tacrolimus and tofacitinib

The success of solid-organ transplantation was made possible by recognizing that destruction of the graft is caused by an alloimmune-mediated process. For the past decade, immunosuppressive protocols have used a combination of drugs that significantly decreased the rate of acute organ rejection. Despite advances in surgical and medical care of recipients of solid-organ transplants, long-term graft survival and patient survival have not improved during the past 2 decades. Current immunosuppression protocols include a combination of calcineurin inhibitors, such as tacrolimus, and antiproliferative agents (most commonly mycophenolate mofetil), with or without different dosing regimens of corticosteroids. Mammalian target of rapamycin inhibitors were introduced to be used in combination with cyclosporine-based therapy, but they did not gain much acceptance because of their adverse event profile. Belatacept, a costimulatory inhibitor, is currently being studied in different regimens in an effort to replace the use of calcineurin inhibitors to induce tolerance and to improve long-term outcomes. Induction therapy is now being used in more than 90% of kidney transplants and more than 50% cases of other solid-organ transplantation such as lung, heart, and intestinal transplants. As a result of these combination immunosuppressive (IS) therapy protocols, not only the incidence but also the intensity of episodes of acute rejection have decreased markedly, and at present 1-year graft and patient survival is almost 98% for kidney transplant recipients and approximately greater than 80% for heart and lung transplants. Evolving concepts include the use of donor-derived bone marrow mesenchymal cells to induce tolerance, to minimize the use of maintenance IS agents, and to prevent the development of adverse events associated with long-term use of maintenance IS therapy.

Topics: Abatacept; Alemtuzumab; Animals; Antibodies, Monoclonal, Humanized; Azathioprine; Bone Marrow Transplantation; Calcineurin Inhibitors; Cyclosporine; Disease Models, Animal; Everolimus; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lung Transplantation; Mycophenolic Acid; Piperidines; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Sirolimus; Tacrolimus

The common γ-chain (γ(c)) cytokines signal through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway and play pivotal roles in lymphocyte activation. We investigated the effect of immunosuppressive drugs targeting this pathway, the JAK inhibitor tofacitinib (CP-690,550) and the anti-interleukin (IL)-2R antibody basiliximab, as part of a phase 2 study.. After whole-blood activation with the γ(c) cytokines IL-2, IL-7, and IL-15, STAT5 phosphorylation was determined in T cells of de novo kidney transplantation patients treated with tofacitinib/basiliximab (n=5), calcineurin inhibitor (CNI) (cyclosporine A)/basiliximab (n=4) or CNI (tacrolimus)-based immunosuppression (n=6). The IC(50) for phosphorylated STAT (P-STAT) 5 inhibition by tofacitinib was determined in cytokine-activated CD4(+) and CD8(+) T cells from healthy individuals (n=4).. IC(50) was 26, 72, and 37 ng/mL for IL-2, IL-7, and IL-15 activation, in CD4(+) T cells, respectively; and 35, 61, and 76 ng/mL for IL-2, IL-7, and IL-15 activation, in CD8(+) T cells, respectively. In kidney transplantation patients, 7 days after starting tofacitinib/basiliximab treatment, cytokine-induced P-STAT5 was inhibited in CD4(+) T cells (92% for IL-2 activation, 60% for IL-7, and 75% for IL-15), which persisted for the 2-month study period. In contrast, CNI/basiliximab treatment did not affect IL-7-activated or IL-15-activated P-STAT5; only IL-2-activated P-STAT5 was reduced by 77% on day 7 and recovered to pretreatment levels within 2 months. CD8(+) T cells showed a comparable profile to CD4(+) T cells. P-STAT5 was not inhibited in CNI-treated control patients.. Tofacitinib therapy strongly inhibits γ(c) cytokine-induced JAK/STAT5 activation, whereas basiliximab suppresses IL-2-stimulated activation only. Pharmacodynamic monitoring offers a unique tool to evaluate the biologic effects of immunosuppressive drugs.

