Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease

BACKGROUND Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and inter-leukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn’s disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. METHODS We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn’s Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). RESULTS The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P = 0.005 and P = 0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. CONCLUSIONS Among patients with moderately to severely active Crohn’s disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355.

On the Action of Cyclosporine A, Rapamycin and Tacrolimus on M. avium Including Subspecies paratuberculosis

BACKGROUND: Mycobacterium avium subspecies paratuberculosis (MAP) may be zoonotic. Recently the "immuno-modulators" methotrexate, azathioprine and 6-MP and the "anti-inflammatory" 5-ASA have been shown to inhibit MAP growth in vitro. We concluded that their most plausible mechanism of action is as antiMAP antibiotics. The "immunosuppressants" Cyclosporine A, Rapamycin and Tacrolimus (FK 506) treat a variety of "autoimmune" and "inflammatory" diseases. Rapamycin and Tacrolimus are macrolides. We hypothesized that their mode of action may simply be to inhibit MAP growth. METHODOLOGY: The effect on radiometric MAP (14)CO(2) growth kinetics of Cyclosporine A, Rapamycin and Tacrolimus on MAP cultured from humans (Dominic & UCF 4) or ruminants (ATCC 19698 & 303) and M. avium subspecies avium (ATCC 25291 & 101) are presented as "percent decrease in cumulative GI" (%-DeltacGI.) PRINCIPAL FINDINGS: The positive control clofazimine has 99%-DeltacGI at 0.5 microg/ml (Dominic). Phthalimide, a negative control has no dose dependent inhibition on any strain. Against MAP there is dose dependent inhibition by the immunosuppressants. Cyclosporine has 97%-DeltacGI by 32 microg/ml (Dominic), Rapamycin has 74%-DeltacGI by 64 microg/ml (UCF 4) and Tacrolimus 43%-DeltacGI by 64 microg/ml (UCF 4) CONCLUSIONS: We show heretofore-undescribed inhibition of MAP growth in vitro by "immunosuppressants;" the cyclic undecapeptide Cyclosporine A, and the macrolides Rapamycin and Tacrolimus. These data are compatible with our thesis that, unknowingly, the medical profession has been treating MAP infections since 1942 when 5-ASA and subsequently azathioprine, 6-MP and methotrexate were introduced in the therapy of some "autoimmune" and "inflammatory" diseases

Inflammatory bowel disease: past, present, and future

Crohn’s disease and ulcerative colitis, collectively known as the inflammatory bowel diseases (IBD), are largely diseases of the twentieth century, and are associated with the rise of modern, Westernized industrial society. Although the causes of these diseases remain incompletely understood, the prevailing model is that the intestinal flora drives an unmitigated intestinal immune response and inflammation in the genetically susceptible host. A review of the past and present of these diseases shows that detailed description preceded more fundamental elucidation of the disease processes. Working out the details of disease pathogenesis, in turn, has yielded dividends in more focused and effective therapy for IBD. This article highlights the key descriptions of the past, and the pivotal findings of current studies in disease pathogenesis and its connection to medical therapy. Future directions in the IBD will likely explicate the inhomogeneous causes of these diseases, with implications for individualized therapy

Bedside Leukoreduction of Cellular Blood Components in Preventing Cytomegalovirus Transmission in Pediatric Allogeneic Hematopoietic Stem Cell Transplant Recipients.

Abstract Background: Leukoreduction of cellular blood components is a standard practice in the Blood Bank to prevent cytomegalovirus transmission. This process is of utmost importance in our pediatric hematopoietic stem cell transplant (HSCT) patients who are immunocompromized and thus are susceptible to this infection. The objective of this study is to show that bedside leukoreduction of cellular blood products is a safe alternative to blood components from a very limited pool of CMV seronegative donors in pediatric HSCT recipients. Methods: We conducted a retrospective analysis of our pediatric HSCT performed between 02/23/96 and 03/11/05. Screening for CMV antibody in our donors was discontinued in 02/23/96. Instead, we switched to bedside leukoreduction for patients who need CMV negative blood products, including the pediatric HSCT recipients. Transplant recipients and donors were tested for CMV antibody prior to transplant date. Patients and donors who were CMV seronegative pairs were included in this study. Transfusion history of these patients was reviewed. CMV surveillance was performed by antigenemia assays once to twice weekly. Clinical evidence for CMV infection such as viral cultures of urine, blood, bronchial washings and pathology reports were reviewed. Results: A total of 12 CMV-seronegative patient-donor pairs were identified among 128 transplants performed in this time period. Patients excluded from this study are 18 years of age and above and those who had received CMV screened blood products. Characteristics of these patients are: Age ranges from 35 months to 17 years; 9 were males and 3 were females; Diagnoses: acute lymphoblastic leukemia(5); acute myelogenous leukemia(3), Hodgkin’s disease,(1);Aplastic anemia,(1);Malignant Osteopetrosis(1) and CML (1). Three patients received mismatched unrelated donor cord blood transplant;3 had matched unrelated bone marrow transplants; 5 had matched sibling donor; and one had two transplants from his mother. All patients received red cells and platelets from random donors;10/12 received single donor platelets;3/12 had fresh frozen plasma;3/12 had granulocyte transfusions;1/12 had cryoprecipitate and 11/12 received IVIg. All blood products were infused at bedside using a leukoreduction filter(Baxter Healthcare Corp., Deerfield, IL). 2/12(17%) had positive CMV antigenemia assays. One patient had CMV antigenemia testing positive 22 days pre-transplant and 149 days post-transplant. He did not have evidence of CMV disease and there was no subsequent CMV seroconversion. The other patient had positive CMV antigenemia 27 days post-transplant. The first patient mentioned had been infused with 8 units of granulocytes, while the later did not receive any granulocyte unit. Both patients had anti-viral therapy. A third patient seroconverted 3 months post-transplant. All CMV antigenemia testing on this patient were negative and he had no evidence of CMV disease. Conclusion: Our study showed that bedside leukoreduction of cellular blood products, coupled with CMV surveillance may be a safe alternative to blood components from CMV seronegative donors for pediatric HSCT patients.</jats:p

Costs of blood transfusion: a process-flow analysis.

PURPOSE To determine the cost of transfusing 2 units (U) of packed RBCs at a comprehensive cancer center. METHODS We performed a process-flow analysis to identify all costs of transfusing 2 U of allogeneic packed RBCs on an outpatient basis to patients with either (1) solid tumor who did not undergo bone marrow transplantation (BMT), (2) solid tumor who underwent BMT, (3) hematologic malignancy who did not undergo BMT, (4) hematologic malignancy who underwent allogeneic BMT, or (5) hematologic malignancy who underwent autologous BMT. We conducted structured interviews to determine the personnel time used and physical resources necessary at all steps of the transfusion process. RESULTS The mean cost of a 2-U transfusion of allogeneic packed RBCs was $548,$565, $569,$569, and $566 for patients with non-BMT solid tumor, BMT solid tumor, non-BMT hematologic malignancy, allogeneic BMT hematologic malignancy, and autologous BMT hematologic malignancy, respectively. Sensitivity analysis showed that total transfusion costs were sensitive to variations in the amount of clinician compensation and overhead costs, but were relatively insensitive to reasonable variations in the direct costs of blood tests and the blood itself, or the probability or extent of transfusion reaction. CONCLUSION The costs of the transfusion of packed RBCs are greater than previously analyzed, particularly in the cancer care setting. </jats:sec