March 23, 2015
Editor: Andrew H. Lichtman, MD, PhD, Brigham & Women's Hospital
Editorial Board: Abul K. Abbas, MD, University of California, San Francisco | Carla J. Greenbaum, MD, Benaroya Research Institute | Andrew H. Lichtman, MD, PhD, Brigham & Women's Hospital
|Highlights from Recent Literature|
A review of Julia Cuende et al. Monoclonal antibodies against GARP/TGF-b1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo. Science Translational Medicine (2015) 7, 274ra18. PMID: 25904740
Regulatory T cells (Treg) play critical roles in initiating and maintaining self tolerance but they can also interfere with tumor immunity and permit the persistence of chronic infections. One of the mechanisms by which Treg suppress other T cells is by presenting inactive TGFb1 on the cell surface that becomes activated to immunosuppressive active TGFb1 by unknown mechanisms. The authors demonstrate that the protein GARP plays a key role in TGFb1 activation and that a monoclonal antibody that blocks this conversion inhibits Treg function.
By creating and studying antibodies against GARP, a protein that associates with latent TGFb1 on the surface of Treg, the authors demonstrated that GARP is involved in the activation of TGFb1 by Treg and that inhibition of this activity abrogates Treg mediated suppression in vitro and in an in vivo human anti-mouse GvHD model. Neutralizing anti-GARP antibodies are therefore a novel new class of Treg inhibitory therapeutics that may be valuable in the treatment of cancers and chronic infections.
Reviewed by Rachael A. Clark, MD, PhD, Brigham and Women's Hospital
A review of Mannick J., et al. mTOR inhibition improves immune function in the elderly. Science Translational Medicine. 6, 268ra179 (2014). PMID:25540326
Inhibition of the mammalian target of rapamycin (mTOR) pathway extends the life spans of multiple animal species but its effect on human aging is poorly characterized. In this report, the authors took the first steps towards characterizing mTOR inhibition in human aging by studying its effect on immune function in elderly individuals.
The authors found that a relatively short course of mTOR inhibitor therapy significantly increased the responses to influenza vaccination and reduced the number of PD-1 expressing T cells. Moreover, the authors noted efficacy at lower doses than those used in organ transplantation, thereby minimizing side effects. Further studies to characterize the effect of mTOR inhibition in younger individuals following vaccination and on other aspects of the immune system in elderly individuals are warranted.
Reviewed by Rachel A. Clark, MD, PhD, Brigham and Women's Hospital
A review of Becattini, et al. Functional heterogeneity of human memory CD4+ T cell primed by pathogens or vaccines. Nature Immunology. 2015; 347: 400-405. PMID:25477212
The nature and breadth of heterogeneity in human T cell responses has been the focus of many recent exciting studies. In this study, Becattini et al examine whether individual pathogens (including a fungus, bacteria and a vaccine) instigate one predominant subtype of human CD4+ helper cells and whether a single antigen specific clone can differentiate to multiple subtypes.
This group was able to delve deeper than previous studies into the nature and extent of flexibility of CD4+ T cells responses to pathogens and vaccinations. They demonstrated that diverse repertoires can be stimulated to expand in response to a given pathogen, and that individual clonotypes can be driven by a given antigenic experience to differentiate among each of the four examined CD4+ T cell subtypes. Different pathogens have an effect on the nature of the skewing of the CD4+ T cell subsets, but the mechanism remains unclear. This study emphasizes diversity and complexity at all levels in the immune response and raises many questions, from the mechanism and timing and signals that tip two given naïve T cells with the same clonotype down two different differentiation pathways, to the varied signals from a given pathogen that yield multiple T cell subsets. Becattini et al have further clarified in this elegant study the extent to which the human immune system is an amalgam of dynamic, interconverting, unique cells, wherein each variable (amplitude and type of antigenic stimulation, APC type, APC number, cytokine environment, etc.) has fundamental impact on both the population level as well as on each individual cell.
