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Rheumatology International May 2016The diverse clinical picture of PsA suggests the need to identify suitable therapies to address the different combinations of clinical manifestations. This review aimed... (Review)
Review
The diverse clinical picture of PsA suggests the need to identify suitable therapies to address the different combinations of clinical manifestations. This review aimed to classify the available biologic agents and new small molecule inhibitors (licensed and nonlicensed) based on their proven efficacy in treating different clinical manifestations associated with psoriasis and PsA. This review presents the level of evidence of efficacy of different biologic treatments and small molecule inhibitors for certain clinical features of treatment of PsA and psoriasis, which was graded in categories I-IV. The literature searches were performed on the following classes of biologic agents and small molecules: TNF inhibitors (adalimumab, etanercept, infliximab, golimumab, certolizumab), anti-IL12/IL23 (ustekinumab), anti-IL17 (secukinumab, brodalumab, ixekizumab), anti-IL6 (tocilizumab), T cell modulators (alefacept, efalizumab, abatacept, itolizumab), B cell depletion therapy (rituximab), phosphodiesterase 4 inhibitor (apremilast) and Janus kinase inhibitor (tofacitinib). A comprehensive table including 17 different biologic agents and small molecule inhibitors previously tested in psoriasis and PsA was generated, including the level of evidence of their efficacy for each of the clinical features included in our review (axial and peripheral arthritis, enthesitis, dactylitis, and nail and skin disease). We also proposed a limited set of recommendations for a sequential biologic treatment algorithm for patients with PsA who failed the first anti-TNF therapy, based on the available literature data. There is good evidence that many of the biologic treatments initially tested in psoriasis are also effective in PsA. Further research into both prognostic biomarkers and patient stratification is required to allow clinicians the possibility to make better use of the various biologic treatment options available. This review showed that there are many potentially new treatments that are not included in the current guidelines that can be used for selected categories of patients based on their disease phenotype, clinician experience and access to new biologic therapies.
Topics: Antirheumatic Agents; Arthritis, Psoriatic; Biological Products; Humans; Interleukins; Precision Medicine; Psoriasis; Tumor Necrosis Factor-alpha
PubMed: 26892034
DOI: 10.1007/s00296-016-3436-0 -
Current Diabetes Reports Nov 2015Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to progressive destruction of pancreatic beta cells. Compared to healthy controls, a characteristic... (Review)
Review
Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to progressive destruction of pancreatic beta cells. Compared to healthy controls, a characteristic feature of patients with T1D is the presence of self-reactive T cells with a memory phenotype. These autoreactive memory T cells in both the CD4(+) and CD8(+) compartments are likely to be long-lived, strongly responsive to antigenic stimulation with less dependence on costimulation for activation and clonal expansion, and comparatively resistant to suppression by regulatory T cells (Tregs) or downregulation by immune-modulating agents. Persistence of autoreactive memory T cells likely contributes to the difficulty in preventing disease progression in new-onset T1D and maintaining allogeneic islet transplants by regular immunosuppressive regimens. The majority of immune interventions that have demonstrated some success in preserving beta cell function in the new-onset period have been shown to deplete or modulate memory T cells. Based on these and other considerations, preservation of residual beta cells early after diagnosis or restoration of beta cell mass by use of stem cell or transplantation technology will require a successful strategy to control the autoreactive memory T cell compartment, which could include depletion, inhibition of homeostatic cytokines, induction of hyporesponsiveness, or a combination of these approaches.
Topics: Animals; Cytokines; Diabetes Mellitus, Type 1; Homeostasis; Humans; Immunologic Memory; Signal Transduction; T-Lymphocytes
PubMed: 26370695
DOI: 10.1007/s11892-015-0659-5 -
The Journal of Clinical Investigation Aug 2015Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D.
METHODS
In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses.
RESULTS
A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4+ and CD8+ central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1+CD4+ Tem and Tcm (P < 0.01).
CONCLUSIONS
In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy.
TRIAL REGISTRATION
https://clinicaltrials.gov/ NCT00965458.
FUNDING
NIH and Astellas.
