Endocrine, Metabolic & Immune Disorders - Drug Targets

ISSN: 1871-5303

Endocrine, Metabolic & Immune Disorders - Drug Targets
Volume 6, Number 4, December 2006

Contents

Recent Developments and Future Directions in the Treatment of Systemic Rheumatic Diseases
Guest Editor: Minoru Satoh


Editorial Pp. 303-304


Signaling Abnormalities in Systemic Lupus Erythematosus as Potential Drug Targets Pp. 305-311
D. Fernandez, E. Bonilla, P. Phillips and A. Perl
[Abstract]


Blockade of Chemokine-Mediated Tissue Injury in Lupus Nephritis Pp. 313-321
V. Vielhauer and H.-J. Anders
[Abstract]


Type I Interferon as a Target of Treatment in SLE Pp. 323-330
P.Y. Lee and W.H. Reeves
[Abstract]


Viral Anti-Inflammatory Reagents: The Potential for Treatment of Arthritic and Vasculitic Disorders Pp. 331-343
G. Munuswamy-Ramanujam, K.A. Khan and A.R. Lucas
[Abstract]


Targeting B Cells in SLE: The Experience with Rituximab Treatment (Anti-CD20) Pp. 345-350
R. Eisenberg
[Abstract]


Therapeutic Targeting of B Lymphocyte Stimulator (BLyS) in the Rheumatic Diseases Pp. 351-358
W. Stohl
[Abstract]


NF-κB and Rheumatic Diseases Pp. 359-372
T. Okamoto
[Abstract]

NF-κB is constitutively activated in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) as well as cancer and leukemia. The pathologic involvement of NF-κB is overviewed and a novel therapeutic strategy is discussed.


Anti-Interleukin-6 Receptor Antibody Therapy in Rheumatic Diseases Pp. 373-381
H. Nakahara and N. Nishimoto
[Abstract]


Role of PGE2 and EP Receptors in the Pathogenesis of Rheumatoid Arthritis and as a Novel Therapeutic Strategy Pp. 383-394
J. Akaogi, T. Nozaki, M. Satoh and H. Yamada
[Abstract]


Targeting Fibrosis in Systemic Sclerosis Pp. 395-400
R. Lafyatis
[Abstract]


Targeting Vascular Disease in Systemic Sclerosis Pp. 401-407
O. Kowal-Bielecka
[Abstract]


Recent Advances in the Treatment of Interstitial Lung Disease in Patients with Polymyositis/Dermatomyositis Pp. 409-415
H. Kameda and T. Takeuchi
[Abstract]




Abstracts

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Editorial

Recent Developments and Future Directions in the Treatment of Systemic Rheumatic Diseases

Non-steroidal anti-inflammatory drugs (NSAIDs) and steroids have been serving as standard drugs to control inflammation in systemic rheumatic diseases for several decades. While they are certainly beneficial in relieving acute inflammation and related symptoms, their effects on progression of chronic tissue damage have been unsatisfactory. Immunosuppressive drugs for lupus nephritis and for interstitial lung disease (ILD) and disease modifying anti-rheumatic drugs (DMARDs) for chronic destructive arthritis in rheumatoid arthritis (RA) are representative attempts to prevent chronic progression of the pathological processes. Significant progress in understanding the pathogenesis of systemic autoimmune rheumatic diseases at cellular and molecular levels has been made in recent years, leading to the identification of several key pathways in autoimmune inflammation and tissue destruction.

These findings have culminated in the development of many new biological agents that specifically target a single pathway critical to disease pathogenesis, in contrast to the non-specific broad effects of classic anti-inflammatory or immunosuppressive drugs. Some targets of these new therapeutic agents are molecules secreted from cells such as cytokines and chemokines, whereas others are cell surface molecules with key biological functions such as receptors or ligands. No rheumatologists would disagree that the introduction of anti-TNF-α therapy and other biological agents have revolutionized the treatment of RA with unprecedented efficacy. Importantly, the new biological agents hold promise in preventing chronic progression of rheumatic diseases. This line of drugs is rapidly becoming a key component of therapeutic strategy and development of new biological agents will continue for years to come.

