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Indian Journal of Dermatology Sep 2014The advent of biologics in dermatologic treatment armentarium has added refreshing dimensions, for it is a major breakthrough. Several agents are now available for use.... (Review)
Review
The advent of biologics in dermatologic treatment armentarium has added refreshing dimensions, for it is a major breakthrough. Several agents are now available for use. It is therefore imperative to succinctly comprehend their pharmacokinetics for their apt use. A concerted endeavor has been made to delve on this subject. The major groups of biologics have been covered and include: Drugs acting against TNF-α, Alefacept, Ustekinumab, Rituximab, IVIG and Omalizumab. The relevant pharmacokinetic characteristics have been detailed. Their respective label (approved) and off-label (unapproved) indications have been defined, highlighting their dosage protocol, availability and mode of administration. The evidence level of each indication has also been discussed to apprise the clinician of their current and prospective uses. Individual anti-TNF drugs are not identical in their actions and often one is superior to the other in a particular disease. Hence, the section on anti-TNF agents mentions the literature on each drug separately, and not as a group. The limitations for their use have also been clearly brought out.
PubMed: 25284845
DOI: 10.4103/0019-5154.139859 -
Cutaneous and Ocular Toxicology 2015Alopecia areata is a common form of non-scarring hair disorder. The development of alopecia areata during anti-psoriatic treatment has been reported with the systemic...
Alopecia areata is a common form of non-scarring hair disorder. The development of alopecia areata during anti-psoriatic treatment has been reported with the systemic therapies such as infliximab, etanercept, adalimumab, alefacept and efalizumab. Retinoid-induced alopecia areata on the eyelash and eyebrow has not been reported in the literature. We report a female patient who presented with alopecia areata of the eyebrow and eyelash one month after the initiation of acitretin therapy for psoriasis.
Topics: Acitretin; Adult; Alopecia Areata; Female; Humans; Keratolytic Agents; Psoriasis
PubMed: 25198403
DOI: 10.3109/15569527.2014.948684 -
Experimental and Clinical... Mar 2014Induction therapy after kidney transplantation is intensive immunosuppression in the initial days after transplant when the immune system of the recipient has the first... (Review)
Review
Induction therapy after kidney transplantation is intensive immunosuppression in the initial days after transplant when the immune system of the recipient has the first contact with donor antigens. Initial intensive immunosuppression may be required to prevent acute rejection and graft loss, and subsequent immunosuppression may be decreased to minimize adverse events associated with immunosuppressive drugs. Induction agents include lymphocyte-depleting antibodies such as rabbit antithymocyte globulin, alemtuzumab, muromonab-CD3, rituximab, and bortezomib; lymphocyte-nondepleting antibodies such as interleukin 2 receptor antibodies; and other discontinued or investigational agents such as efalizumab and alefacept. Induction therapy may be adjusted for special situations such as living-donor kidney transplant, pediatric transplant, hepatitis C virus-seropositive recipients, recipients who require desensitization, patients who are at risk for developing delayed graft function, and old donors. The optimal immunosuppressive regimen may vary, and clinical practice guidelines are available.
Topics: Acute Disease; Drug Administration Schedule; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Patient Selection; Risk Factors; Time Factors; Treatment Outcome
PubMed: 24635795
DOI: 10.6002/ect.25liver.l58 -
The Lancet. Diabetes & Endocrinology Dec 2013Type 1 diabetes results from autoimmune targeting of the pancreatic β cells, likely mediated by effector memory T (Tem) cells. CD2, a T cell surface protein highly... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Type 1 diabetes results from autoimmune targeting of the pancreatic β cells, likely mediated by effector memory T (Tem) cells. CD2, a T cell surface protein highly expressed on Tem cells, is targeted by the fusion protein alefacept, depleting Tem cells and central memory T (Tcm) cells. We postulated that alefacept would arrest autoimmunity and preserve residual β cells in patients newly diagnosed with type 1 diabetes.
