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Experimental and Clinical... Feb 2017We review different immunosuppressant protocols used for living-donor kidney transplant recipients at our center.
OBJECTIVES
We review different immunosuppressant protocols used for living-donor kidney transplant recipients at our center.
MATERIALS AND METHODS
Many prospective randomized studies from our center have been reported between March 1976 and 2016, with more than 2700 renal transplant procedures conducted. The first study was a prospective randomized trial of azathioprine versus cyclosporine. The second study compared triple therapy (prednisolone + azathioprine + cyclosporine) versus conventional therapy (prednisolone + azathioprine). The third study was a cost-saving study, in which 100 patients received ketoconazole along with the triple regimen. Another trial demonstrated the advantages of a microemulsion form of cyclosporine. A subsequent trial compared calcineurin inhibitor minimization versus avoidance protocols. Rescue therapies were carried out to intensify immunosuppressive regimens after repeated rejection. In addition, steroid-free regimens were evaluated during both short- and long-term treatment. A recent trial reported a step-forward avoidance protocol with a calcineurin inhibitor and a steroid-free regimen, whereas another current study is the TRANSFORM one. The rationale behind antibody therapy was tho roughly evaluated among living-donor renal trans plant recipients with different agents, including basiliximab, daclizumab, antithymocyte globulin, and alemtuzumab.
RESULTS
Earlier studies have demonstrated the efficacy of conventional regimens without induction therapy, especially in longer follow-up. The standard triple therapy has emerged with intensified immunosuppressive and lowered dose of each drug, especially cyclosporine. In minimization studies, no significant differences were encountered regarding patient and graft survival, even in the long-term. Steroid avoidance was safe and effective. Calcineurin inhibitors and steroid-free regimens have shown comparable patient and graft survival. Induction therapy has lowered the incidence and severity of acute rejection.
CONCLUSIONS
A better 5-year graft survival and less posttransplant complications have been achieved with steroid avoidance after induction with basiliximab. Induction therapy did not affect graft and patient survival rates despite lowered incidence and severity of acute rejections.
Topics: Drug Administration Schedule; Drug Substitution; Drug Therapy, Combination; Egypt; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Severity of Illness Index; Time Factors; Treatment Outcome
PubMed: 28260425
DOI: 10.6002/ect.mesot2016.L46 -
Neurology and Therapy Dec 2016Multiple sclerosis (MS) is a chronic, autoimmune, inflammatory, demyelinating disease of the central nervous system. MS is increasingly recognized in the pediatric... (Review)
Review
Multiple sclerosis (MS) is a chronic, autoimmune, inflammatory, demyelinating disease of the central nervous system. MS is increasingly recognized in the pediatric population, and it is usually diagnosed around 15 years of age. The exact etiology of MS is still not known, although autoimmune, genetic, and environmental factors play important roles in its development, making it a multifactorial disease. The disease in children almost always presents in the relapsing-remittent form. The therapy involves treatment of relapses, and immunomodulatory and symptomatic treatment. The treatment of children with MS has to be multidisciplinary and include pediatric neurologists, ophthalmologists, psychologists, physiotherapists, and if necessary, pediatric psychiatrists and pharmacologists. The basis of MS therapy should rely on drugs that are able to modify the course of the disease, i.e. immunomodulatory drugs. These drugs can be subdivided into two general categories: first-line immunomodulatory therapy (interferon beta-1a, interferon beta-1b, glatiramer acetate) and second-line immunomodulatory therapy (natalizumab, mitoxantrone, fingolimod, teriflunomide, azathioprine, rituximab, dimethyl fumarate, daclizumab). Treatment of relapses involves the use of high intravenous doses of corticosteroids, administration of intravenous immunoglobulins, and plasmapheresis. We summarize here the current available information related to the etiology and treatment options in MS. Early administration of immunomodulatory therapy is beneficial in adults, while more studies are needed to prove their effectiveness in pediatric populations. Therefore, pediatric MS still represents a great challenge for both, the early and correct diagnosis, as well as its treatment.
