml. In cases of recurrence, a negative inhibitor titer was achieved again in 1 patient by increasing FIX dose and in 4 patients who received additional courses of CIT. Repeat recurrence was seen in these patients following repeat CIT, although at low titer with a median of 1 BU/ml (range 1-4), allowing ongoing management with FIX in 3 of the 4. Overall, patients have had a median follow-up of 61 months following CIT, 9/11 patients are currently managed with factor IX for prophylaxis and bleeding, while 2/11 use bypassing agents. The most common complication was hospitalization for central venous catheter-related bacterial infection that occurred from < 1 to > 12 months after the use of rituximab in 3/11 patients. Nephrotic syndrome occurred in 3/11 patients. In each case, nephrotic syndrome responded to corticosteroids or re-initiation of CIT and FIX could be resumed. Conclusions FIX ITI with CIT targeting both B and T cells in hemophilia B is an effective means of achieving a negative inhibitor titer with tolerable safety in this series, allowing return to use of FIX for hemostasis and prophylaxis in most patients. Although recurrence is common and longer follow up is needed, when compared to the experience with using FIX alone, outcomes appear to be improved using CIT with FIX ITI as an initial approach. Disclosures Abajas: Bayer: Honoraria; CSL Limited: Honoraria. Allen:Shire: Employment, Equity Ownership. Oldenburg:Pfizer: Honoraria, Research Funding; Biogen: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Grifols: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Shire: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Swedish Orphan Biovitrum: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding.

scholarly journals What is the role of an extended half-life product in immune tolerance induction in a patient with severe hemophilia A and high-titer inhibitors?

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 648-649 ◽  
Author(s):  
Maissaa Janbain ◽  
Steven Pipe
Keyword(s):  
Immune Tolerance ◽  
Half Life ◽  
Hemophilia A ◽  
High Titer ◽  
Tolerance Induction ◽  
High Dose ◽  
Severe Hemophilia ◽  
Immune Tolerance Induction ◽  
History Of

Abstract A 10-year-old boy presents with a history of severe hemophilia A and high-titer inhibitor that had failed high-dose immune tolerance induction (ITI) with a recombinant factor VIII (rFVIII) product and a plasma-derived FVIII product. You are asked by his mother whether he should be tried on ITI with an extended half-life product, in particular, consideration of a rFVIIIFc concentrate.

scholarly journals High-Dose Azithromycin versus High-Dose Amoxicillin-Clavulanate for Treatment of Children with Recurrent or Persistent Acute Otitis Media

2003 ◽  
Vol 47 (10) ◽  
pp. 3179-3186 ◽  
Author(s):  
Antonio Arrieta ◽  
Adriano Arguedas ◽  
Pilar Fernandez ◽  
Stan L. Block ◽  
Paz Emperanza ◽  
...  
Keyword(s):  
Otitis Media ◽  
Clinical Success ◽  
Acute Otitis Media ◽  
High Dose ◽  
Success Rates ◽  
Double Blind ◽  
Amoxicillin Clavulanate ◽  
Risk Patients ◽  
History Of ◽  
Intent To Treat

ABSTRACT Infants and young children, especially those in day care, are at risk for recurrent or persistent acute otitis media (AOM). There are no data on oral alternatives to high-dose amoxicillin-clavulanate for treating AOM in these high-risk patients. In this double-blind, double-dummy multicenter clinical trial, we compared a novel, high-dose azithromycin regimen with high-dose amoxicillin-clavulanate for treatment of children with recurrent or persistent AOM. Three hundred four children were randomized; 300 received either high-dose azithromycin (20 mg/kg of body weight once a day for 3 days) or high-dose amoxicillin-clavulanate (90 mg/kg divided twice a day for 10 days). Tympanocentesis was performed at baseline; clinical response was assessed at day 12 to 16 and day 28 to 32. Two-thirds of patients were aged ≤2 years. A history of recurrent, persistent, or recurrent plus persistent AOM was noted in 67, 18, and 14% of patients, respectively. Pathogens were isolated from 163 of 296 intent-to-treat patients (55%). At day 12 to 16, clinical success rates for azithromycin and amoxicillin-clavulanate were comparable for all patients (86 versus 84%, respectively) and for children aged ≤2 years (85 versus 79%, respectively). At day 28 to 32, clinical success rates for azithromycin were superior to those for amoxicillin-clavulanate for all patients (72 versus 61%, respectively; P = 0.047) and for those aged ≤2 years (68 versus 51%, respectively; P = 0.017). Per-pathogen clinical efficacy against Streptococcus pneumoniae and Haemophilus influenzae was comparable between the two regimens. The rates of treatment-related adverse events for azithromycin and amoxicillin-clavulanate were 32 and 42%, respectively (P = 0.095). Corresponding compliance rates were 99 and 93%, respectively (P = 0.018). These data demonstrate the efficacy and safety of high-dose azithromycin for treating recurrent or persistent AOM.

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