The papers presented in this Hot Topics issue focus on the key molecules/pathways or critical pathological process in inflammation and chronic tissue damage in systemic rheumatic diseases. The primary defect in SLE may be T-cell signaling abnormalities, which may serve as a target for future drugs (Felnandez et al.). NFκB is a key player in various inflammatory and immunological processes in systemic rheumatic diseases and therapeutic modulation of its activity may be a more effective and specific way to control pathological inflammation (Okamoto). Type-I interferon (Lee and Reeves) and chemokines (Vielhauer and Anders) are both currently under extensive investigation in which a major development from basic studies to clinical application is expected. Viral anti-inflammatory proteins may be applied to various inflammatory conditions in addition to (or instead of) the currently used monoclonal antibodies and recombinant soluble endogenous ligand (Munuswamy-Ramanujam et al.).

Some of the new successful therapeutic approaches in rheumatic diseases are actually derived from applications proven effective for other diseases. Examples of these approaches include intravenous cyclophosphamide treatment and anti-TNF-α therapy in various autoimmune diseases. Several new reagents such as rituximab (Eisenberg), BLyS antagonist (Stohl) and anti-IL-6 antibodies (Nakahara and Nishimoto) also have been or will be tested in different autoimmune diseases, assuming common underlying pathogenic mechanisms among those conditions. Combination of drugs that target different types of cells or pathways may also be a logical and effective approach to utilize the previously unrecognized power of available drugs for life-threatening conditions as illustrated by a combination therapy for ILD in polymyositis/dermatomyositis (Kameda and Takeuchi). A careful evaluation of basic pathophysiological abnormalities in SSc such as fibrosis and vascular abnormalities should lead to the discovery of new targets to control these intractable processes (Lafyatis, Kowel-Bielecka). PGE2 has been known for a long time as a classic mediator of inflammation. However, the recent identification of subsets of PGE2 receptors (EPs) that signal through distinctive pathways, leading to either pro- or anti-inflammatory effects, have boosted our understanding of its complex biological functions and paved the path for a new strategy to control unwanted inflammation (Akaogi et al.).

Despite the seemingly bright future in developing new drugs for autoimmune rheumatic diseases, there are several potential concerns we need to keep in mind when applying new therapies to human diseases.

First, we need to remember that the etiology of each systemic rheumatic disease still remains to be determined and is presumably heterogeneous. Thus, the patients under the same single diagnosis are simply a mixture of individuals with different genetic backgrounds and environmental exposures, defined by classification criteria. Naturally, their response to the same drug can be quite heterogeneous. Any therapies, including highly effective biological agents, are effective only in certain percentage of patients. Thus, identifying the “right” patients for a particular therapy will be more and more important with the dramatically increasing use of expensive biological agents. In some cases, heterogeneity in the pathogenesis may be significant enough enabling the same therapy to ameliorate disease in some patients while accelerating disease in other patients, as suggested by opposite effects of type I IFN in different models of murine lupus.

Secondly, it appears that the health of our immune system relies on a very delicate balance of various cytokines and other humoral factors. Disturbing this balance to any direction can be potentially harmful. For instance, the development of autoimmune diseases in patients under cytokine or anti-cytokine therapy are well described, which may be reminiscent to the development of lupus-like autoimmunity in various cytokine transgenic mice and certain cytokine knockout mice. It is possible that manipulating this delicate balance of the immune system with future drugs can induce unexpected development of autoimmune and other diseases.

Finally, evaluation of the long-term effects of a new drug whose pharmacological and biological effects are only partially understood, is just at its beginning. This cannot be replaced by in vitro studies or by animal studies. Efficient long-term monitoring of side effects and safety will be critical for recent and future new drugs.

Recent research has identified a significant number of promising key molecules/pathways that play a critical role in disease processes in systemic rheumatic diseases. Therapeutic agents targeting these pathways are under intensive investigation and some have already shown beneficial effects clinically. Suppression and if possible, prevention and reversal of chronic tissue damage will be the main goal of future long-term therapy. Hopefully, we can witness the development of new lines of drugs capable of accomplishing this goal in the near future.

Minoru Satoh, MD, PhD
Division of Rheumatology and Clinical Immunology
Department of Medicine
University of Florida
P.O.Box 100221
Gainesville, FL 32610-0221
USA
E-mail: satohm@medicine.ufl.edu


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Signaling Abnormalities in Systemic Lupus Erythematosus as Potential Drug Targets
D. Fernandez, E. Bonilla, P. Phillips and A. Perl

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease characterized by T-cell, B-cell, and dendritic cell dysfunction and antinuclear autoantibody production. Much of the knowledge that has been gained about SLE in recent years is related to molecular signaling abnormalities present in the disease.