Reviewed by Sarah Henrickson, MD, PhD, Children's Hospital of Philadelphia
A review of Brodin, et al. Variation in the human immune system is largely driven by non-heritable influences. Cell. 2015; 160: 37-47. PMID:2594173
Investigation of twins is a fundamental tool in the study of the genetic component of human disease. By comparing monozygotic (MZ) and dizygotic (DZ) twins, it is possible to isolate the role of inherited factors on immune function. While these types of studies have previously been undertaken, this study allows for systems level analysis because many factors were studied in parallel. While the nature of the adaptive immune system, with its inherent somatic diversification of antigen receptors, makes possible an important role for somatic and environmental factors, the degree to which heritable factors are important in human immunology is a fascinating question.
This group was able to show that the immense variation in the human immune response is primarily non-heritable, merging the most traditional genetic technique (twin study) with cutting edge evaluation of immune system components, function and production and systems level analysis of that data. This study is fascinating both from the analysis of the data and the definitions it provides for cell populations and analysis technique.
Reviewed by Sarah Henrickson, MD, PHD, Children's Hospital of Philadelphia
A review of Liang L., et al. An epigenome-wide association study of total serum immunoglobin E concentration. Nature Immunology. 2015. PMID:2570780
Asthma and allergy are IgE-related diseases that affect millions of patients worldwide. The role of genetics in IgE regulation in human allergy and asthma is poorly understood. Genome-wide association studies (GWAS) have revealed polymorphisms in STAT6. FCER1A, IL4/RAD50 and the MHC locus that only account for 1-2% of the variation in IgE levels. By using 95 nuclear family pedigrees and methylation arrays, Liang and colleagues examine the genome-wide epigenetic associations between serum IgE levels and methylation at loci with CpG islands. The authors used Illumina HumanMethylation27 arrays to examine individual CpG loci within the proximal promoter regions of 14,475 genes. Models were fitted with log-normalized IgE as a dependent variable and methylation status of each Illumina probe as a predictor. Their epigenomic analysis implicates eosinophils and their associated proteins in governing IgE concentration. There are several intriguing observations from this work:
These data suggest that eosinophil counts and methylation at genes encoding eosinophil proteins contribute to serum IgE levels. The top three loci in the authors’ analysis account for 13% of IgE variation in their cohort and represent novel druggable targets for the treatment of allergy and asthma. This work also supports epigenome approaches as a useful way to understand disease pathogenesis and to identify new therapeutic approaches.
Reviewed by Michelle L. Hermiston, MD, PhD, University of California, San Francisco
A review of Chavele K.M., et al. Circulating plasmablasts induce the differentiation of human T follicular helper cells via IL-6 production. Journal of Immunology. 2015; 194(6):2482-5. PMID:25681343
Previous work has shown that CD4+ T follicular helper (Tfh) B cell interactions in the follicles of lymphoid organs are required for B cell survival, high-affinity B cell responses to antigen, and facilitating differentiation into plasma cell and memory B cells. Production of IL-21 by Tfh cells is critical for optimal B cell responses to antigen. In turn, murine studies indicate B cells production of IL-6 can influence Tfh differentiation. However, the role of B cells in human Tfh cell differentiation is poorly understood. In this study, Chavele and colleagues demonstrate the role of human B cell production of IL-6 on Tfh differentiation in healthy controls and elucidate a novel mechanism of action for the anti-IL-6 biologic agent Tocilizumab in Rheumatoid Arthritis (RA) patients. There are several important findings from this work.
Taken together, these data support a model for a positive feedback loop between Tfh cell and plasmablast differentiation in which plasmablasts induce Tfh cell differentiation by IL-6 production and Tfh cells augment plasmablast differentiation by IL-21 production. While such a feedback loop could be beneficial in infection, it could be detrimental in autoimmune disease due to the rapid proliferation and differentiation of antibody-secreting cells in RA. An important next step is to determine how this feedback loop is initially triggered. This work also supports a novel mechanism of action for the anti-IL6R antibody Tocilizumab in RA and potentially other autoimmune diseases. Conversely, augmenting this pathway could be beneficial in boosting adaptive immune responses to vaccines.
