Novel therapeutic strategies for multiple sclerosis--a multifaceted adversary

Therapeutic strategies for multiple sclerosis have radically changed in the past 15 years. Five regulatory-approved immunomodulatory agents are reasonably effective in the treatment of relapsing-remitting multiple sclerosis, and appear to delay the time to progression to disabling stages. Inhibiting disease progression remains the central challenge for the development of improved therapies. As understanding of the immunopathogenesis of multiple sclerosis has advanced, a number of novel potential therapeutics have been identified, and are discussed here. It has also become apparent that traditional views of multiple sclerosis simply as a CD4+ T-cell-mediated disease of the central nervous system are incomplete. The pathogenic role of other immune components such as the innate immune system, regulatory T cells, T helper 17 cells and B cells is reaching centre stage, opening up exciting avenues and novel potential targets to affect the natural course of multiple sclerosis.     

GM-CSF treatment for Crohn's disease: a stimulating new therapy?

Crohn's disease (CD) has been classically viewed as an overactive intestinal immune response to the normal constituents of the gut flora. Most therapeutic strategies to date have tried to suppress this overactive adaptive immune response. Recently, a novel, rather alternative therapeutic strategy has been proposed, wherein the approach is to stimulate the innate immune system with growth factors. This review will take a closer look at this unconventional hypothesis and the data that support it, and will place the information in the context of some of the other biological and experimental therapies currently under consideration for the treatment of CD.     

Emerging targeted therapies for melanoma

Introduction: Melanoma is an aggressive cutaneous malignancy associated with poor response to traditional therapies. Recent regulatory approval for immune checkpoint inhibitors and agents targeting mutated BRAF has led to a tremendous expansion of effective treatment options for patients with advanced melanoma. Unfortunately, primary or acquired resistance develops in most patients, highlighting the need for additional therapies. Numerous genetic and other molecular features of this disease may provide effective targets for therapy development.

Areas covered: This article reviews available melanoma treatments, including immune and molecularly-targeted therapies. We then discuss agents in development, with a focus on targeted (rather than immune) therapies. In particular, we discuss agents that block mitogen-activated protein kinase (MAPK) signaling, as well as other emerging approaches such as antibody-drug conjugates, cell-cycle targeting, and novel genetically-informed clinical trials.

Expert opinion: Despite the incredible advances in melanoma therapeutics over the last several years, a clear need to develop more effective therapies remains. Molecularly-targeted therapy approaches will likely remain a cornerstone of melanoma treatment in parallel to immune therapy strategies.     

Considerations on long-term immuno-intervention in the treatment of multiple sclerosis: an expert opinion

Introduction: As management of multiple sclerosis (MS) requires life-long treatment with disease-modifying agents, any risks associated with long-term use should be considered when evaluating therapeutic options.

Areas covered: Immune cells of the innate and adaptive immune systems play various roles in the pathogenesis of MS. MS therapies affect the immune system, each with a unique mode of action, and consequently possess different long-term safety profiles. Rare, but serious safety concerns, including an increased risk of infection and cancer, have been associated with immunosuppressant use. The risks associated with newer immunosuppressive agents, which target specific elements of MS disease pathophysiology, are not yet fully established as the duration of clinical trials is relatively short and post-marketing experience is limited. Non-immunosuppressants used to treat MS have well-defined safety profiles established over a large number of patient-years demonstrating them to be well-tolerated long-term treatment options. When considering the long-term use of disease-modifying agents for treating MS, classification as immunosuppressants or non-immunosuppressants can be useful when evaluating potential risks associated with chronic use.

Expert opinion: A successful therapeutic strategy for any serious, chronic disease such as MS should weigh effectiveness versus long-term safety of available treatments.     