Signaling through the T-cell receptor (TCR) is affected in SLE by alterations in the localization, amount, and activity of numerous protein kinases. TCR stimulation releases calcium from intracellular stores, which triggers an influx of extracellular calcium and activates the transcription of many genes, including interleukin-2. Short-term calcium fluxing is exag-gerated in SLE, but long-term calcium fluxing is diminished and may account for sub-optimal interleukin-2 production.

SLE T-cells have persistently hyperpolarized mitochondria associated with increased mitochondrial mass, high levels of reactive oxygen species (ROS) and low levels of ATP, which decrease activation induced apoptosis and instead predispose T cells for necrosis, thus stimulating inflammation in SLE. The pentose phosphate pathway impacts the mitochondrial potential and represents a target for possible intervention.

Nitric oxide (NO) is a potential link to tie together the signaling and mitochondrial abnormalities in SLE. NO-induced mitochondrial biogenesis recapitulates the TCR-stimulated calcium fluxing abnormalities of SLE T-cells. Since mitochondria can store calcium, the increase in mitochondrial mass may be implicated in the aberrant calcium fluxing in SLE T cells. The mammalian target of rapamycin senses the mitochondrial potential and regulates calcium release, serving as a novel target of treatment of SLE.


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Blockade of Chemokine-Mediated Tissue Injury in Lupus Nephritis
V. Vielhauer and H.-J. Anders

Pro-inflammatory chemokines are important mediators of inflammation and autoimmune injury. The spatial and temporal expression of chemokines and chemokine receptors in the nephritic kidney suggests that targeting the chemokine system may represent a valuable approach for anti-inflammatory therapy of lupus nephritis. In this review we summarize the available data on the pathogenic role of chemokines and chemokine receptors in lupus nephritis and particularly focus on epidemiological data in lupus patients and interventional studies with chemokine or chemokine receptor antagonists in experimental lupus.


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Type I Interferon as a Target of Treatment in SLE
P.Y. Lee and W.H. Reeves

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characterized by the production of antibodies against a spectrum of autoantigens. Recent evidence suggests that type-I interferons (IFN-I) are critically involved in the pathogenesis of SLE. Initially recognized for their anti-viral properties, IFN-I play important roles in immunity and autoimmunity by promoting DC maturation, T cell survival, and antibody production. Onset of SLE has been reported in patients with hepatitis or neoplastic diseases undergoing treatment with recombinant IFN-I while elevated serum IFN-I and IFN-stimulated gene expression are found in ~2/3 of SLE patients. This “interferon signature” is clinically important as it correlates with disease activity and renal as well as CNS involvement. Supporting these findings, genetic abnormalities resulting in increased IFN-I production and/or signaling are associated with SLE. In view of the accumulating evidence linking IFN-I to the pathogenesis of SLE, targeting of IFN-I may be beneficial therapeutically while avoiding the side effects associated with conventional immunosuppressive therapy. To this end, IFN-I and IFN-producing cells as well as IFN-inducers and molecules of the IFN signaling pathway may all serve as potential therapeutic targets. Several anti-IFN-I approaches have already shown promising effects in animal studies and clinical trials will likely begin in the near future.


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Viral Anti-Inflammatory Reagents: The Potential for Treatment of Arthritic and Vasculitic Disorders
G. Munuswamy-Ramanujam, K.A. Khan and A.R. Lucas

Inflammatory and immune responses are inherent in the development of progressive arthritic or vasculitic disorders. Arthritis is frequently associated with accelerated forms of vasculitis; atherosclerosis being one form of accelerated vasculitis that blocks blood flow causing heart attacks and strokes. The arterial supply is central to maintaining normal articular function and acts as a conduit for inflammatory (innate) and immune (antigen dependent) cell trafficking in joints. The vasculature in some cases can become inflamed in the disease process. While treatment of severely debilitating arthritic disorders has improved, some current treatments are limited to reducing symptoms while others act as disease modifying drugs (DMARDs), but may have limited success. Many current treatments also have reported adverse side effects. Vasculitic disorders are similarly debilitating with high associated morbidity and mortality and current therapy for these disorders is only partially successful. Immune-modifying agents, which alter vascular inflammation, thus have potential for application in rheumatologic diseases.

Viral immune modulating proteins reduce early arterial inflammatory responses with associated reductions in atherosclerotic plaque development and transplant rejection in a wide range of animal models. A clinical trial utilizing one such viral reagent, a secreted myxomaviral serpin, is currently in progress, assessing treatment of acute coronary syndrome, a vascular syndrome with marked up-regulation of systemic inflammatory responses. In this review we examine viral anti-inflammatory proteins as potential therapeutic reagents for arthritic and vasculopathic disorders.