Reviewed by Melissa, Ruck, MD, PhD, and Michelle Hermiston, MD, PhD, University of California, San Francisco
A review of Brough, H.A., et al. IL-9 is a key compontent of TH cell peanut-specific responses from children with peanut allergy. J Allergy Clinical Immunology 134: 1329-1338.
Peanut allergy affects ~1.4% children in the United States, and its prevalence has been reported to be on rise. Definition of criteria that help distinguish between peanut-allergic (PA) and peanut-sensitized (PS) individuals safely is an unmet need in the clinical diagnosis of peanut allergy. In this study, the authors carried out an exploratory microarray investigation of gene expression in peanut-activated memory Th (CD4+ CD69+ CD45RO+) subsets from children, who are PA, or PS, or atopic without peanut allergy (NA) to identify diagnostic biomarkers. The following results were reported:
The findings from this study thus have important implications with regards to diagnosis and clinical desensitization of peanut-allergic children.
Reviewed by Kari Nadeau, MD, PhD, Stanford School of Medicine
A review of Stephan S.B., et al. Biopolymer implants enhance the efficacy of adoptive T cell therapy. Nature Biotechnology 33, 94-98. 2015. PMID:25503382
Adoptive T cell therapy has shown promise for the treatment of some cancers; but unfortunately for most solid tumors is limited by the inefficient trafficking of transferred lymphocytes to the tumor site and poor expansion of the infused cells within the immunosuppressive tumor microenvironment. In this study, Stephan and colleagues describe a bioactive polymer implant capable of improving the delivery and expansion of tumor reactive T cells in the tumor microenvironment, thereby inducing more potent antitumor responses when compared to more traditional methods of adoptive T cell therapy.
This study shows that the antitumor efficacy of adoptive lymphocyte transfer may be improved by delivering them in biopolymer scaffolds engineered to promote lymphocyte expansion and migration in the tumor microenvironment; and suggests that scaffold-based T cell delivery may provide an effective therapy for incompletely resected and/or inoperable tumors. In addition, the use of scaffolds does not require patient irradiation, systemic cytokine administration, or chemotherapeutic lymphodepletion; and therefore also has the potential to minimize toxicity.
Reviewed by Heather Kinkead and Eric Lutz, PhD, Johns Hopkins University
A review of Soares K.C., et al. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector t cell infiltration into pancreatic tumors. Journal of Immunotherapy 38, 1-11. 2015. PMID:25415283
Pancreatic cancer is predominantly infiltrated with immunosuppressive cells and signals and has historically been considered as a non-immunogenic tumor In concordance with this notion, pancreatic cancer has not responded to treatment with single-agent checkpoint inhibitors targeting PD-1, PD-L1 or CTLA-4 that have shown promise for other cancers, including melanoma, renal cell carcinoma, and lung cancer. Treatment with a GM-CSF-secreting allogeneic whole pancreatic cancer cell vaccine (GVAX) can activate tumor specific T cells and induce the formation of intratumoral tertiary lymphoid aggregates, and thereby convert the immunologically quiescent pancreatic cancer microenvironment into an active one. However, like single-agent checkpoint inhibitors, treatment with GVAX alone produces limited survival benefit to patients with pancreatic cancer. In this study, Soares et al show that treatment with GVAX induces both the infiltration of activated effector T cells, and the upregulation of PD-L1 expression in the pancreatic cancer tumor microenvironment; and that the combination of GVAX with PD-1-targeted checkpoint blockade is more effective than either single therapy alone.
This study demonstrates that vaccination can convert a non-immunogenic tumor that does not respond to PD-1-targeted checkpoint therapy into a tumor that does respond to PD-1-targeted checkpoint therapy by inducing the infiltration of T cells and the upregulation of PD-L1 expression. This study may explain why vaccines and immune checkpoint inhibitors as single agents have failed against pancreatic cancer, and possibly other non-immunogenic cancers (vaccines alone fail because the T cells they induce are inhibited by immunosuppressive mechanisms, such as the PD-1 pathway; and immune checkpoint inhibitors alone fail because there are too few effector T cells for them to act on). Most importantly, this study supports a new approach for evaluating checkpoint inhibitors in “non-immunogenic” cancers, like pancreatic cancer.