CD26/dipeptidyl peptidase IV as a novel therapeutic target for cancer and immune disorders

CD26 is a 110 kDa surface glycoprotein with intrinsic dipeptidyl peptidase IV (DPPIV) activity that is expressed on numerous cell types and has a multitude of biological functions. An important aspect of CD26 biology is its peptidase activity and its functional and physical association with molecules with key roles in various cellular pathways and biological programs. CD26 role in immune regulation has been extensively characterized, with recent findings elucidating its linkage with signaling pathways and structures involved in T-lymphocyte activation as well as antigen presenting cell-T-cell interaction. Recent work also suggests that CD26 has a significant role in tumor biology, being both a marker of disease behavior clinically as well as playing an important role in tumor pathogenesis and development. In this paper, we will review emerging data that suggest CD26 may be an appropriate therapeutic target for the treatment of selected neoplasms and immune disorders. Through the use of various experimental approaches and agents to influence CD26/DPPIV expression and activity, such as anti-CD26 antibodies, CD26/DPPIV chemical inhibitors, siRNAs to inhibit CD26 expression, overexpressing CD26 transfectants and soluble CD26 molecules, our group has shown that CD26 interacts with structures with essential cellular functions. Its association with such key molecules as topoisomerase IIalpha, p38 MAPK, and integrin beta1, has important clinical implications, including its potential ability to regulate tumor sensitivity to selected chemotherapies and to influence tumor migration/metastases and tumorigenesis. Importantly, our recent in vitro and in vivo data support the hypothesis that CD26 may indeed be an appropriate target for therapy for selected cancers and immune disorders.     

Targeting fibrosis in systemic sclerosis

Finding effective treatments for patients with systemic sclerosis (SSc) remains one of the final frontiers in therapeutic discovery. Although remarkable progress has been made in the symptomatic treatment of various organ system manifestations, little is available that treats the underlying disease process. SSc patients do not respond to many of the medications that provide benefit in related diseases, such as systemic lupus erythematosus, polymyositis and chronic graft-versus-host disease. Current research has not even clarified whether the complex pathogenesis starts primarily in vascular, immunological or connective tissues. Herein are discussed selected emerging therapeutics and therapeutic approaches designed to target the underlying immunological and fibrotic disease processes. Distinctive fibrotic features and data from translational research consistently place transforming growth factor-beta (TGFbeta) as a central mediator in SSc. The discovery of agents targeting TGFbeta, its activation or its intracellular signaling suggest that TGFbeta pathway inhibitors efficacious for the treatment of SSc may soon be identified. IL-4 and IL-13 are other fibrotic mediators produced during immune activation that might be targeted for SSc therapy, and therapeutics targeting these interleukins are also being developed. Immune dysregulation, leading to overproduction of these or other fibrotic mediators might respond to currently available immunosuppressives: mycophenolate, cyclosporine, tacrolimus or sirolimus, alone or in combination. Nucleic acid-containing immune complexes may also contribute to toll-like receptor mediated immune dysregulation in SSc, suggesting that agents targeting the innate immune system may ameliorate SSc. Thus, the complexity of SSc pathogenesis provides a plethora of targets for urgently needed new therapies.     

Role of Immunotherapy in Targeting the Bone Marrow Microenvironment in Multiple Myeloma: An Evolving Therapeutic Strategy

Multiple myeloma (referred to henceforth as myeloma) is a B‐cell malignancy characterized by unregulated growth of plasma cells in the bone marrow. The treatment paradigm for myeloma underwent significant evolution in the last decade, with an improved understanding of the pathogenesis of the disease as well as the development of therapeutic agents that target not only the tumor cells but also their microenvironment. Despite these therapeutic advances, the prognosis of patients with relapsed or refractory myeloma remains poor. Accordingly, a need exists for new therapeutic avenues that can overcome resistance to current therapies and improve survival outcomes. In addition, myeloma is associated with progressive immune dysregulation, with defects in T‐cell immunity, natural killer cell function, and the antigen‐presenting capacity of dendritic cells, resulting in a tumor microenvironment that promotes disease tolerance and progression. Together, the immunosuppressive microenvironment and oncogenic mutations activate signaling networks that promote myeloma cell survival. Immunotherapy incorporates novel treatment options (e.g., monoclonal antibodies, antibody‐drug conjugates, chimeric antigen receptor T‐cell therapy, immune checkpoint inhibitors, bispecific antibodies, and tumor vaccines) either alone or in combination with existing lines of therapies (e.g., immunomodulatory agents, proteasome inhibitors, and histone deacetylase inhibitors) to enhance the host anti myeloma immunity within the bone marrow microenvironment and improve clinical response. Following the U.S. Food and Drug Administration approval of daratumumab and elotuzumab in 2015, more immunotherapeutic agents are expected to be become available as valuable treatment options in the near future. This review provides a basic understanding of the role of immunotherapy in modulating the bone marrow tumor microenvironment and its role in the treatment of myeloma. Clinical efficacy and safety of recently approved therapeutic monoclonal antibodies (daratumumab, elotuzumab) are discussed, along with the therapeutic potential of emerging immunotherapies (antibody‐drug conjugates, chimeric antigen receptor T‐cell therapy, tumor vaccines, and immune checkpoint inhibitors).     