Topics: Antibodies, Monoclonal; Basiliximab; Cyclosporine; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Interleukin-15; Interleukin-2; Interleukin-7; Janus Kinases; Kidney Transplantation; Lymphocyte Activation; Lymphocyte Count; Lymphocytes; Netherlands; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Receptors, Interleukin-2; Recombinant Fusion Proteins; Signal Transduction; STAT5 Transcription Factor; Tacrolimus; Time Factors; Treatment Outcome

Tasocitinib (CP-690,550) is an orally active Janus kinase inhibitor that is in development for prophylaxis of acute rejection after kidney transplantation and for the treatment of select autoimmune diseases. The current study was conducted to evaluate the systemic exposure of mycophenolic acid (MPA) in de novo kidney transplant patients when coadministered with tasocitinib compared with exposure in patients receiving tacrolimus, which has no effect on MPA pharmacokinetics. Plasma MPA concentrations were obtained from 17 adult patients who received either 15 mg or 30 mg tasocitinib twice daily (eight patients) or tacrolimus (nine patients) after kidney transplantation. All patients also received concomitant mycophenolate mofetil, prednisone, and basiliximab induction. The median mycophenolate mofetil dose was 1000 mg twice daily. A two-compartment population pharmacokinetic model estimating oral clearance, between-patient variability in oral clearance, central volume of distribution, and residual variability in combination with historical estimates of first-order absorption rate constant, intercompartmental clearance, and peripheral volume of distribution adequately described the sparse MPA data. Based on individual estimates oral clearance from the population pharmacokinetic model, mean steady-state area under the concentration-time curve values for a mycophenolate mofetil dose of 1000 mg twice daily were 63 mg·hr/L (22%) and 59 mg·hr/L (36%) for the tasocitinib and tacrolimus groups, respectively. These results indicate that tasocitinib does not influence systemic MPA exposure.

Topics: Adult; Area Under Curve; Dose-Response Relationship, Drug; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Models, Biological; Mycophenolic Acid; Piperidines; Pyrimidines; Pyrroles; Tacrolimus

This randomized, pilot study compared the Janus kinase inhibitor CP-690,550 (15 mg BID [CP15] and 30 mg BID [CP30], n = 20 each) with tacrolimus (n = 21) in de novo kidney allograft recipients. Patients received an IL-2 receptor antagonist, concomitant mycophenolate mofetil (MMF) and corticosteroids. CP-690,550 doses were reduced after 6 months. Due to a high incidence of BK virus nephropathy (BKN) in CP30, MMF was discontinued in this group. The 6-month biopsy-proven acute rejection rates were 1 of 20, 4 of 20 and 1 of 21 for CP15, CP30 and tacrolimus groups, respectively. BKN developed in 4 of 20 patients in CP30 group. The 6-month rates of cytomegalovirus disease were 2 of 20, 4 of 20 and none of 21 for CP15, CP30 and tacrolimus groups, respectively. Estimated glomerular filtration rate was >70 mL/min at 6 and 12 months (all groups). NK cells were reduced by

Topics: Adrenal Cortex Hormones; Adult; Aged; Biopsy; Calcineurin Inhibitors; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Janus Kinases; Kaplan-Meier Estimate; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Piperidines; Pyrimidines; Pyrroles; Tacrolimus; Transplantation, Homologous; Young Adult

The efficacy of tofacitinib (TOF) in the early diagnosis of melanoma differentiation-associated gene 5 (MDA5)-related interstitial lung disease (ILD) has been described. However, whether TOF exposure is associated with a reduced 1-year mortality rate remains undetermined.. Patients diagnosed with MDA5-ILD receiving TOF or tacrolimus (TAC) treatment were included. A Cox proportional hazards model, which was adjusted for age, sex, smoking history, anti-MDA5 antibody titers, and concurrent use of other steroid-sparing agents, was performed to compare all-cause mortality and to investigate the risk factors predicting 1-year mortality rates in the 2 treatment groups.. During the study period, 26 patients were treated with TOF and 35 were treated with TAC. The 6-month (38.5% vs 62.9%;. Our observational study showed that TOF use might have a potential effect on improving the outcomes of MDA5-ILD. Future clinical trials are needed to assess the long-term efficacy and tolerability of TOF.

