Diverse strategies to develop novel treatments for rheumatoid arthritis which specifically target those patients who do not respond to available medications, including biologics, are currently being explored. New potential therapeutic approaches which may become available as part of standard therapeutic regimens include the propagation of regulatory T cells and—in the future—of regulatory B cells. New biologic disease-modifying antirheumatic drugs (b-DMARDs) against interleukin-17 and -6, granulocyte-macrophage colony-stimulating factor, and complement component 5 are now standard components of clinical treatment programs. In addition, recent data indicate that bispecific monoclonal antibody therapies may be more effective than monoclonal antibody monotherapies. It is also becoming apparent that the use of more toxic b-DMARDs against B cells, a therapeutic strategy already being applied in the treatment of hematological diseases, may also be efficacious for treating B cell-mediated autoimmune diseases. Undoubtedly, more small molecules will be developed in the future, and combination therapies with, for example, kinase inhibitors and b-DMARDs, will most likely be tested. Finally, immunoproteasome inhibitors will become available for patients with B cell-mediated autoimmunities, which are refractory to currently available treatment options. The new and exciting extension of current treatment options for rheumatoid arthritis, biosimilars, will not be discussed in this review as details on these agents are available in recently published reports.
Bregs; Novel b-DMARDs; Small molecules; Kinase inhibitors; Proteasome inhibitor; Tregs
Treatment of inflammatory arthritides - including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis - has seen much progress in recent years, partially due to increased understanding of the pathogenesis of these diseases at the cellular and molecular levels. These conditions share some common mechanisms. Biologic therapies have provided a clear advance in the treatment of rheumatological conditions. Currently available TNF-targeting biologic agents that are licensed for at east one of the above-named diseases are etanercept, infliximab, adalimumab, golimumab, and certolizumab. Biologic agents with a different mechanism of action have also been approved in rheumatoid arthritis (rituximab, abatacept, and tocilizumab). Although these biologic agents are highly effective, there is a need for improved management strategies. There is also a need for education of family physicians and other healthcare professionals in the identification of early symptoms of inflammatory arthritides and the importance of early referral to rheumatologists for diagnosis and treatment. Also, researchers are developing molecules - for example, the Janus kinase inhibitor CP-690550 (tofacitinib) and the spleen tyrosine kinase inhibitor R788 (fostamatinib) - to target other aspects of the inflammatory cascade. Initial trial results with new agents are promising, and, in time, head-to-head trials will establish the best treatment options for patients. The key challenge is identifying how best to integrate these new, advanced therapies into daily practice.
Autoantibodies against double-stranded DNA (dsDNA) and nucleosomes represent a hallmark of systemic lupus erythematosus (SLE). However, the mechanisms involved in breaking the immunological tolerance against these poorly immunogenic nuclear components are not fully understood. Impaired phagocytosis of apoptotic cells with consecutive release of nuclear antigens may contribute to the immune pathogenesis. The architectural chromosomal protein and proinflammatory mediator high mobility group box protein 1 (HMGB1) is tightly attached to the chromatin of apoptotic cells. We demonstrate that HMGB1 remains bound to nucleosomes released from late apoptotic cells in vitro. HMGB1–nucleosome complexes were also detected in plasma from SLE patients. HMGB1-containing nucleosomes from apoptotic cells induced secretion of interleukin (IL) 1β, IL-6, IL-10, and tumor necrosis factor (TNF) α and expression of costimulatory molecules in macrophages and dendritic cells (DC), respectively. Neither HMGB1-free nucleosomes from viable cells nor nucleosomes from apoptotic cells lacking HMGB1 induced cytokine production or DC activation. HMGB1-containing nucleosomes from apoptotic cells induced anti-dsDNA and antihistone IgG responses in a Toll-like receptor (TLR) 2–dependent manner, whereas nucleosomes from living cells did not. In conclusion, HMGB1–nucleosome complexes activate antigen presenting cells and, thereby, may crucially contribute to the pathogenesis of SLE via breaking the immunological tolerance against nucleosomes/dsDNA.
Stress in patients with chronic inflammatory diseases such as rheumatoid arthritis (RA) stimulates proinflammatory mechanisms due to the defect of stress response systems (for example, the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis). Among other mechanisms, the loss of sympathetic nerve fibers in inflamed tissue and inadequate cortisol secretion in relation to inflammation lead to an enhanced proinflammatory load in RA. Stress and the subsequent stimulation of inflammation (systemic and local) lead to increased sensitization of pain and further defects of stress response systems (vicious cycle of stress, pain, and inflammation).