Possible drug targets for celiac disease

Celiac disease (CD) is an intestinal disorder caused by an altered immune response against wheat gluten, a common dietary antigen, and related cereal proteins. Both CD4+ and CD8+ T cells have a role in inducing the intestinal damage, although recent studies have also pinpointed the involvement of the innate immune response in CD pathogenesis. So far, the only available treatment for CD is the strict avoidance of gluten in the diet, but the poor compliance and the associated complications demand alternative therapies. During the last decade, the knowledge of genetic, molecular and cellular mechanisms leading to CD pathogenesis made great progress. The improved understanding of gluten peptides activating either adaptive or innate immune response, of HLA restriction molecules, as well as of cytokines that mediate most of the inflammatory reactions, opens several new promising perspectives for therapeutic intervention. This review discusses both molecular and cellular strategies to treat CD, including the use of proteolytic enzymes active on gluten peptides, antibodies neutralising IL-15 and IFN-gamma, drugs targeting HLA, regulatory cytokines and T cells.     

An overview of immunomodulatory intervention in rheumatoid arthritis

In recent years there has been exceptional progress in the development of immunomodulatory interventions for the treatment of rheumatoid arthritis (RA). Part of the impetus for the creation of novel therapies for RA has come from a growing appreciation of the substantial morbidity and mortality that this chronic, progressive disease causes for affected patients. In addition, there has been the realization that currently available therapeutics are suboptimal as regards both their efficacy and tolerability. The development of newer therapies has been facilitated by two factors; a greater understanding of the immunopathogenesis of RA and progress in biotechnology that has allowed the creation of specific inhibitors and other agents. Myriad studies performed by investigators throughout the world have helped delineate the immunologic basis of RA. It appears that various components of the immune system are involved in the initiation and propagation of this systemic inflammatory disease. T-cells, and in particular activated CD4(+) 'memory' T-cells, serve a central role in orchestrating the immune response that underlies rheumatoid inflammation. Other cells, including monocytes, fibroblasts, B-cells, dendritic cells, mast cells and neutrophils also contribute significantly to various aspects of disease. Adhesion molecules mediate many intercellular interactions, thus contributing to activities such as the accrual of cells within the synovium and the activation of cells. Cytokines, small peptides that exert numerous inflammatory activities and cause many of the signs and symptoms of RA, play a crucial role. Indeed, RA may be considered a disorder of 'cytokine dysregulation' in that the activity of proinflammatory cytokines such as TNF-alpha and IL-1 is enhanced, and overwhelms the effects of antiinflammatory factors. Finally, a host of other inflammatory mediators are involved in the disease process. Thus, many components of the immune response may be attractive therapeutic targets for immunomodulatory intervention in RA. Advances in biotechnology have permitted the creation of specific inhibitors of distinct components of the immune system. Monoclonal antibodies (MAbs) have been created to target various cell surface molecules and cytokines. At first, most MAbs were murine in origin, which can present problems as regards immunogenicity. More recently, progress in molecular biologic techniques has allowed the synthesis of hybrid antibodies that are partly human. Such techniques have also allowed the creation of cytokine receptors coupled to immunoglobulin molecules, and other constructs. These agents can be modified to provide optimal characteristics in terms of half-life, immunogenicity and specificity, and this is an exciting area of new development. Progress has also been made in molecular-based agents that directly modify the genes or gene products for specific targets. To date, a number of trials assessing novel immunomodulatory therapies have been undertaken. In some cases, such as with inhibitors of TNF-alpha, the results have been dramatic and exciting. Further development and refinement may allow the introduction of these agents into the clinic in the foreseeable future, and will provide an important area for further research. In other cases, for example with therapies targeting CD4(+) molecules, the results have not been as promising as was hoped. Nevertheless, critical analysis of the results of these studies has provided insights into the pathogenesis of RA which may prove quite valuable for future trials. A number of agents are being studied actively at the present time, and it is hoped that they too may generate novel therapies for, and a greater understanding of, this difficult disease. The future for immunomodulatory intervention in RA looks very promising. Greater understanding of the intricacies of the immune response that underlie this disease should continue to yield viable, specific targets for novel therapies. Advances in biopharmaceuticals should generate treatments that maximize efficacy while minimizing toxicity. This should allow the clinician truly to modify the disease and achieve tangible improvements in the lives of RA patients.     

