Current Rheumatology Reviews - Volume 7, Issue 4, 2011

This has been an interesting year in rheumatology. After about 50 years, we have a drug approved for the treatment of SLE. There are several investigational molecules currently in advanced clinical trials in several conditions, and our group completed the biggest controlled trial in Myositis ever. In this issue, we take a step back to understand the mechanisms of several signaling pathways such as NF-kB, the RAS system, IL-6 and the MAP kinases and their contribution to the development of autoimmune diseases. A clear understanding of the role that these pathways play in the development of autoimmune diseases will help rheumatologists understand and use the therapeutic agents that are being developed to target abnormalities in these pathways. It has been our aim to provide a forum for investigators to air their unique insights into the pathogenesis and treatment of autoimmune disease. In this context, it is my pleasure to present the paper on Ankylosing spondylitis, HLA B27 and Popper sequences. In this thought provoking piece, Dr. Ebringer and colleagues postulate that Klebsiella microbes are causative of Ankylosing Spondylitis and support their theory with Popperian principles. We would love to hear your thoughts about this and the other articles in the current issue as well as suggestions for future topics.

During the past two decades intense research expanded our understanding of the mechanisms underlying the pathogenesis of autoimmune diseases. As a result, a new class of antirheumatic drugs, designed to target various signaling pathways abnormally activated in the immune system have been introduced into the clinic. The proliferation, differentiation and function of various cellular components of the immune system are mediated through a variety of extracellular and intracellular signals. This issue of Current Rheumatology Reviews focuses on the role signaling pathways play in the pathogenesis of rhematological diseases, and the clinical benefits specific signal transduction inhibitors provide. In their Chapter, Oshugi and Kishimoto outline the role of interleukin (IL)-6 and its signaling pathway in the pathogenesis of rheumatoid arthritis (RA) and the role of this pathway in the induction of Th 17 cells. In the second part of their review they focus on the emerging role of tocilizumab - an anti-IL-6 receptor monoclonal antibody in the treatment of RA. Yamaoka and Tanaka reviewed the role of Janus kinases (JAKs) in the signaling of inflammatory cytokines. They provide preclinical and clinical data on the effects of JAK inhibitors in animal models of autoimmune diseases and in patients with RA. They point out that activation of JAK3 is restricted to the hematopoietic cells. Therefore inhibition of JAK3 should not cause detrimental effects outside the hematologic/immune system. This makes JAK3 an attractive target in autoimmune disorders. Indeed, the JAK3 inhibitor Tasocitinib (CP690,550) was found to be safe and effective in phase II trials of patients with RA. Activation of the nuclear factor (NF)-κB is thought to play a key role in the pathogenesis of autoimmune disorders. Therefore, the role of NF-κB in systemic lupus erythematosus (SLE), anti-phospholipid syndrome (APS), and erosive arthritis was discussed in two separate chapters written by Kubota and Umezawa. Kubota outlines the role of NF-κB in establishing and maintaining self-tolerance and in its breakdown. He describes the role of B cell activating factor (BAFF), a member of the tumor necrosis factor (TNF) family, in the pathogenesis of SLE, the role of NF-κB in the thrombogenesis in APS, and the benefits of NF-κB inhibition in SLE and APS. In a separate chapter, Kubota and Umezawa focus on the activation of NF-κB in pannus and synoviocytes obtained from patients with RA. They describe the development of NF-κB inhibitors and discuss their mechanism of action. They also describe the therapeutic modalities used to inhibit NF-κB, such as gene therapy, small molecules and specific inhibitors in animal models of erosive arthritis. In the last chapter, Rapoport et al. review the role of aberrations in the p21/Ras/MAP kinase pathway in the pathophysiology of autoimmune diseases such as autoimmune diabetes, SLE, chronic idiopathic urticaria and Celiac disease. They discuss whether monitoring the activity of the p21/Ras pathway might serve as a biomarker for disease activity, and whether this signaling pathway should be considered a therapeutic target in autoimmune diseases. Major breakthroughs in basic and translational research broadened our understanding of the pathbiology of autoimmune disorders. Drugs, broadly used to treat patients with these disorders, are being replaced by novel, targeted therapeutic modalities in recent years. As reviewed in this volume, targeted therapy has been successfully revolutionizing our therapeutic approach to autoimmune diseases.

Excess activation of NF-kappa B is often involved in inflammation and cancer progression. We have developed a specific NF-kappa B inhibitor dehydroxyepoxyquinomicin (DHMEQ). It binds to the specific cysteine residue of Rel family proteins. DHMEQ inhibited cytokine secretions and osteoclastogenesis in cultured macrophages. It inhibited various animal models of inflammation and cancer. Especially, it inhibited type 2-induced rheumatoid arthritis without any toxicity in mice. It also decreased the number of osteoclasts in the inflammatory tissues. Thus, excess activation of NF-kappa B is essential for rheumatoid arthritis, and DHMEQ is a candidate of new anti-rheumatoid chemotherapeutic agent.

The nuclear factor-κB (NF-κB) family of transcription factors consists of the five members; RelA, RelB, c-Rel, NF-κB1 and NF-κB2, which form homodimers or heterodimers and act via two distinct pathways known as the canonical and non-canonical pathways. A multitude of intracellular molecules participates in the positive and negative regulation of these pathways. Under physiological conditions, signaling via NF-κB plays an important role in the establishment of immunological self-tolerance in the bone marrow and thymus, and defects in these pathways can cause manifestations of autoimmunity. Under pathological conditions, aberrantly upregulated signaling cascades, including NF-κB, result in the expression of many proinflammatory molecules. Indeed, NF-κB pathways are activated in peripheral blood cells and the diseased organs of patients with systemic lupus erythematosus and antiphospholipid syndrome, as well as in animal models thereof. Recent in vitro and in vivo studies suggest that key molecules in the NF-κB pathways represent promising therapeutic targets.