METHODS
The T1DAL study is a phase 2, double-blind, placebo-controlled trial in patients with type 1 diabetes, aged 12-35 years who, within 100 days of diagnosis, were enrolled at 14 US sites. Patients were randomly assigned (2:1) to receive alefacept (two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause) or a placebo. Randomisation was stratified by site, and was computer-generated with permuted blocks of three patients per block. All participants and site personnel were masked to treatment assignment. The primary endpoint was the change from baseline in mean 2 h C-peptide area under the curve (AUC) at 12 months. Secondary endpoints at 12 months were the change from baseline in the 4 h C-peptide AUC, insulin use, major hypoglycaemic events, and HbA1c concentrations. This trial is registered with ClinicalTrials.gov, number NCT00965458.
FINDINGS
Of 73 patients assessed for eligibility, 33 were randomly assigned to receive alefacept and 16 to receive placebo. The mean 2 h C-peptide AUC at 12 months increased by 0.015 nmol/L (95% CI -0.080 to 0.110) in the alefacept group and decreased by 0.115 nmol/L (-0.278 to 0.047) in the placebo group, and the difference between groups was not significant (p=0.065). However, key secondary endpoints were met: the mean 4 h C-peptide AUC was significantly higher (mean increase of 0.015 nmol/L [95% CI -0.076 to 0.106] vs decrease of -0.156 nmol/L [-0.305 to -0.006]; p=0.019), and daily insulin use (0.48 units per kg per day for placebo vs 0.36 units per kg per day for alefacept; p=0.02) and the rate of hypoglycaemic events (mean of 10.9 events per person per year for alefacept vs 17.3 events for placebo; p<0.0001) was significantly lower at 12 months in the alefacept group than in the placebo group. Mean HbA1c concentrations at week 52 were not different between treatment groups (p=0.75). So far, no serious adverse events were reported and all patients had at least one adverse event. In the alefacept group, 29 (88%) participants had an adverse event related to study drug versus 15 (94%) participants in the placebo group. In the alefacept group, 14 (42%) participants had grade 3 or 4 adverse events compared with nine (56%) participants in the placebo group; no deaths occurred.
INTERPRETATION
Although the primary outcome was not met, at 12 months, alefacept preserved the 4 h C-peptide AUC, lowered insulin use, and reduced hypoglycaemic events, suggesting efficacy. Safety and tolerability were similar in the alefacept and placebo groups. Alefacept could be useful to preserve β-cell function in patients with new-onset type 1 diabetes.
Topics: Adolescent; Adult; Alefacept; Child; Diabetes Mellitus, Type 1; Double-Blind Method; Drug Delivery Systems; Female; Humans; Hypoglycemic Agents; Immunologic Memory; Male; Recombinant Fusion Proteins; T-Lymphocytes; Young Adult
PubMed: 24622414
DOI: 10.1016/S2213-8587(13)70111-6 -
The Lancet. Diabetes & Endocrinology Dec 2013
Topics: Alefacept; Diabetes Mellitus, Type 1; Drug Delivery Systems; Female; Humans; Immunologic Memory; Male; Recombinant Fusion Proteins; T-Lymphocytes
PubMed: 24622404
DOI: 10.1016/S2213-8587(13)70123-2 -
World Journal of Transplantation Dec 2013Excellent outcomes have been achieved in the field of renal transplantation. A significant reduction in acute rejection has been attained at many renal transplant... (Review)
Review
Excellent outcomes have been achieved in the field of renal transplantation. A significant reduction in acute rejection has been attained at many renal transplant centers using contemporary immunosuppressive, consisting of an induction agent, a calcineurin inhibitor, an antiproliferative agent plus or minus a corticosteroid. Despite improvements with these regimens, chronic allograft injury and adverse events still persist. The perfect immunosuppressive regimen would limit or eliminate calcineurin inhibitors and/or corticosteroid toxicity while providing enhanced allograft outcomes. Potential improvements to the calcineurin inhibitor class include a prolonged release tacrolimus formulation and voclosporin, a cyclosporine analog. Belatacept has shown promise as an agent to replace calcineurin inhibitors. A novel, fully-human anti-CD40 monoclonal antibody, ASKP1240, is currently enrolling patients in phase 2 trials with calcineurin minimization and avoidance regimens. Another future goal of transplant immunosuppression is effective and safe treatment of allograft rejection. Novel treatments for antibody mediated rejection include bortezomib and eculizumab. Several investigational agents are no longer being pursed in transplantation including the induction agents, efalizumab and alefacept, and maintenance agents, sotrastaurin and tofacitinib. The purpose of this review is to consolidate the published evidence of the effectiveness and safety of investigational immunosuppressive agents in renal transplant recipients.