Possible drug targets for celiac disease

Celiac disease (CD) is an intestinal disorder caused by an altered immune response against wheat gluten, a common dietary antigen, and related cereal proteins. Both CD4⁺ and CD8⁺ T cells have a role in inducing the intestinal damage, although recent studies have also pinpointed the involvement of the innate immune response in CD pathogenesis. So far, the only available treatment for CD is the strict avoidance of gluten in the diet, but the poor compliance and the associated complications demand alternative therapies. During the last decade, the knowledge of genetic, molecular and cellular mechanisms leading to CD pathogenesis made great progress. The improved understanding of gluten peptides activating either adaptive or innate immune response, of HLA restriction molecules, as well as of cytokines that mediate most of the inflammatory reactions, opens several new promising perspectives for therapeutic intervention. This review discusses both molecular and cellular strategies to treat CD, including the use of proteolytic enzymes active on gluten peptides, antibodies neutralising IL-15 and IFN-γ, drugs targeting HLA, regulatory cytokines and T cells.     

Novel approaches in the treatment of lupus nephritis

In systemic lupus erythematosus hyperactive helper T-cells drive polyclonal B-cell activation and secretion of pathogenic auto-antibodies. The auto-antibodies form immune complexes with their respective auto-antigens, which in turn deposit in sites such as the kidney and initiate a destructive inflammatory reaction. Lupus nephritis can be managed successfully in the majority of cases; however, the most widely used immunosuppressive therapies, notably corticosteroids and cyclophosphamide are non-specific and are associated with substantial toxicities. Novel treatments for lupus nephritis have to be at least as effective and less toxic than existing therapies. The ultimate aim is to develop treatments that target specific steps in the disease process. Novel therapeutic strategies in the short-term more likely will focus on refining regimens of drugs that are already in use (mycophenolate mofetil, adenosine analogues) and combinations of existing chemotherapeutic agents, as well as attempts to achieve immunological reconstitution using immunoablative chemotherapy with or without haematopoietic stem cell rescue. Several new agents targeting specific steps in the pathogenesis of lupus are in various phases of clinical development. Interrupting the interactions between T-lymphocytes and other cells by blocking co-stimulatory molecules, such as CD40 ligand or CTLA4-Ig, may interfere with the early steps of pathogenesis. Blocking IL-10 may decrease auto-antibody production and help normalise T-cell function. Treating patients with DNase or interfering with the complement cascade by blocking C5, or neutralising pathogenic antibodies by administering specific binding peptides or inducing specific anti-idiotype antibodies may prevent immune complex formation and/or deposition.     

Emerging biological therapies for the treatment of myelodysplastic syndromes

Introduction: No drug has resulted in a survival advantage in patients with lower-risk myelodysplastic syndromes (MDS). While hypomethylating agents (HMA) have revolutionized treatment options for patients with higher-risk MDS, the prognosis remains dismal after HMA treatment failure. Novel effective therapies are urgently needed especially after HMA failure.

Areas covered: This review covers the current approach to disease prognostication and risk-adaptive therapy, as well as novel therapeutic approaches. We discuss the recent advancements in the understanding of MDS disease biology as a basis of targeted drug development. Several classes of novel agents are reviewed including drugs targeting dysregulated epigenetic control mechanisms, signaling pathways, abnormal splicing, as well as agents that target the immune system and the MDS bone marrow niche.