PubMed: 27640189
DOI: 10.1007/s40120-016-0052-6 -
Neurotherapeutics : the Journal of the... Jan 2016Therapeutic options for multiple sclerosis (MS) have significantly increased over the last few years. T lymphocytes are considered to play a central role in initiating... (Review)
Review
Therapeutic options for multiple sclerosis (MS) have significantly increased over the last few years. T lymphocytes are considered to play a central role in initiating and perpetuating the pathological immune response. Currently approved therapies for MS target T lymphocytes, either in an unspecific manner or directly by interference with specific T-cell pathways. While the concept of "T-cell-specific therapy" implies specificity and selectivity, currently approved approaches come from a general shaping of the immune system towards anti-inflammatory immune responses by non-T-cell-selective immune suppression or immune modulation (e.g., interferons-immune modulation approach) to a depletion of immune cell populations involving T cells (e.g., anti-CD52, alemtuzumab-immune selective depletion approach), or a selective inhibition of distinct molecular pathways in order to sequester leucocytes (e.g., natalizumab-leukocyte sequestration approach). This review will highlight the rationale and results of different T-cell-directed therapeutic approaches coming from basic animal experiments to clinical trials. We will first discuss the pathophysiological rationale for targeting T lymphocytes in MS leading to currently approved treatments acting on T lymphocytes. Furthermore, we will disuss previous promising concepts that have failed to show efficacy in clinical trials or were halted as a result of unexpected adverse events. Learning from the discrepancies between expectations and failures in practical outcomes helps to optimize future research approaches and clinical study designs. As our current view of MS pathogenesis and patient needs is rapidly evolving, novel therapeutic approaches targeting T lymphocytes will also be discussed, including specific molecular interventions such as cytokine-directed treatments or strategies enhancing immunoregulatory mechanisms. Based on clinical experience and novel pathophysiological approaches, T-cell-based strategies will remain a pillarstone of MS therapy.
Topics: Animals; Humans; Immunotherapy; Multiple Sclerosis; T-Lymphocytes
PubMed: 26563391
DOI: 10.1007/s13311-015-0405-3 -
Annals of Indian Academy of Neurology Sep 2015The newer immunotherapies for multiple sclerosis (fingolimod, natalizumab, dimethyl fumarate, teriflunomide, alemtuzumab) offer advantages of efficacy or tolerability... (Review)
Review
The newer immunotherapies for multiple sclerosis (fingolimod, natalizumab, dimethyl fumarate, teriflunomide, alemtuzumab) offer advantages of efficacy or tolerability over the injectable therapies of the 1990s. But they also have greater risks. As further treatments emerge (daclizumab and ocrelizumab are likely to be licensed in the next two years), the physician needs to be able to place them within a complex landscape of drugs and a specific treatment strategy, which may be an "escalation" or "induction" approach. Whilst on treatment, neurologist and patient need to be vigilant to signs of disease breakthrough or adverse effects.
PubMed: 26538846
DOI: 10.4103/0972-2327.164824 -
Annals of Medicine Aug 2017Antibody induction therapy aims at preventing acute cellular rejection by reducing T-cell proliferation and activation. We evaluated the efficacy and side effects of two... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Antibody induction therapy aims at preventing acute cellular rejection by reducing T-cell proliferation and activation. We evaluated the efficacy and side effects of two anti-interleukin-2 receptor antibodies (IL2RAs), basiliximab and daclizumab, for prevention of liver transplant rejection in adult patients.
METHODS
Randomized controlled trials (RCTs) on basiliximab or daclizumab were identified by searching multiple databases and reference lists published up to July, 2015. Endpoints included acute rejection events and mortality rates. Risk ratio (RR) and 95% confidence interval (CI) were calculated and pooled for a meta-analysis.
RESULTS
Patients treated with IL2RA-based therapy were less likely to suffer acute rejection compared to control group (steroid or steroid-free). Patients in all groups had similar mortality rate. In the subgroup analysis, basiliximab and daclizumab-based therapies did not reduced acute rejection rate. No significant difference was found in mortality rate between both types of IL-2RA treatment groups and control groups. In the subgroup analysis regarding experimental design, no significant difference in the acute rejection and mortality rates were found between "steroid plus IL2RA versus steroid" and "IL2RA versus steroid" groups.
CONCLUSION
IL2RA-based induction therapy reduces rate of acute rejection events but does not reduce mortality. However, optimal regimen relating to IL2RA-based induction therapy remains undetermined. KEY MESSAGES IL2RA-based induction therapy was effective in reduction of acute rejection events but it did not reduce mortality rate. Basiliximab-based induction therapy might be more effective than daclizumab-based induction therapy in reduction of acute rejection. No significant difference in acute rejection and mortality rate was found between types of IL2RAs or IL2RA-steroid combined therapy.
Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Basiliximab; Daclizumab; Female; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Interleukin-2; Liver Transplantation; Male; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Treatment Outcome
PubMed: 27813419
DOI: 10.1080/07853890.2016.1257862 -
Neurotherapeutics : the Journal of the... Oct 2017Patient-reported outcomes (PROs) are playing an increasing role in multiple sclerosis (MS) research and practice, and are essential for understanding the effects that MS... (Review)
Review
Patient-reported outcomes (PROs) are playing an increasing role in multiple sclerosis (MS) research and practice, and are essential for understanding the effects that MS and MS treatments have on patients' lives. PROs are captured directly from patients and include symptoms, function, health status, and health-related quality of life. In this article, we review different categories (e.g., generic, targeted, preference-based) of PRO measures and considerations in selecting a measure. The PROs included in MS clinical research have evolved over time, as have the measures used to assess them. We describe findings from recent MS clinical trials that included PROs when evaluating Food and Drug Administration-approved disease-modifying therapies (e.g., daclizumab, teriflunomide). Variation in the measures used in these trials makes it difficult to draw any conclusions from the data. We therefore suggest a standardized approach to PRO assessment in MS research and describe 2 generic, National Institutes of Health-supported measurement systems [Neuro-QoL and the Patient-Reported Outcomes Measurement Information System (PROMIS)] that would facilitate such an approach. The use of PROs in MS care and research is expanding beyond clinical trials, as is demonstrated by examples from comparative effectiveness and other patient-centered research. The importance of PRO assessment is expected to continue to grow in the future.
Topics: Clinical Trials as Topic; Endpoint Determination; Humans; Multiple Sclerosis; Patient Reported Outcome Measures; Quality of Life; Treatment Outcome
PubMed: 28913785
DOI: 10.1007/s13311-017-0571-6 -
Journal of Internal Medicine Jun 2021The treatment of multiple sclerosis (MS), the most common chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS),... (Review)
Review
The treatment of multiple sclerosis (MS), the most common chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS), continues to transform. In recent years, a number of novel and increasingly effective disease-modulatory therapies (DMTs) have been approved, including oral fumarates and selective sphingosine 1-phosphate modulators, as well as cell-depleting therapies such as cladribine, anti-CD20 and anti-CD52 monoclonals. Amongst DMTs in clinical development, inhibitors of Bruton's tyrosine kinase represent an entirely new emerging drug class in MS, with three different drugs entering phase III trials. However, important remaining fields of improvement comprise tracking of long-term benefit-risk with existing DMTs and exploration of novel treatment targets relating to brain inherent disease processes underlying the progressive neurodegenerative aspect of MS, which accumulating evidence suggests start already early in the disease process. The aim here is to review current therapeutic options in relation to an improved understanding of the immunopathogenesis of MS, also highlighting examples where controlled trials have not generated the desired results. An additional aim is to review emerging therapies undergoing clinical development, including agents that interfere with disease processes believed to be important for neurodegeneration or aiming to enhance reparative responses. Notably, early trials now have shown initial evidence of enhanced remyelination both with small molecule compounds and biologicals. Finally, accumulating evidence from clinical trials and post-marketing real-world patient populations, which underscore the importance of early high effective therapy whilst maintaining acceptable tolerability, is discussed.
Topics: Clinical Trials as Topic; Humans; Immunosuppressive Agents; Multiple Sclerosis
PubMed: 33258193
DOI: 10.1111/joim.13215 -
Revista de Neurologia Apr 2018
Topics: Daclizumab; Humans; Immunosuppressive Agents; Interferon-beta; Multiple Sclerosis
PubMed: 29645067
DOI: No ID Found -
Multiple Sclerosis (Houndmills,... Sep 2021In multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses.
OBJECTIVE
To distinguish siponimod's direct effects on disability progression from those on relapses in the EXPAND phase 3 trial.
METHODS
Three estimands, one based on principal stratum and two on hypothetical scenarios (no relapses, or equal relapses in both treatment arms), were defined to determine the extent to which siponimod's effects on 3- and 6-month confirmed disability progression were independent of on-study relapses.
RESULTS
Principal stratum analysis estimated that siponimod reduced the risk of 3- and 6-month confirmed disability progression by 14%-20% and 29%-33%, respectively, compared with placebo in non-relapsing patients. In the hypothetical scenarios, risk reductions independent of relapses were 14%-18% and 23% for 3- and 6-month confirmed disability progression, respectively.
CONCLUSION
By controlling the confounding impact of on-study relapses on confirmed disability progression, these statistical approaches provide a methodological framework to assess treatment effects on disability progression in relapsing and non-relapsing patients. The analyses support that siponimod may be useful for treating secondary progressive multiple sclerosis in patients with or without relapses.
Topics: Azetidines; Benzyl Compounds; Disease Progression; Humans; Multiple Sclerosis, Chronic Progressive; Recurrence
PubMed: 33205682
DOI: 10.1177/1352458520971819