Topics: Autoantibodies; Dermatomyositis; Humans; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Melanoma; Retrospective Studies; Tacrolimus

The management of patients with ulcerative colitis who are dependent on corticosteroid for control of symptoms, or refractory to corticosteroids or standard immunosuppressive therapy, is challenging. The development of newer medical therapies has increased the options for managing patients in this situation, but access and funding remain limited. This guideline summarises the literature regarding this situation and provides guidance as to the management of refractory colitis in the New Zealand setting.

Topics: Adalimumab; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Appendectomy; Azathioprine; Colitis, Ulcerative; Cyclosporine; Drug Resistance; Drug Therapy, Combination; Fecal Microbiota Transplantation; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Leukapheresis; Mercaptopurine; Mesalamine; Methotrexate; New Zealand; Pediatrics; Piperidines; Proctocolectomy, Restorative; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Recurrence; Severity of Illness Index; Tacrolimus; Tumor Necrosis Factor-alpha

To describe current trends in the numbers of rheumatoid arthritis (RA)-related surgeries.. The number of operations was determined for patients with RA in a large observational cohort [Institute of Rheumatology, Rheumatoid Arthritis (IORRA)] enrolled from 2001 to 2012.. The total number of operations peaked in 2002 and gradually decreased thereafter, but began to increase again in 2008. The number of total knee replacements has decreased since 2003, while the number of wrist and foot arthroplasties and the number of artificial finger prosthesis surgeries have increased gradually.. Our results suggest that the number of orthopedic surgeries may change in response to changes in the drug therapy for RA.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Chromones; Cohort Studies; Databases, Factual; Female; Humans; Japan; Joints; Male; Orthopedic Procedures; Piperidines; Pyrimidines; Pyrroles; Quality of Life; Sulfonamides; Tacrolimus

Data on how different immunosuppressive drugs affect cytomegalovirus (CMV)-specific T-cell responses may help guide more rational modification of immunosuppression in patients with CMV replication. We assessed the in vitro effects of individual standard and novel immunosuppressive drugs on a broad range of CMV-specific T-cell responses.. Peripheral blood mononuclear cells from healthy CMV-seropositive donors were preincubated with serial dilutions of tacrolimus, mycophenolate (MPA), sirolimus, tofacitinib, and belatacept. CMV-pp65 or CMV-pp72 peptide pools were used for stimulation. CMV-specific cytokine (Th1 and Th2) and chemokine responses were determined (a total of 5400 measurements). P<0.01 was set as significant.. After CMV stimulation, dose-dependent suppression of Th1, Th2, and chemokines was seen, but significant differences between drugs were present. For example, tacrolimus was more potent in inhibiting CMV-specific Th1 cytokines versus Th2, whereas MPA preferentially inhibited Th2 cytokines. In a comparison of the relative potency of each drug at different dosing ranges, tacrolimus had the strongest Th1 inhibitory effect (median inhibition of interferon-γ at 97.5%; P=0.004-0.008) followed by sirolimus (median inhibition at 82.4%). The remaining agents (MPA, belatacept, and tofacitinib) had less apparent dose-dependent effects on interferon-γ (belatacept median inhibition at 21.5%; P=0.004 vs. tacrolimus).. Immunosuppression-specific and dose-dependent reductions in CMV-specific cytokine release were observed with significant differences in Th1 versus Th2 profiles and in relative potency of the drugs.

Topics: Abatacept; Adult; Cytokines; Cytomegalovirus; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Humans; Immunoconjugates; Immunosuppressive Agents; In Vitro Techniques; Middle Aged; Mycophenolic Acid; Piperidines; Pyrimidines; Pyrroles; Sirolimus; T-Lymphocytes; Tacrolimus; Th1 Cells; Th2 Cells; Transcriptome