Expert opinion: Significant advancements in the understanding of the underlying biology of MDS are only starting to be translated into novel treatment options for MDS. Epigenetic therapy has shown significant clinical activity with HMA but the results of clinical trials combining HMAs with histone deacetylase inhibitors (HDACi) have been disappointing to date. Similarly, targeting several aberrant pathways in MDS has not resulted in significant improvements in therapy. Future therapies will focus both on synergic combination of existing drugs as well as novel agents targeting dysregulated immune responses and abnormal RNA splicing in MDS.     

The Annual European Congress of Rheumatology: recent advances in the treatment of rheumatic diseases. Lisbon, Portugal, June 18-21, 2003

The topics discussed at this conference covered many aspects of the pathogenesis, epidemiology, diagnosis and treatment of rheumatic diseases, from the search of new therapeutic targets and evaluation of new diagnostic techniques to preclinical and clinical development of novel therapies. This contribution focuses primarily on two issues that dominated this meeting. First, a number of interesting studies presented during this conference examined the possible value of novel selective therapies directed against recently identified targets of the immune system including cytokines (TNF-alpha, IL-6, IL-15) and inflammatory cells, such as B cells, CD4(+) T cells or memory/effector T cells. Second, clinical experience with newer anti-inflammatory treatments, such as TNF-alpha-blocking agents or leflunomide, is growing judging by the number of reports of their use in clinical practice and new indications. Several studies presented at this meeting examined the value of currently licensed drugs in new indications, such as ankylosing spondylitis or psoriatic arthritis, or studied new combinations of drugs, for example, a combination of different biological treatments (e.g., anakinra, etanercept), in already established indications. Interestingly, the results of these studies were not always as expected, thus increasing the importance of these particular trials. The growing experience with some of these novel therapies clarify the role of these treatments in particular forms of rheumatic diseases and will help to develop guidelines for the use of these sometimes powerful but also possibly harmful agents in clinical practice.     

CD26/dipeptidyl peptidase IV: a regulator of immune function and a potential molecular target for therapy

CD26 is a 110 kDa surface-bound ectopeptidase with intrinsic dipeptidyl peptidase IV (DPP IV) activity, which has multiple biological functions. In this review, we will focus specifically on work demonstrating that CD26 has a key role in immune function as a T cell activation molecule and a regulator of the functional effect of selected biological factors through its DPP IV enzyme activity. As further evidence of the important role played by this multifaceted molecule in immune regulation, we will also discuss experimental attempts from our laboratory and others to influence immune-mediated conditions through CD26 monoclonal antibodies and DPP IV activity with various agents, including anti-CD26 monoclonal antibodies and DPP IV chemical inhibitors. Of special significance from a clinical perspective is also CD26 effect on glucose metabolism through its DPP IV activity and its potential role as a therapeutic target in diabetes. In addition, we will review recent studies that describe the physical and functional interaction of CD26 with other essential cellular structures and the biological consequences of their association. In particular, we will present recent data from our laboratory that demonstrates the correlation between CD26, especially its DPP IV activity, and the key nuclear protein topoisomerase II alpha, an interaction that has important clinical implications. In summary, we will examine the biology of the multifaceted CD26/DPP IV molecule, focusing particularly on its function in immune regulation and its potential role as a molecular target for novel treatment modalities for a number of disease states, ranging from autoimmune diseases, diabetes to malignancies.     

Therapeutic targeting of Toll-like receptors in cutaneous disorders

Introduction: The role of skin, as a part of the immune system has long been elucidated. Toll-like receptors (TLRs), a group of pattern recognition receptors, are involved in the recognition of invading pathogens, initiation of immune responses and regulation of both innate and adaptive immune systems. There is a growing body of evidence supporting the role of TLRs in the pathophysiology of several skin conditions, which mandates the development and study of therapeutic strategies that target TLRs.

Areas covered: With regards to the role of TLRs in pathogenesis of diverse cutaneous conditions, recent advances, as well as the future prospects of therapeutic implications of TLRs in cutaneous disorders is reviewed in this article.

Expert opinion: Although non-specific therapeutic strategies seem to reduce the symptoms in majority of patients, a considerable proportion remain untreated or have to deal with inevitable adverse effects of such therapies. Since TLRs regulate many patholophysiological processes, they could be good candidates for more specific therapeutic approaches. TLR targeting as the first recipient of invading pathogens is a growing concept in this field.     