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Targeting B Cells in SLE: The Experience with Rituximab Treatment (Anti-CD20)
R. Eisenberg

B cells play a central role in the pathogenesis of SLE. Not only do they make autoantibodies, but they can provide immunoregulatory controls of T cells, dendritic cells, and other B cells, in part through cytokine production. The availability of a chimeric monoclonal antibody that targets B cells has made it possible to treat SLE by B-cell depletion. Rituximab binds to the B-cell specific antigen CD20, and depletes B cells from the peripheral blood and lymphoid tissues. A growing number of anecdotal series and case reports suggest that rituximab may provide clinical benefit in SLE with acceptable toxicity, although the variability in responses of individual patients is not yet fully understood. Two large ongoing randomized controlled trials will determine the efficacy of rituximab in SLE, both renal and extra-renal, and will inform us better about the biology of the B cell in this disease and the effects of B-cell depletion.


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Therapeutic Targeting of B Lymphocyte Stimulator (BLyS) in the Rheumatic Diseases
W. Stohl

B lymphocyte stimulator (BLyS) is a vital B cell survival factor. Overexpression of BLyS in mice can lead to clinical and serological features of systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). Treatment with BLyS antagonists of mice with established SLE ameliorates disease progression and enhances survival. Moreover, similar treatment of mice with inflammatory arthritis ameliorates the ongoing inflammation and subsequent joint destruction. In humans, BLyS overexpression is common in patients with several rheumatic diseases, including SLE, rheumatoid arthritis (RA), Sjogren’s syndrome, scleroderma, Wegener’s granulomatosis, and ANCA-associated vasculitis. Results from phase-II clinical trials with a BLyS antagonist in human SLE and RA have shown the antagonist to have biological and clinical activity along with a favorable safety profile. These features collectively point to BLyS as an attractive therapeutic target in human rheumatic diseases.


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NF-κB and Rheumatic Diseases
T. Okamoto

NF-κB is an inducible transcription factor that is controlled by the signal activation cascades. NF-κB controls a number of genes involved in immuno-inflammatory responses, cell cycle progression, inhibition of apoptosis, and cell adhesion, thus promoting chronic inflammatory responses. In fact, NF-κB is constitutively activated in some rheumatic conditions such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Interestingly, a number of anti-RA compounds have been shown to exhibit anti-NF-κB activities. In addition, NF-κB activation has been linked to carcinogenesis and its constitutive activation has been demonstrated in some cancers and leukemias. These findings have substantiated the long-standing proposal of the link among chronic inflammation, autoimmunity, and carcinogenesis by molecular terms. In this review, I have attempted to overview the pathologic involvement of NF-κB in rheumatic diseases and discuss the feasibility of a therapeutic strategy with NF-κB and its signaling cascade as novel molecular targets.


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Anti-Interleukin-6 Receptor Antibody Therapy in Rheumatic Diseases
H. Nakahara and N. Nishimoto

In the treatment of rheumatic diseases such as rheumatoid arthritis (RA) or systemic onset juvenile idiopathic arthritis (soJIA), new therapies targeting pro-inflammatory cytokines have been developed. IL-6 is a pleiotropic cytokine with a wide range of biological activities including a pro-inflammatory mediator activity. Overproduction of IL-6 has been reported to be pathologically involved in the rheumatic diseases and, therefore, blockade of IL-6 actions may improve the disease. Tocilizumab, a humanized monoclonal antibody against human interleukin-6 receptor (IL-6R), inhibits IL-6 binding to IL-6R and specifically interferes with IL-6 actions. Castleman’s disease is an atypical lymphoproliferative disorder caused by the overproduction of IL-6. Tocilizumab therapy improves immunological and hematological abnormalities as well as systemic inflammatory symptoms including wasting. This translational study also confirmed the pathological significance of IL-6 in the disease. RA is a representative autoimmune inflammatory disease characterized by bone and cartilage destruction in multiple joints. Since IL-6 also plays pathological roles in RA, tocilizumab therapy has been introduced to the patients with refractory disease and has shown a strong therapeutic effect. Besides Castleman’s disease and RA, tocilizumab has been shown to be effective for patients with soJIA and Crohn’s disease. Tocilizumab treatment is generally well tolerated and safe. Therefore, tocilizumab can be a promising therapeutic agent for the rheumatic diseases in which IL-6 overproduction is pathologically involved.