Topics: Adolescent; Adult; Alefacept; C-Peptide; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Child; Dermatologic Agents; Diabetes Mellitus, Type 1; Double-Blind Method; Female; Humans; Immunologic Memory; Male; Recombinant Fusion Proteins; Time Factors
PubMed: 26193635
DOI: 10.1172/JCI81722 -
Biology of Blood and Marrow... Oct 2015Transfusion-related alloimmunization is a potent barrier to the engraftment of allogeneic hematopoietic stem cells in patients with nonmalignant diseases (NMDs). Memory... (Clinical Trial)
Clinical Trial
Transfusion-related alloimmunization is a potent barrier to the engraftment of allogeneic hematopoietic stem cells in patients with nonmalignant diseases (NMDs). Memory T cells, which drive alloimmunization, are relatively resistant to commonly used conditioning agents. Alefacept, a recombinant leukocyte function antigen-3/IgG1 fusion protein, targets CD2 and selectively depletes memory versus naive T cells. Three multiply transfused pediatric patients with NMD received a short course of high-dose i.v. alefacept (.25 mg/kg/dose on days -40 and -9 and .5 mg/kg/dose on days -33, -26, -19, and -12) before undergoing unrelated allogeneic transplant in the setting of reduced-intensity pretransplant conditioning and calcineurin inhibitor-based post-transplant graft-versus-host disease (GVHD) prophylaxis. Alefacept infusions were well tolerated in all patients. Peripheral blood flow cytometry was performed at baseline and during and after alefacept treatment. As expected, after the 5 weekly alefacept doses, each patient demonstrated selective loss of CD2(hi)/CCR7(-)/CD45RA(-) effector memory (Tem) and CD2(hi)/CCR7(+)/CD45RA(-) central memory (Tcm) CD4(+) and CD8(+) T cells with relative preservation of the CD2(lo) Tem and Tcm subpopulations. In addition, depletion of CD2(+) natural killer (NK) cells also occurred. Neutrophil recovery was rapid, and all 3 patients had 100% sorted (CD3/CD33) peripheral blood donor chimerism by day +100. Immune reconstitution (by absolute neutrophil, monocyte, and lymphocyte counts) was comparable with a cohort of historical control patients. All 3 patients developed GVHD but are all now off immune suppression and >2 years post-transplant with stable full-donor engraftment. These results suggest that alefacept at higher dosing can deplete both memory T cells and NK cells and that incorporating CD2-targeted depletion into a reduced-intensity transplant regimen is feasible and safe in heavily transfused patients.
Topics: Alefacept; Anemia, Aplastic; Blood Component Transfusion; Bone Marrow Transplantation; CD2 Antigens; Child; Cord Blood Stem Cell Transplantation; Dyskeratosis Congenita; Fanconi Anemia; Female; Graft Survival; Graft vs Host Disease; Historically Controlled Study; Humans; Immunologic Memory; Immunophenotyping; Infant; Killer Cells, Natural; Lymphocyte Depletion; Male; Pilot Projects; Recombinant Fusion Proteins; T-Lymphocyte Subsets; Transplantation Conditioning; Unrelated Donors
PubMed: 26095669
DOI: 10.1016/j.bbmt.2015.06.005 -
World Journal of Hepatology Apr 2015Lymphomas may be induced by the systemic immunosuppressive therapies used to treat psoriasis, such as ciclosporin, methotrexate and tumour necrosis factor (TNF)-α...
Lymphomas may be induced by the systemic immunosuppressive therapies used to treat psoriasis, such as ciclosporin, methotrexate and tumour necrosis factor (TNF)-α blockers. The biologic agents currently used in psoriasis include alefacept, efalizumab, and the TNF-α antagonists etanercept, infliximab, and adalimumab. Infections and cancer are the main possible consequences of intended or unexpected immunosuppression. We report a 59-year-old man with a history of severe psoriasis vulgaris treated with traditional immunosuppressant drugs followed by anti-TNF-α therapy; the patient was firstly hospitalized for an acute cholestatic toxic hepatitis, which we supposed to be related to adalimumab. The first liver biopsy showed active disease with severe hepatocellular damage caused by heavy lymphocytes infiltrate in portal tracts at in the interface with a not conclusive diagnosis of lymphoproliferative disease. The correct diagnosis of T cell/histiocyte- rich large B cell lymphoma (T/HRBCL) was only reached through a gastric biopsy and a second liver biopsy. T/HRBCL is an uncommon morphologic variant of diffuse large B-cell lymphoma not described until now in psoriatic patients receiving immunosuppressive biologic agents. In psoriatic patients, treated with biologic immunosuppressive agents, the suspect of abdominal lymphoma should always be included as differential diagnosis. Abdominal ultrasound evaluation need therefore to be included in the pre-treatment screening as in the follow-up surveillance.
