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.). NFκ B 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 antiinflammatory 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.......
Division of Rheumatology and Clinical Immunology Department of Medicine University of Florida P.O.Box 100221 Gainesville, FL 32610-0221 USA.
Publication date: December 1, 2006
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This journal is devoted to timely reviews of experimental and clinical studies in the field of endocrine, metabolic, and immune disorders. Specific emphasis is placed on humoral and cellular targets for natural, synthetic, and genetically engineered drugs that enhance or impair endocrine, metabolic, and immune parameters and functions. Topics related to the neuroendocrine-immune axis are given special emphasis in view of the growing interest in stress-related, inflammatory, autoimmune, and degenerative disorders.