Reviewed by Alexander Hopkins and Eric Lutz, PhD, Johns Hopkins University
|Highlights From Clinical Immunology, the Official Journal of FOCIS|
A review of Renauera A.,et al. The DNA methylation signature of human TCRαβ+CD4-CD8- double negative T cells reveals CG demthylation and a unique epigenetic architecture permissive to a broad stimulatory immune response. Clinical Immunology 156, 19-27, 2015. PMID:25451162
Peripheral TCR αβCD4-CD8- “double negative” T cells (DN T) are a poorly understood subset of T cells which appear to have TCR-dependent regulatory functions against single positive effector T cells in healthy individuals but are expanded and have a pro-inflammatory phenotype in patients with various auto-immune diseases. In this paper, the authors characterized DNA methylation (the “methylome”) of DN T cells and used bioinformatics tools to look for patterns of of immune activity and regulation. They FACs isolated TCR αβCD4-CD8-, TCR αβCD4+CD8- and TCR αβCD4-CD8+ cells from healthy women, ages 25-60 years, purified DNA, and performed a chip based assessment of methylation of both CGs and non CG sites, across the genome. The major findings included the following:
DNA methylation has been shown to be an important epigenetic mechanism for regulation of T cell subset lineages, such as TH1, TH2, and TH17 cells. Epigenetic suppression of CD8 expression in DN T cells has been previously shown as well. This study broadens our knowledge of the DNA methylation status of DN T cells, and establishes that there is a global hypomethylation status of many immune genes, consistent with a pro-inflammatory function of these T cells. Furthermore, the study suggests that methylation of CD4 may be related to DN T cell differentiation. It would be interesting to know of the methylaltion status of genes in DN T cells from patients with SLE, or other autoimmune diseases, in which these cells are expanded, compared to the healthy women studied here.
Reviewed by Andrew H. Lichtman, MD, PhD, Brigham and Women’s Hospital
A review of Young NA., et al. A chimeric human-mouse model of Sjögren’s Syndrome. Clinical Immunology 156, 1-8, 2015. PMID:25451161
Sjögren's Syndrome (SjS) is a systemic autoimmune disease that mainly affects women. Manifestations typically include dry eyes and mouth, but also systemic manifestations, such as arthritis, neuropathy and lung fibrosis. The underlying mechanisms of Sjögren's Syndrome are not known, and although there are mouse models of the disease, there translatability to testing therapies for the human disease is questionable. To this end, Young et al. have developed a humanized mouse SjS model, by adoptively transferring peripheral blood mononuclear cells (PBMCs) from SjS patients into immunodeficient NOD-scid γc-null mice (NSG). NSG mice are known to stably engraft human lymphcoytes, and have been used to study T1D, but not other human autoimmune diseases. The authors compared several parameters in NDG mice with SjS PBMC transfers vs. NSD mice with healthy control PMBM transfers:
This new humanized mouse model of SjC syndrome recapitulates some important features of the human disease, especially salivary and lacrimal gland inflammation by CD4+ T cells. The model has the potential to enable studies of immunopathogenesis and therapy. It is not clear for this report how the human T cells become specifically recruited to or activated in the mouse lachrymal and salivary glands. If the CD4+ T cells in the tissues are typical TCR αβ T cells, it will be of interest to know if they being activated mouse tissue antigens homologous to human antigens, and if so, what the antigen presenting cells are.
|Human Immunophenotyping Update|
J. Phillip McCoy, Jr. PhD, National Institute of Health
All too often I have read papers in highly respected journals where data from flow cytometric experiments are published in a manner that makes me cringe. Generally, the methods section reads ‘we performed FACS on these cells’ with no other experimental detail. The results generally show a figure with one or more dot plots having no scales or labels on the axes. Why do these make me cringe? I cringe because there is little chance of anyone being able to duplicate the authors’ results given this paucity of information, and the lack of replication would lead to skepticism over the data and conclusions.