PubMed: 24392311
DOI: 10.5500/wjt.v3.i4.68 -
American Journal of Transplantation :... Jan 2014De novo donor-specific antibody (DSA) after organ transplantation promotes antibody-mediated rejection (AMR) and causes late graft loss. Previously, we demonstrated that...
De novo donor-specific antibody (DSA) after organ transplantation promotes antibody-mediated rejection (AMR) and causes late graft loss. Previously, we demonstrated that depletion using anti-CD3 immunotoxin combined with tacrolimus and alefacept (AMR regimen) reliably induced early DSA production with AMR in a nonhuman primate kidney transplant model. Five animals were assigned as positive AMR controls, four received additional belatacept and four received additional anti-CD40 mAb (2C10R4). Notably, production of early de novo DSA was completely attenuated with additional belatacept or 2C10R4 treatment. In accordance with this, while positive controls experienced a decrease in peripheral IgM(+) B cells, bela- and 2C10R4-added groups maintained a predominant population of IgM(+) B cells, potentially indicating decreased isotype switching. Central memory T cells (CD4(+) CD28(+) CD95(+)) as well as PD-1(hi) CD4(+) T cells were decreased in both bela-added and 2C10R4-added groups. In analyzing germinal center (GC) reactions in situ, lymph nodes further revealed a reduction of B cell clonal expansion, GC-follicular helper T (Tfh) cells, and IL-21 production inside GCs with additional belatacept or 2C10R4 treatment. Here we provide evidence that belatacept and 2C10R4 selectively suppresses the humoral response via regulating Tfh cells and prevents AMR in this nonhuman primate model.
Topics: Abatacept; Alefacept; Animals; Antibodies; B-Lymphocytes; CD4-Positive T-Lymphocytes; Germinal Center; Graft Rejection; Immunoconjugates; Kidney Transplantation; Lymph Nodes; Macaca mulatta; Male; Recombinant Fusion Proteins; T-Lymphocytes, Helper-Inducer; Tacrolimus
PubMed: 24354871
DOI: 10.1111/ajt.12526 -
Nature Reviews. Endocrinology Dec 2013Alefacept, a fusion protein approved for psoriasis, has been trialled in patients with new-onset type 1 diabetes mellitus. However, the withdrawal of the drug from the...
Alefacept, a fusion protein approved for psoriasis, has been trialled in patients with new-onset type 1 diabetes mellitus. However, the withdrawal of the drug from the US market and the unmet primary end point do not raise hope for this drug, even though some secondary end points were met and the study highlighted interesting immunological efficacy.
Topics: Alefacept; Diabetes Mellitus, Type 1; Humans; Immunotherapy; Recombinant Fusion Proteins
PubMed: 24189510
DOI: 10.1038/nrendo.2013.221 -
American Journal of Transplantation :... Dec 2013Renal allograft tolerance has been achieved in MHC-mismatched primates via nonmyeloablative conditioning beginning 6 days prior to planned kidney and donor bone marrow...