PubMed: 25914782
DOI: 10.4254/wjh.v7.i5.814 -
Drug Safety May 2015Chimeric fusion proteins, produced by genetic engineering, are currently made up of effector peptides, for example, a ligand-binding portion of a cytokine or growth... (Review)
Review
Chimeric fusion proteins, produced by genetic engineering, are currently made up of effector peptides, for example, a ligand-binding portion of a cytokine or growth factor, extracellular domains of lymphocyte antigens, or a toxin linked to a suitable fusion partner. This review covers eight fusion proteins that have received regulatory approval for human therapy: etanercept, belatacept, abatacept, alefacept, rilonacept, romiplostim, aflibercept, and denileukin-diftitox. Important requirements for an effective fusion protein are effective targeting and binding, cytotoxicity, and a stable molecule with an extended half-life. The Fc region of human IgG1 is generally chosen as the fusion partner for the effector molecule(s) because it extends the fusion protein half-life by recycling via the salvage neonatal FcRn receptor and protects the molecule from lysosomal degradation. Each of the fusion proteins has IgG1 Fc as a fusion partner except denileukin-diftitox, which employs a modified diphtheria toxin effector peptide linked to interleukin-2. For six of the Fc fusion proteins, the effector peptide(s) is linked to the N-terminus of the Fc piece but for the thrombopoietin-mimetic romiplostim, linkage is through the C-terminus. Although some clear type I and IV hypersensitivities are known to be induced by fusion protein therapy, the pathomechanisms underlying many adverse hematologic, respiratory, renal, and cutaneous events have generally not been investigated. Assessment of immunogenicity risk is important because a number of immune-based, or influenced, adverse reactions such as anaphylaxis, cutaneous manifestations, infusion, and injection-site reactions, and cytokine release syndrome can occur. Features of many reactions, some autoimmune in nature, suggest type II, III, or IV hypersensitivities. Clinical findings with the anti-arthritis anti-psoriasis biologic etanercept provide the largest body of current knowledge of fusion protein-induced adverse events. For most fusion proteins, little information is available on appropriate diagnostic and desensitization procedures for hypersensitivity and other adverse responses, although skin test concentrations and some successful desensitization protocols have been published for etanercept.
Topics: Animals; Drug Eruptions; Drug Hypersensitivity; Drug Monitoring; Drug Stability; Glycoproteins; Humans; Protein Stability; Recombinant Fusion Proteins; Risk
PubMed: 25832756
DOI: 10.1007/s40264-015-0285-9 -
American Journal of Transplantation :... Mar 2015Depletional strategies directed toward achieving tolerance induction in organ transplantation have been associated with an increased incidence and risk of...
Depletional strategies directed toward achieving tolerance induction in organ transplantation have been associated with an increased incidence and risk of antibody-mediated rejection (AMR) and graft injury. Our clinical data suggest correlation of increased serum B cell activating factor/survival factor (BAFF) with increased risk of antibody-mediated rejection in alemtuzumab treated patients. In the present study, we tested the ability of BAFF blockade (TACI-Ig) in a nonhuman primate AMR model to prevent alloantibody production and prolong allograft survival. Three animals received the AMR inducing regimen (CD3-IT/alefacept/tacrolimus) with TACI-Ig (atacicept), compared to five control animals treated with the AMR inducing regimen only. TACI-Ig treatment lead to decreased levels of DSA in treated animals at 2 and 4 weeks posttransplantation (p < 0.05). In addition, peripheral B cell numbers were significantly lower at 6 weeks posttransplantation. However, it provided only a marginal increase in graft survival (59 ± 22 vs. 102 ± 47 days; p = 0.11). Histological analysis revealed a substantial reduction in findings typically associated with humoral rejection with atacicept treatment. More T cell rejection findings were observed with increased graft T cell infiltration in atacicept treatment, likely secondary to the graft prolongation. We show that BAFF/APRIL blockade using concomitant TACI-Ig treatment reduced the humoral portion of rejection in our depletion-induced preclinical AMR model.