Interleukin (IL)-6 has many biological functions. It induces acute-phase reactants (CRP, SAA) and suppresses albumin. It induces hepcidin, which regulates iron recycling and absorption, causing iron-deficiency anemia. It induces synovial cells to express receptor activator of nuclear factor-κB ligand (RANKL) and secrete vascular endothelial growth factor (VEGF), leading to osteoclast differentiation and neovascularization. In mice, it promotes development of Th17 cells (a new type of T cell) and inhibits Treg cells. Imbalance between these T cells may contribute to RA pathogenesis. In various clinical studies in RA, IL-6 signaling pathway blockade by a recombinant humanized anti-IL-6 receptor antibody, tocilizumab (TCZ), dramatically improved clinical symptoms. TCZ prevented radiographic progression of joint destruction by inhibiting synovial hyperplasia and cartilage/bone resorption. TCZ improved hematological abnormalities, including hypergammaglobulinemia, autoantibodies, and elevation of erythrocyte sedimentation rate and acute phase proteins. TCZ also improved systemic symptoms such as fatigue, anemia, anorexia and fever, improving quality of life. Many patients achieved clinical remission associated with decreased serum IL-6. These findings suggest that the proinflammatory cytokine, IL-6, also affects basic autoimmunity and they confirm that IL-6 hyper-production is responsible for joint destruction and the above clinical symptoms. Here, we discuss IL-6 signaling and its blockade by TCZ in RA.

Loss of self tolerance is the key feature of autoimmunity. The p21Ras/MAP kinase pathway plays a major role in the regulation, selection, differentiation and maturation of lymphocytes. Therefore it is conceivable that malfunctioning of this pathway due to permanent or transient signaling defects can lead to an aberrant clonal selection at the thymus or loss of anergy in the periphery. Multiple disease dependent signaling abnormalities along the p21Ras/MAP kinase pathway have been described in different autoimmune diseases including autoimmune diabetes, chronic idiopathic urticaria, inflammatory bowel diseases, celiac disease, multiple sclerosis and systemic lupus erythematosus. This underscores the concept that aberrant function of the p21Ras/MAP kinase pathway may be a common denominator in the pathogenesis of autoimmune diseases. This review focuses solely on evidence derived from animal models and human patients supporting the link between signaling aberrations along the p21Ras/MAP kinase pathway and several representative autoimmune diseases. Significance of these findings and implications regarding the monitoring and treatment of these diseases are discussed.

Treatment of rheumatoid arthritis (RA) with biologic agents targeting inflammatory cytokines and cell surface molecules such as Tumor necrosis factor (TNF), Interleukin-6 (IL-6) and CTLA-4 has become a major focus in the field. Biologic agents are generally more effective than traditional disease-modifying antirheumatic drugs (DMARDs) when combined with MTX. However, not only about 30% of patients respond poorly to treatment but also the parenteral mode of administration and expenses are issues to be solved. Recently, a kinase inhibitor targeting Janus kinases (JAKs), has shown high efficacy on active RA in clinical trials. Among several JAK inhibitors under clinical trials for RA, tofacitinib (former CP690,550) which is highly specific for JAK3 is a step ahead for use in clinic. Kinase inhibitors are orally available, which is a major advantage over biologic agents, in addition to being less expensive than biologics. This review describes recent advances in JAK inhibitors for the treatment of RA and their possible mechanism of action.

The antiphospholipid syndrome is characterized by the presence of arterial or venous thrombosis or recurrent miscarriages in a patient with positive laboratory tests for antiphospholipid antibodies (anticardiolipin antibodies and/or lupus anticoagulant and/or anti-beta2-glycoprotein I). Despite the strong association between antiphospholipid antibodies and thrombosis and obstetric morbidity, their pathogenic role in the development of these clinical features has not been fully elucidated. With respect to the treatment, at present there is consensus in treating patients with thrombosis with longterm oral anticoagulation. The approach for women with obstetric manifestations is based on the use of aspirin and heparin. However, the knowledge of new pathogenic mechanisms might identify novel therapeutic targets and therefore may improve the management of these patients.

The cause of ankylosing spondylitis (AS) was investigated through 11 Karl Popper sequences. “Popper sequences&rdquo provide a powerful method of investigating a scientific problem. A “Popper sequence” consists of a “problem”, “tentative theory”, “error elimination” which then leads to a “new fact”. The 11 “Popper sequences” establish that: (1) HLA-B27 lymphocytes injected into a rabbit evoke antibodies against Klebsiella, (2) anti-HLA-B27 tissue typing sera bind to Klebsiella antigens, (3) total serum IgA is elevated in AS patients, (4) antibodies to Klebsiella are present in AS patients from 16 different countries, (5) antibodies to Klebsiella in AS patients are disease specific, (6) Klebsiella bacteria can be grown from fecal cultures, (7) the sequence QTDRED found in HLA-B27 resembles a sequence DRDE found in pullulanase-D enzyme of Klebsiella, (8) Klebsiella pullulanase-A contains a sequence which resembles type I, II, and IV collagens, (9) sera from AS patients have cytopathic properties against sheep red cells coated with the crossreacting peptides found in Klebsiella and HLA-B27 sequences, (10) Klebsiella bacteria grow preferentially on carbohydrate substrates, and this could be used to decrease bowel bacteria which may lead to a reduction of inflammatory parameters, (11) post-pubertal hormonally-induced muscle mass leads to increased starch consumption and onset of AS. The use of “Popper Sequences” suggests that Klebsiella microbes are the probable causative agents of AS.