B-cell-targeted therapy for systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex disease characterised by numerous autoantibodies and clinical involvement in multiple organ systems. The immunological events triggering the onset of clinical manifestations have not yet been fully defined, but a central role for B cells in the pathogenesis of this disease has more recently gained prominence as a result of research in both mice and humans. Both antibody-dependent and -independent mechanisms of B cells are important in SLE. Autoantibodies contribute to autoimmunity by multiple mechanisms, including immune complex-mediated type III hypersensitivity reactions, type II antibody-dependent cytotoxicity, and by instructing innate immune cells to produce pathogenic cytokines such as interferon-alpha, tumour necrosis factor and interleukin-1. Suggested autoantibody-independent B-cell functions include antigen presentation, T-cell activation and polarisation, and dendritic-cell modulation. Several of these functions are mediated by the ability of B cells to produce immunoregulatory cytokines, chemokines and lymphangiogenic growth factors, and by their critical contribution to lymphoid tissue development and organisation, including the development of ectopic tertiary lymphoid tissue. Given the large body of evidence implicating abnormalities in the B-cell compartment in SLE, a recent therapeutic focus has been to develop interventions that target the B-cell compartment by multiple mechanisms.Rituximab, a mouse-human chimeric monoclonal antibody against CD20 that specifically depletes B cells, has been studied the most extensively. Although promising open-label data await confirmation in ongoing multicentre placebo-controlled trials, a number of preliminary conclusions can be drawn. The adequacy of peripheral B-cell depletion depends on achieving high and sustained serum rituximab concentrations, pharmacokinetics that can be varied with treatment dose and factors that may affect drug clearance, such as human anti-chimeric antibodies. In SLE patients with effective B-cell depletion, the clinical response can be significant, with favourable responses observed in a diverse array of disease manifestations. Moreover, rituximab appears to have the potential to induce clinical remission in severe, refractory disease. B-cell depletion has the potential to induce disease amelioration by inhibiting autoantibody production and/or by interfering with other B-cell pathogenic functions. The fact that clinical improvement correlates with B-cell depletion and precedes by several months any decline in serum levels of relevant autoantibodies suggests a predominant effect of autoantibody-independent functions of B cells, although the subset of patients with disease remission ultimately also experience autoantibody normalisation. Significant questions remain about rituximab therapy in SLE, including the immunological determinants of treatment response and remission, the role of combination therapy, and the safety of repeated courses of rituximab. In addition, the efficacy and role of other B-cell-depleting approaches, such as humanised anti-CD20 antibodies and anti-CD22, remain to be defined.Another B-cell-targeted therapeutic approach is to block costimulatory interactions between T and B cells. Blockade of the CD40-CD40 ligand pathway has met with variable clinical benefit and unfortunate thromboembolic complications, although inhibition of the B7 pathway with cytotoxic T-lymphocyte antigen-4Ig is currently under early investigation in SLE clinical trials. Preliminary data on the treatment of SLE with belimumab, a fully human monoclonal antibody that specifically binds to and neutralises the B-lymphocyte stimulator (BLyS or B-cell-activating factor [BAFF]), are now available. In a phase II double-blind, placebo-controlled trial of the safety and efficacy of three different doses administered in addition to standard therapy, belimumab was well tolerated but reportedly did not meet primary efficacy endpoints. Blockade of BAFF is still viewed as a promising therapeutic approach and additional agents that interfere with the BAFF pathway are under study.Overall, therapies targeting B cells appear to be promising in the treatment of SLE, provide additional evidence for the importance of B cells to disease pathogenesis, and will continue to elucidate the diverse roles of B cells in this disease.     