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Role of PGE2 and EP Receptors in the Pathogenesis of Rheumatoid Arthritis and as a Novel Therapeutic Strategy
J. Akaogi, T. Nozaki, M. Satoh and H. Yamada

Recent progress in understanding the pathogenesis of rheumatoid arthritis (RA) in parallel with elucidation of the functional role of the prostaglandin receptor subfamily has revealed an important regulatory role of PGE2, in addition to its well-known proinflammatory role in the progression of RA. Characteristic features of RA are synovial proliferation and pannus formation, which result in the destruction of cartilage and bone. Pannus tissue is mainly composed of macro-phages and fibroblast-like synoviocytes. Both T cell-derived IL-17 and macrophage-derived TNF-alpha seem to play a central role in the progression of proinflammatory cascades in RA. PGE2 is also produced in response to proinflammatory cytokines, which in turn negatively regulates both IL-17 and TNF-alpha expression and TNF/IL-1-induced activation of fibroblast-like synoviocytes through EP2/EP4 receptors, resulting in the modulation of proinflammatory cascades. IL-17- and TNF-activated macrophages differentiate into osteoclasts in the presence of M-CSF and RANKL expressed by fibroblast-like synoviocytes. PGE2 binding to EP4 stimulates osteoclastogenesis through enhancing RANKL expression. At the same time, PGE2 suppresses osteoclastogenesis by inhibiting M-CSF expression of fibroblast-like synoviocytes as well as both IL-17 and IL-17-induced TNF-alpha expression of macrophages. PGE2-EP4 also activates osteoblastogenesis through increasing cbfa1 and osterix, two essential transcription factors required for bone formation. The net effect of PGE2 may direct toward repair of eroding bone through the suppression of inflammation and enhancement of bone remodeling. Here, we discuss a diverse action of PGE2/EP receptors and their important regulatory roles in the pathogenesis of RA, which may lead to a novel therapeutic strategy.


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Targeting Fibrosis in Systemic Sclerosis
R. Lafyatis

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-β (TGFβ) as a central mediator in SSc. The discovery of agents targeting TGFβ, its activation or its intracellular signaling suggest that TGFβ 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 over-production 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.


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Targeting Vascular Disease in Systemic Sclerosis
O. Kowal-Bielecka

Systemic sclerosis (scleroderma, SSc) is a chronic connective tissue disease of unknown etiology characterized by progressive fibrosis of the skin and a distinctive pattern of internal organ involvement. Excessive fibrosis, vascular injury, autoimmunity and inflammation are permanent features of the disease process leading to irreversible organ damage and significant morbidity and mortality in SSc patients. Recent progress in understanding the pathogenesis of SSc as well as diagnostic and therapeutic advances in medicine have made more effective treatment strategies possible. So far, therapies targeting vascular aspects of SSc have been most successful. This underlines the role of vascular injury in the pathogenesis of the disease and raising hopes of significant improvement in the management of SSc patients. The aim of this review is to summarize recent and potential future treatments of SSc-associated vascular disease.


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Recent Advances in the Treatment of Interstitial Lung Disease in Patients with Polymyositis/Dermatomyositis
H. Kameda and T. Takeuchi

Interstitial lung disease (ILD) develops in 30-50% of patients with polymyositis/dermatomyositis (PM/DM) and negatively affects their prognosis. The progression of PM/DM-ILD may be acute, subacute, chronic, or chronic becoming acute. The histopathological classification of PM/DM-ILD includes non-specific interstitial pneumonia (NSIP), organizing pneumonia (OP), diffuse alveolar damage (DAD), and usual interstitial pneumonia (UIP) or mixed variations. Some patients with acute/subacute interstitial pneumonia (A/SIP), typically with lung histology of OP or cellular NSIP, respond favorably to corticosteroid treatment, while others do not. Japanese patients with DM, especially those with clinically amyopathic DM (C-ADM) and palmar papules, seem to be at a greater risk of developing fulminant A/SIP with DAD histology resulting in pneumomediastinum and fatal outcome in a few months. An aggressive combination regimen including cyclosporine A (or tacrolimus) and cyclophosphamide should be immediately added to corticosteroid treatment for such patients. Sequential follow-up examination using high-resolution computed tomography (HRCT) of the chest and careful monitoring for bacterial and viral infections are essential. However, intensive immunosuppression alone may not be sufficient to control fulminant A/SIP, and other therapeutic targets, such as fibroblasts, should be considered.