Topics: Animals; Antibodies, Neutralizing; Antibody Formation; B-Cell Activating Factor; Graft Survival; Humans; Kidney Transplantation; Lymphocyte Depletion; Macaca mulatta; Male; Models, Animal; Recombinant Fusion Proteins; T-Lymphocytes; Tumor Necrosis Factor Ligand Superfamily Member 13
PubMed: 25675879
DOI: 10.1111/ajt.13045 -
Journal of Cutaneous Medicine and... Nov 2014Psoriasis affects approximately 500,000 Canadians. Eight treatments are currently licensed for chronic plaque psoriasis in Canada. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Psoriasis affects approximately 500,000 Canadians. Eight treatments are currently licensed for chronic plaque psoriasis in Canada.
OBJECTIVE
To compare the efficacy of systemic treatments for chronic plaque psoriasis for the outcome > 75% reduction in the Psoriasis Area and Severity Index (PASI) using network meta-analysis.
METHODS
PubMed and clinicaltrials.gov databases were searched up until October 15, 2013, for phase III clinical trials. A consistency model based on a random-effects bayesian statistical framework was used to compare the rates of > 75% PASI reduction across trials.
RESULTS
Twenty-one studies were included in the network analysis. Infliximab had significantly greater odds of producing > 75% reduction in the PASI compared to all treatments. All treatments conferred greater odds of > 75% PASI reduction compared to placebo.
CONCLUSION
Although infliximab had the highest efficacy relative to other systemic treatments for psoriasis, adverse effects, cost, and patient preferences should also be considered when deciding on treatment.
Topics: Adalimumab; Alefacept; Canada; Clinical Trials, Phase III as Topic; Dermatologic Agents; Etanercept; Humans; Infliximab; Methotrexate; Network Meta-Analysis; Psoriasis; Recombinant Fusion Proteins; Severity of Illness Index; Ustekinumab
PubMed: 25348757
DOI: 10.2310/7750.2014.13191 -
Rheumatology (Oxford, England) Feb 2015SS is a chronic systemic autoimmune disease characterized by decreased exocrine gland function. A variety of other disease manifestations may also be present, including... (Review)
Review
SS is a chronic systemic autoimmune disease characterized by decreased exocrine gland function. A variety of other disease manifestations may also be present, including general constitutional symptoms and extraglandular features. A multidisciplinary approach focused on both local and systemic medical therapies is needed as the disease has a wide clinical spectrum. The current treatment for SS is mainly symptomatic. However, there is evidence that systemic drugs are effective in controlling extraglandular manifestations of the disease. Overall evidence for the role of conventional immunosuppressive therapy is limited. A number of attempts to use biologic therapies have led to variable results. Biologic agents targeting B cells, such as rituximab, epratuzumab and belimumab, have shown promising results, but further studies are needed to validate the findings. Early-phase studies with abatacept and alefacept proved that T cell stimulation inhibition is another potentially effective target for SS treatment. Modulation or inhibition of other targets such as IFN, IL-6 and Toll-like receptor are also currently being investigated. We have summarized the available evidence regarding the efficacy of biologic treatments and discuss other potential therapies targeting pathways or molecules recognized as being involved in the pathogenesis of SS.
Topics: Adult; Animals; Antibodies, Monoclonal; Antirheumatic Agents; B-Cell Activating Factor; Biological Factors; Biological Products; Biological Therapy; Cytokines; Epidemiologic Methods; Humans; Mice; Molecular Targeted Therapy; Sjogren's Syndrome; T-Lymphocytes
PubMed: 25342375
DOI: 10.1093/rheumatology/keu417 -
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