Let’s begin with the methods. The statement “We performed FACS” gives little information and what information is given might be misleading. The acronym FACS stands for Fluorescent-Activated Cell Sorting. If you did not physically sort the cells, you did not perform FACS, rather you performed immunophenotyping or flow cytometry. Semantics aside, to reproduce these data much more information is needed – even if it is provided as supplemental data. To start, the reagents and fluorochromes (or dyes) used should be specified. Ideally, for antibodies, this would include the clone or catalog number for the reagent. Why? Not all clones, even for the same CD are identical. For example, as we discovered in our preparation for the FOCIS HIPC Lyoplate study, not all CD38 clones give equivalent results. Furthermore, fluorochromes have different quantum yields, or “brightness”. Staining relatively dim markers, such as intracellular cytokines, with a relatively dim fluorochrome such as FITC will yield substantially less cytokine detection than staining with a brighter fluorochrome such as phycoerythrin (PE). Similarly, information about the cytometer would be highly useful. For example, what laser(s) were used to excite the fluorochromes? This is important because particular laser wavelengths may better excite fluorochromes than other wavelength, thus affecting the brightness of fluorochromes. An example of this would be the excitation of PE. PE will excite off of a 488nm laser, but is brighter when excited with a 532nm laser, and brighter still when excited at 561nm. Referring again to the cytokine example, the laser excitation will potentially influence the number of cells determined to be positive for staining. PMT voltages and compensation values will vary on every instrument and would not need to be included in the methods, but the filter configuration in the cytometer would be useful. To summarize, including complete information is vital to the credibility of the publication. Including the information as a table when publishing flow cytometry experiments, even as a supplement can be quite powerful as seen in Tables 1 and 2. In addition, the clarity gained from using this format to publish the information rather than publishing no information at all or listing the information as an endless paragraph of CDs, clones and fluorochromes is obvious.
Moving to the results and presentation of the flow cytometry data, what sense does it make to publish dot plots with no scales or labels? Can you think of any other data, chart, or graph that you would publish without a scale or labels? Probably not. Flow cytometers can collect, and present data, on either logarithmic or linear scales, and log scales may cover differing numbers of decades. Axis scales can even bi-exponential or log-linear. Thus the scale on a dot plot is very informative, particularly if you want others to be able to replicate your work. Labels such as “FL1” or “FL2” have little meaning in comparison to labels such as “FITC CD3” and “PE CD4” and therefore it is recommended that the labels include the antibody and fluorochrome (or dye) (Figure 1). It is also quite useful to know precisely how a gate was determined, or how ‘positive’ events were calculated. Was it through the use of an “N-1” control, an isotype control, or perhaps by cluster analysis? It is common practice to publish only the final, most pertinent dot plot showing the data of interest. This is understandable considering the page and figure constraints imposed by many journals. Nonetheless, it would be most useful to include dot plots of the entire gating scheme leading to the final dot plot as supplemental figures.
Figure 1. Examples of uninformative (left) and informative (right) dot plots of the same data
Reporting of flow cytometry data should also be very specific on what data are being presented. For example, stating that there are “x % memory T cells” does not tell the reader if the denominator is all T cells or all lymphocytes, or even all leukocytes. A clearer manner of stating this would be to say “of the CD3+ T cells, x% displayed a memory phenotype.” If data are presented concerning the mean fluorescence intensity (MFI), a statement should be included to explain how the MFI was obtained and whether or not these values were normalized based on a negative population.