This prospective open-label pilot study evaluated the effectiveness and safety of adalimumab and the relationship to antibodies against infliximab (IFX) in adult patients with active rheumatoid arthritis (RA) who had been treated previously with IFX and experienced treatment failure owing to lack or loss of response or intolerance. Patients self-administered adalimumab 40 mg subcutaneously every other week for 16 weeks, followed by maintenance therapy for up to Week 56. Measures of effectiveness included American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria, 28-joint Disease Activity Score, and the Health Assessment Questionnaire Disability Index. Serum IFX concentrations, human antichimeric antibody against IFX (HACA), adalimumab serum concentrations, antiadalimumab antibody, and safety also were assessed. Of the 41 enrolled patients, 37 completed 16 weeks and 30 completed 56 weeks of treatment. Patients experienced clinically meaningful improvements in all measures of RA activity, with greater response rates observed for patients who had experienced loss of initial response to or intolerance of IFX. At Week 16, 46% of patients achieved an ACR20 and 28% achieved an ACR50; 61% achieved an at least moderate and 17% achieved a good EULAR response. Clinical benefit was maintained through Week 56 in all effectiveness parameters. Baseline HACA status did not significantly impact effectiveness. No new safety signals were observed; neither former IFX intolerance status nor baseline HACA status had a clinically relevant impact on adverse event frequency or severity. Adalimumab was effective and well-tolerated in patients with RA who previously failed IFX therapy, irrespective of reason for discontinuation and of HACA status.
Adalimumab; Infliximab; Rheumatoid arthritis; Treatment failure; Tumor necrosis factor antagonist
Rheumatoid arthritis (RA) is characterized by the recruitment of leukocytes and the accumulation of inflammatory mediators within the synovial compartment. Release of the chemokine CCL18 has been widely attributed to antigen-presenting cells, including macrophages and dendritic cells. This study investigates the production of CCL18 in polymorphonuclear neutrophils (PMN), the predominant cell type recruited into synovial fluid (SF). Microarray analysis, semiquantitative and quantitative reverse transcriptase polymerase chain reaction identified SF PMN from patients with RA as a novel source for CCL18 in diseased joints. Highly upregulated expression of other chemokine genes was observed for CCL3, CXCL8 and CXCL10, whereas CCL21 was downregulated. The chemokine receptor genes were differentially expressed, with upregulation of CXCR4, CCRL2 and CCR5 and downregulation of CXCR1 and CXCR2. In cell culture experiments, expression of CCL18 mRNA in blood PMN was induced by tumor necrosis factor α, whereas synthesis of CCL18 protein required additional stimulation with a combination of IL-10 and vitamin D3. In comparison, recruited SF PMN from patients with RA were sensitized for CCL18 production, because IL-10 alone was sufficient to induce CCL18 release. These results suggest a release of the T cell-attracting CCL18 by PMN when recruited to diseased joints. However, its production is tightly regulated at the levels of mRNA expression and protein synthesis.
On the basis of their biological function, potential genetic candidates for susceptibility to rheumatoid arthritis can be postulated. IFNGR1, encoding the ligand-binding chain of the receptor for interferon gamma, IFNγR1, is one such gene because interferon gamma is involved in the pathogenesis of the disease. In the coding sequence of IFNGR1, two nucleotide positions have been described to be polymorphic in the Japanese population. We therefore investigated the association of those two IFNGR1 single nucleotide polymorphisms with rheumatoid arthritis in a case-control study in a central European population. Surprisingly, however, neither position was polymorphic in the 364 individuals examined, indicating that IFNGR1 does not contribute to susceptibility to rheumatoid arthritis, at least in Caucasians.
Strategies to enhance the immunogenicity of tumors are urgently needed. Although vaccination with irradiated dying lymphoma cells recruits a tumor-specific immune response, its efficiency as immunogen is poor. Annexin V (AxV) binds with high affinity to phosphatidylserine on the surface of apoptotic and necrotic cells and thereby impairs their uptake by macrophages. Here, we report that AxV preferentially targets irradiated lymphoma cells to CD8+ dendritic cells for in vivo clearance, elicits the release of proinflammatory cytokines and dramatically enhances the protection elicited against the tumor. The response was endowed with both memory, because protected animals rejected living lymphoma cells after 72 d, and specificity, because vaccinated animals failed to reject unrelated neoplasms. Finally, AxV–coupled irradiated cells induced the regression of growing tumors. These data indicate that endogenous adjuvants that bind to dying tumor cells can be exploited to target tumors for immune rejection.
apoptosis; phagocytosis; cancer; adjuvants; dendritic cells
In autoimmune polyglandular syndromes (APS), several organ-specific autoimmune diseases are clustered. Although APS type I is caused by loss of central tolerance, the etiology of APS type II (APS-II) is currently unknown. However, in several murine models, depletion of CD4+ CD25+ regulatory T cells (Tregs) causes a syndrome resembling human APS-II with multiple endocrinopathies. Therefore, we hypothesized that loss of active suppression in the periphery could be a hallmark of this syndrome. Tregs from peripheral blood of APS-II, control patients with single autoimmune endocrinopathies, and normal healthy donors showed no differences in quantity (except for patients with isolated autoimmune diseases), in functionally important surface markers, or in apoptosis induced by growth factor withdrawal. Strikingly, APS-II Tregs were defective in their suppressive capacity. The defect was persistent and not due to responder cell resistance. These data provide novel insights into the pathogenesis of APS-II and possibly human autoimmunity in general.