Renal allograft tolerance has been achieved in MHC-mismatched primates via nonmyeloablative conditioning beginning 6 days prior to planned kidney and donor bone marrow transplantation (DBMT). To extend the applicability of this approach to deceased donor transplantation, we recently developed a novel-conditioning regimen, the "delayed protocol" in which donor bone marrow (DBM) is transplanted several months after kidney transplantation. However, activation/expansion of donor-reactive CD8(+) memory T cells (TMEM) occurring during the interval between kidney and DBM transplantation impaired tolerance induction using this strategy. In the current study, we tested whether, Alefacept, a fusion protein which targets LFA-3/CD2 interactions and selectively depletes CD2(high) CD8(+) effector memory T cells (TEM) could similarly induce long-term immunosuppression-free renal allograft survival but avoid the deleterious effects of anti-CD8 mAb treatment. We found that Alefacept significantly delayed the expansion of CD2(high) cells including CD8(+) TEM while sparing naïve CD8(+) T and NK cells and achieved mixed chimerism and long-term immunosuppression-free renal allograft survival. In conclusion, elimination of CD2(high) T cells represents a promising approach to prevent electively the expansion/activation of donor-reactive TEM and promotes tolerance induction via the delayed protocol mixed chimerism approach.
Topics: Alefacept; Animals; Bone Marrow Cells; Bone Marrow Transplantation; CD2 Antigens; CD8-Positive T-Lymphocytes; Genotype; Graft Survival; Immune Tolerance; Immunologic Memory; Immunosuppression Therapy; Interferon-gamma; Kidney Transplantation; Macaca fascicularis; Major Histocompatibility Complex; Recombinant Fusion Proteins; Transplantation Chimera; Transplantation Conditioning; Transplantation Tolerance
PubMed: 24165326
DOI: 10.1111/ajt.12500 -
BioDrugs : Clinical Immunotherapeutics,... Jan 2013Skin and joint manifestations associated with psoriasis and psoriatic arthritis (PsA) can significantly impact a patient's quality of life. Successful treatment is... (Review)
Review
Skin and joint manifestations associated with psoriasis and psoriatic arthritis (PsA) can significantly impact a patient's quality of life. Successful treatment is imperative in order to improve signs and symptoms of the disease, and to alleviate physical or psychological distress. For patients with mild psoriasis with or without PsA, topical agents and targeted phototherapy are appropriate treatments for psoriasis. Systemic therapies, such as methotrexate and phototherapy are recommended options for patients with more severe psoriasis, but their long-term use is hindered by safety concerns. Advancements in understanding the pathogenesis of psoriasis, including the role of T cells and cytokines, have been crucial to the development of biological therapies. These target the immune system and are suitable options for patients with extensive disease. Biological therapies for the treatment of psoriasis include targeted therapies (alefacept) and anti-cytokine therapies (anti-tumour necrosis factor [TNF] therapies [adalimumab, etanercept, infliximab] and a monoclonal antibody against interleukin [IL]-12 and IL-23 [ustekinumab]). Patients with PsA should be treated appropriately in order to improve symptoms and inhibit structural joint damage. Non-steroidal anti-inflammatory drugs or local intra-articular injections of corticosteroids can be used successfully in patients with mild PsA; however, neither treatment prevents the development of structural joint damage. For patients with moderate to severely active PsA, disease-modifying antirheumatic drugs (such as methotrexate), TNF inhibitor treatments (adalimumab, etanercept, infliximab and golimumab) or their combination are considered first-line treatment. This review provides a brief overview of treatment options for psoriasis and PsA, with an emphasis on the efficacy and safety of anti-TNF therapies.
Topics: Adalimumab; Alefacept; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Arthritis, Psoriatic; Dermatologic Agents; Humans; Infliximab; Interleukin-12; Interleukin-23; Methotrexate; Molecular Targeted Therapy; Psoriasis; Recombinant Fusion Proteins; Ustekinumab
PubMed: 23990277
DOI: 10.1007/BF03325637