The suggestions given here for publishing flow cytometry data permit accurate reporting of these data, enabling other investigators to more readily reproduce your findings. The current suggestions largely reiterate those made in a previous publication (1). Even more rigorous publication guidelines for flow cytometry data can be found in MiFlowCyt (minimum information about a flow cytometry experiment), recommended by the International Society for the Advancement of Cytometry (2).
|Developments in Basic Immunology and Novel Therapies|
Shiv Pillai, MD, PhD, Ragon Institute of MGH, MIT and Harvard; Harvard Medical School
B cell depletion using a monoclonal antibody to CD20, a B cell surface protein whose function remains poorly defined, was first conceived of as a therapeutic strategy to treat B cell lymphomas and chronic lymphocytic leukemia. Although this approach is still utilized for the treatment of B cell malignancies, B cell depletion has since emerged as a powerful way to treat a number of autoimmune and inflammatory conditions, including certain disorders that are generally believed to be caused by T cells. The initial anti-CD20 antibody used for therapy was a chimeric antibody called Rituximab. Rituximab remains the major B cell depleting reagent in clinical use today. The success of Rituximab therapy has spawned the generation of a number of newer therapeutics that also target B cells.
During B cell development, CD20 is first expressed on pre-B cells and can be more readily detected on immature, transitional, mature and memory B cells but is lost when activated B cells differentiate into plasmablasts. It is not normally found on plasma cells though malignant cells in a small subset of multiple myelomas express CD20. Depletion of normal or malignant B cells is influenced by polymorphisms of the FcγRIIIA gene, suggesting that antibody dependent cellular cytotoxicity mediated by NK cells or macrophage mediated antibody dependent phagocytosis contributes to B cell removal. One study has shown that most of the clearance of B cells actually occurs in the liver and is mediated by Kupffer cells.
Rituxan mediated B cell depletion has proved to be an efficacious therapy for a number of autoimmune disorders. An incomplete list would include autoimmune thrombocytopenia, rheumatoid arthritis, relapsing remitting multiple sclerosis, Wegener's granulomatosis, IgG4 related disease and myasthenia gravis. This approach has proved less useful overall in systemic lupus erythematosus, although some subjects with lupus do respond to B cell depletion. It is relatively easy to understand why Rituxan might be useful in diseases like myasthenia gravis, autoimmune thrombocytopenia and pemphigus for instance, all disorders in which autoantibodies play a causal role. Depleting B cells may be considered to be one way in which the titers of disease causing antibodies could be induced to drop.
B cell depletion using anti-CD20 targets B cells but not plasmablasts or plasma cells. If an auto-antibody is largely made in the context of an ongoing immune response and is largely secreted by plasmablasts and short-lived plasma cells then anti-CD20 mediated B cell depletion would likely be clinically effective. Auto-antibodies made by long-lived plasma cells would not be depleted by such a therapy. We can therefore assume that in auto-antibody mediated diseases in which clinical improvement is seen with B cell depletion, the majority of the relevant autoantibodies are in fact secreted by plasmablasts and short-lived plasma cells. The reason why lupus may often not be responsive to anti-CD20 mediated B cell depletion may reflect the central role of nucleic acids and chromatin as the auto-antigens in this disease. The ability of these antigens to also activate endosomal Toll like receptors in B cells may facilitate the differentiation of activated lymphocytes emerging from the germinal center reaction into long-lived plasma cells. It is also possible that in some diseases, B cell depletion, apart from depleting cells poised to differentiate into plasmablasts, also depletes regulatory B cells that may normally function to constrain autoimmunity. In such a context, B cell depletion may indeed cause disease exacerbation rather than remission.
Why does anti-CD20 mediated B cell depletion lead to remission in conditions like multiple sclerosis and other T cell mediated autoimmune diseases? It is likely that some diseases that many immunologists assume are T cell mediated are actually primarily linked to T cell help for B cells that secrete pathogenic autoantibodies. A case in point may be rheumatoid arthritis, a disease in which antibodies against citrullinated proteins and immune complexes incorporating these antibodies may be critical for disease onset and progression. Follicular helper T cells may well be relevant for HLA class II dependent help to disease causing B cells, and Th17 cells may contribute to inflammation in a secondary context. In other diseases like multiple sclerosis in which T cells likely play a predominant role, B cells may provide “help” to T cells. It is well established that effector/memory CD4+ T cells are sustained by B cells. How exactly this occurs is unclear. It is assumed that high affinity somatically mutated memory B cells may be the most effective antigen presenting cells for the activation of rogue effector and effector/memory CD4+ T cells that drive autoimmunity and chronic inflammation.