Bruton’s tyrosine kinase inhibitor suppresses imiquimod-induced psoriasis-like inflammation in mice through regulation of IL-23/IL-17A in innate immune cells

Psoriasis is an unchecked chronic inflammation characterized by thick, erythematous, and scaly plaques on the skin. The role of innate immune cells in the pathogenesis of psoriasis is well documented. Bruton’s tyrosine kinase (BTK) has been reported to execute important signaling functions in innate immune cells such as dendritic cells (DCs) and gamma delta T cells. However, whether inhibition of BTK would lead to modulation of innate immune function in the context of psoriatic inflammation remains largely unexplored. In the present study, we investigated the effect of selective BTK inhibitor, PCI-32765 on inflammatory signaling in CD11c + DCs and gamma delta T cells in imiquimod (IMQ)-induced mouse model of psoriasis-like inflammation. Our results show that IMQ treatment led to induction of p-BTK expression along with concomitant increase in inflammatory cytokines (IL-23, TNF-α) in CD11c + DCs in the skin. Preventive treatment with BTK inhibitor led to significant reversal in IMQ-induced inflammatory changes in CD11c + DCs of skin. Further, there was a significant decrease in dermal IL-17A levels and IL-17A + γδ + T cells after treatment with BTK inhibitor. Furthermore, short treatment of back skin with IMQ led to upregulated expression of p-BTK along with inflammatory cytokines in CD11c + DCs (IL-23, TNF-α) and IL-17A in γδ + T cells which were reversed by BTK inhibitor. Overall, our study proposes that BTK signaling serves a crucial signaling function in innate immune cells in the context of psoriatic inflammation in mice. Therefore, BTK might be a promising therapeutic target to treat psoriatic inflammation.     

Cytokine and anti-cytokine therapies for inflammatory bowel disease

Although the pathogenesis of inflammatory bowel disease (IBD) remains elusive, it appears that there is chronic activation of the immune and inflammatory cascade in genetically susceptible individuals. Current disease management guidelines have therefore focused on the use of anti-inflammatory agents, aminosalicylates and corticosteroids. These conventional therapies continue to be a first choice in the management of IBD. Immunomodulators, such as azathioprine, 6-mercaptopurine, methotrexate or cyclosporin, are demonstrating increasing importance against steroid-resistant and steroid-dependent patients. However, some patients are still refractory to these therapies. Recent advances in the understanding of the pathophysiological conditions of IBD have provided new immune system modulators as therapeutic tools. Other immunosuppressive agents including FK506 and thalidomide have expanded the choice of medical therapies available for certain subgroups of patients. Furthermore, biological therapies have begun to assume a prominent role. Studies with chimeric monoclonal anti-TNF-alpha antibody treatment have been reported with dramatic successes. However, observations in larger numbers of treated patients are needed to explicate fully the safety of or risks posed by this agent such as developing lymphoma, or other malignancies. Another anti-inflammatory cytokine-therapy includes anti anti-IL-6R, anti-IL-12 or toxin-conjugated anti IL-7R, recombinant cytokines (IL-10 or IL-11). Given the diversity of proinflammatory products under its control, NF-kappaB may be viewed as a master switch in lymphocytes and macrophages, regulating inflammation and immunity. Although some of them still need more confirmatory studies, those immune therapies will provide new insights into cell-based and gene-based treatment against IBD in near future.     

The Annual European Congress of Rheumatology: recent advances in the treatment of rheumatic diseases

The topics discussed at this conference covered many aspects of the pathogenesis, epidemiology, diagnosis and treatment of rheumatic diseases, from the search of new therapeutic targets and evaluation of new diagnostic techniques to preclinical and clinical development of novel therapies. This contribution focuses primarily on two issues that dominated this meeting. First, a number of interesting studies presented during this conference examined the possible value of novel selective therapies directed against recently identified targets of the immune system including cytokines (TNF-α, IL-6, IL-15) and inflammatory cells, such as B cells, CD4⁺ T cells or memory/effector T cells. Second, clinical experience with newer anti-inflammatory treatments, such as TNF-α-blocking agents or leflunomide, is growing judging by the number of reports of their use in clinical practice and new indications. Several studies presented at this meeting examined the value of currently licensed drugs in new indications, such as ankylosing spondylitis or psoriatic arthritis, or studied new combinations of drugs, for example, a combination of different biological treatments (e.g., anakinra, etanercept), in already established indications. Interestingly, the results of these studies were not always as expected, thus increasing the importance of these particular trials. The growing experience with some of these novel therapies clarify the role of these treatments in particular forms of rheumatic diseases and will help to develop guidelines for the use of these sometimes powerful but also possibly harmful agents in clinical practice.