suppressor cells; autoimmune polyendocrinopathies; Addison's disease; type I diabetes; autoimmune thyroiditis
The delineation of the in vivo role of GATA-3 in human T cell differentiation is a critical step in the understanding of molecular mechanisms directing human immune responses. We examined T cell differentiation and T cell–mediated effector functions in individuals lacking one functional GATA-3 allele. CD4 T cells from GATA-3+/− individuals expressed significantly reduced levels of GATA-3, associated with markedly decreased T helper cell (Th)2 frequencies in vivo and in vitro. Moreover, Th2 cell–mediated effector functions, as assessed by serum levels of Th2-dependent immunoglobulins (Igs; IgG4, IgE), were dramatically decreased, whereas the Th1-dependent IgG1 was elevated compared with GATA-3+/+ controls. Concordant with these data, silencing of GATA-3 in GATA-3+/+ CD4 T cells with small interfering RNA significantly reduced Th2 cell differentiation. Moreover, GATA-3 mRNA levels increased under Th2-inducing conditions and decreased under Th1-inducing conditions. Taken together, the data strongly suggest that GATA-3 is an important transcription factor in regulating human Th2 cell differentiation in vivo.
Th1/Th2 cells; cellular differentiation; transcription factors; T lymphocytes; siRNA
Tumor necrosis factor alpha (TNF-α) is an inflammatory cytokine that has been implicated in a variety of rheumatic and inflammatory diseases. New understanding of the importance of TNF-α in the pathophysiology of rheumatoid arthritis and Crohn's disease led to the development of a new class of targeted anti-TNF therapies. Anti-TNF-α agents including etanercept (a fusion protein of the p75 TNF receptor and IgG1) and infliximab (a chimeric monoclonal antibody specific for TNF-α) have been approved for the treatment of rheumatoid arthritis. In addition, infliximab has been approved in the treatment of patients with active or fistulating Crohn's disease. A new appreciation of the importance of TNF-α in other rheumatic and inflammatory diseases has led to a broadening of the application of anti-TNF agents. Both etanercept and infliximab have been used in open-label and randomized studies in patients with psoriatic arthritis. Although larger randomized trials are needed to confirm early results, both these anti-TNF-α agents, etanercept and infliximab, have demonstrated activity in improving the signs and symptoms of psoriatic arthritis and psoriasis. Infliximab has also been shown to be effective in patients with other rheumatic diseases, including ankylosing spondylitis, and may be effective in adult-onset Still's disease, polymyositis, and Behçet's disease. Further investigations will fully elucidate the role of infliximab in these and other rheumatic diseases.
anti-tumor necrosis factor; cytokine; infliximab; rheumatic disease; tumor necrosis factor
Rheumatoid arthritis (RA) is the most common chronic autoimmunopathy, clinically leading to joint destruction as a consequence of the chronic inflammatory processes. The pathogenesis of this disabling disease is not well understood, but molecular events leading to tissue inflammation with cartilage and bone destruction are now better defined. Therapy with slow-acting, disease-modifying antirheumatic drugs (DMARDs), such as low-dose methotrexate, which is generally accepted as a standard, leads to a significant amelioration of symptoms but does not stop joint destruction. Due to these disappointing treatment options and the identification of certain inflammatory mediators as therapeutic targets, novel therapeutic agents such as monoclonal antibodies, cytokine-receptor/human-immunoglobulin constructs or recombinant human proteins have been tested in RA with some success. Clinical trials testing anti-TNF-α agents, alone or in combination with methotrexate, have convincingly shown the feasibility and efficacy of these novel approaches to the therapy of RA. A clinical trial testing combination therapy with chimeric (mouse/human) anti-TNF-α monoclonal antibody infliximab and methotrexate showed, for the first time in any RA trial, that there was no median radiological progression in the groups given infliximab plus methotrexate over a 12-month observation period. Similar encouraging results might arise from trials employing other TNF-α-directed agents, such as the fully human monoclonal antibody D2E7, the p75 TNF-α-receptor/Ig construct, etanercept, or others, as discussed in this review. Combination partners other than methotrexate will be established as suitable cotreatment along with anti-TNF-α biologicals. Forthcoming new indications for TNF-α-targeted therapies are discussed.
D2E7; etanercept; infliximab; TNF-α; therapy
The substantial progress in our understanding of molecular and cellular biology has allowed us to design biological therapeutics ('biologicals') with defined targets and effector functions. These biologicals have greatly contributed to our current knowledge of pathogenetic mechanisms in autoimmune diseases. However, although some of the biologicals have been extremely successful in treating the symptoms of chronic inflammation, biological therapy has not yet met the expectations of permanently silencing the chonic immune response. In this commentary we discuss current concepts and future directions of biological therapy, and the potential usefulness of biologicals as a treatment of human autoimmune diseases in appropriate critical applications with the use of suitably designed agents.
biologicals; cytokines; monoclonal antibodies; rheumatoid arthritis; treatment