Although Rituxan is still widely used there are a number of different anti-CD20 agents that have been developed. These include humanized and fully human versions of anti-CD20. Some examples include Ocrelizumab, a humanized anti-CD20 antibody, Obinutuzumab, another humanized anti-CD20 which has been glyco-engineered to facilitate Fc receptor engagement and B cell clearance and Ofatumumab, a fully human version of anti-CD20. Many other B cell therapies have also been developed but a therapeutic that can effectively clear long-lived plasma cells has so far not yet emerged.
|Selected Recent Clinical Trial Results|
Disease: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis.
Why the Trial is of Interest to the Broader FOCIS Community:
Recently, the Chapel Hill Consensus Conference proposed its 2012 classification system which divides ANCA-associated vasculitis (AAV) into multiple subgroups defined by clinical symptoms and pathophysiology. These include granulomatosis with polyangiitis (GPA; formerly termed Wegener’s), microscopic polyangitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA; formerly termed Churg Strauss Syndrome). EGPA is considered separately from GPA and MPA as it has a different clinical presentation and prognosis. GPA is most frequently associated with proteinase 3 (PR3) specific ANCA, and myeloperodiase (MPO) ANCA is associated with MPA, but with significant overlap. Clinically, those with renal-limited disease can be considered another subgroup. In North America and Europe, GPA (Wegener’s) has a higher prevalence than MPA.
Reviewed by Sandra Lord, MD, Benaroya Research Center
Disease: Psoriatic Arthritis
Why The Trial is of Interest to the Broader FOCIS Community:
In contrast, IL-17/IL-23 inhibition has not been as effective for PsA as measured by the ACR (American College of Rheumatology) score, a clinical measure of arthritis activity. ACR 20 indicates a 20% improvement in disease activity and is the endpoint in most inflammatory arthritis trials. Phase III trials of secukinumab (5,6) and ustekinumab (7,8) showed similar treatment response rates: ~50% in treated groups met the ACR 20 at 24 weeks vs ~20% in placebo groups. In the reviewed study, 64% of subjects in the highest-dose brodalumab group met the ACR 20 at 24 weeks. However, it is difficult to compare the results of this study, in which the primary endpoint was at 12 weeks, followed by open label extension, to the secukinumab and ustekinumab studies, in which the primary endpoint was at 24 weeks. Without this comparison, it is unclear whether IL-17R blockade with brodalumab provides a greater clinical response in PsA than do either IL-17A inhibition with secukinumab, or IL-12/IL-23 inhibition with ustekinumab. The continued improvement seen in all treated groups between week 12 and 24 suggests that a full clinical response in psoriatic arthritis might require longer than 12 weeks of treatment.
Reviewed by Sandra Lord, MD, Benaroya Research Institute
Anti-thymocyte Globulin/G-Csf Treatment Preserves B Cell Function in Patients with Established Type 1 Diabetes
Disease: Type 1 diabetes
Why the Trial is of Interest to the Broader FOCIS Community:
Combination therapy may have several advantages, such as reduced risk of adverse effects if the combination permits lower doses or shorter duration of treatment and allowing for more specific targeting of different pathogenic pathways. Thus, a key point of interest from this study is that these positive results are in contrast to results from other studies using the same agents individually. In higher doses than employed in this trial, ATG alone did not preserve insulin secretion in a previously reported fully powered, phase 2, placebo controlled trial of individuals within a few months of diagnosis (1). A smaller study with GCSF alone was also negative (2). By trialing the arms individually in the upcoming TrialNet study, investigators may be able to sort out whether there is therapeutic synergy with the combination, or whether administration of a lower dose of ATG could limit untoward effects on Tregs suggested in the previous negative ATG study.
Reviewed by Sandra Lord, MD, Benaroya Research Center
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