The development of novel therapies for rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease that affects approximately 0.5 – 1% of adults worldwide and commonly results in joint destruction and significant impairment in the quality of life. RA is considered an autoimmune disease with unknown etiology. Many pathogenic pathways of RA have been revealed recently, which has led to development of various novel therapies. Objective: The current treatments for RA fall into four categories: non-steroidal anti-inflammatory drugs, glucocorticoids, non-biological, disease-modifying antirheumatic drugs (DMARDs) and biological DMARDs. In this review, we discuss some of the most recent development in antirheumatic therapies. Methods: Using SciFinder Scholar and PubMed as our main search tools, we evaluated various newly developed therapies for RA. In each drug category, emphases are placed on the mode of action, limitations and new drug candidates from the patent search. Those therapies that are well-established are reviewed only briefly. Conclusion: During the past 20 years, most of the development of new therapies is in DMARDs, especially biological DMARDs. With the discovery of new pathways and the application of drug delivery strategies, more growth is anticipated in this research field.     

Antibody therapy for rheumatoid arthritis

High-quality monoclonal antibodies (mAbs) with specificity for relevant disease molecules can now be produced in abundance. Anti-tumour necrosis factor-alpha therapies have set a new standard for symptom control in rheumatoid arthritis, and blockade of tumour necrosis factor has the potential to protect joints from structural damage. Other targets for therapeutic antibodies include the cytokines interleukin (IL)-1, IL-6, IL-8, IL-15, IL-17 and IL-18. In addition, there is preliminary evidence for the clinical efficacy of both keliximab, a mAb targeting the T cell antigen CD4, and rituximab, a chimeric mAb against the B cell antigen CD20 and CTLA4-Ig, which blocks the CD28/B7 interaction. Phase III studies have yet to be undertaken for these novel biological agents, and it is unclear whether any of these agents will have true disease-modifying capabilities.     

光动力疗法治疗早期类风湿关节炎的实验研究

目的观察光动力疗法(PDT)对早期类风湿关节炎(RA)大鼠的治疗效果并探讨其作用机制。方法 32只SD大鼠任选8只作为空白对照组,其余24只均注射牛源性Ⅱ型胶原蛋白以建立RA动物模型;造模成功后随机将其分为模型对照组、药物治疗组、PDT治疗组;分别对各治疗组进行不同方式的治疗;定期测量各组大鼠右后足踝关节体积变化情况;治疗14d后,获取大鼠血清和踝关节组织,分别从血清学和病理学改变等方面进行实验分析研究。结果①治疗后PDT和药物治疗组大鼠右后足体积[(1.61±0.19),(1.57±0.13)cm3]较治疗前[(1.60±0.20),(1.61±0.16)cm3]变化不明显(P>0.05),而模型对照组大鼠右后足体积(1.88±0.16)cm3较之前(1.63±0.13)cm3变化明显(P>0.05);②PDT和药物治疗组大鼠细胞因子的表达量白细胞介素(IL)-20[(37±11),(42±8)pg/ml]、转铁蛋白受体(sTfR)[(58±4),(63±5)pg/ml]较模型对照组IL-20(63±7)pg/ml、sTfR(72±4)pg/ml有明显降低(P<0.05);PDT治疗组IL-20表达水平较药物治疗组有明显下降(P<0.05);③光学显微镜下病理切片结果显示:各治疗组大鼠右后足踝关节增生的滑膜减轻明显,生成的血管翳也相对减少,骨破坏程度较模型对照组有所减轻;同时PDT治疗组的滑膜增生程度较药物治疗组减轻明显,生成的血管翳也相对较少。结论 PDT治疗可以抑制RA动物模型滑膜细胞的增生,减少血管翳的形成,同时,能抑制细胞因子IL-20和sTfR的表达。     

Rituximab: novel B-cell depletion therapy for the treatment of rheumatoid arthritis

Significant numbers of patients with rheumatoid arthritis (RA) suffer from disease that is refractory to both conventional therapy and newer biological agents such as TNF-alpha inhibitors. These patients may respond insufficiently, lose an effective response, develop toxicity or carry contraindications to such agents. Rituximab, a chimeric monoclonal antibody against CD20 that effectively depletes B cells in peripheral blood, has been licensed for the treatment of certain haematological malignancies for almost 10 years. B cells are now known to have multiple key roles in the pathogenesis of RA. Data is now available that indicates efficacy and safety of B-cell depletion with rituximab in the treatment of RA in a variety of patient groups. The clinical outcomes from these studies, together with its safety profile, have led to rituximab being licensed for the treatment of patients with RA who have failed to obtain benefit from anti-TNF-alpha agents.     

Rituximab: novel B-cell depletion therapy for the treatment of rheumatoid arthritis

Significant numbers of patients with rheumatoid arthritis (RA) suffer from disease that is refractory to both conventional therapy and newer biological agents such as TNF-α inhibitors. These patients may respond insufficiently, lose an effective response, develop toxicity or carry contraindications to such agents. Rituximab, a chimeric monoclonal antibody against CD20 that effectively depletes B cells in peripheral blood, has been licensed for the treatment of certain haematological malignancies for almost 10 years. B cells are now known to have multiple key roles in the pathogenesis of RA. Data is now available that indicates efficacy and safety of B-cell depletion with rituximab in the treatment of RA in a variety of patient groups. The clinical outcomes from these studies, together with its safety profile, have led to rituximab being licensed for the treatment of patients with RA who have failed to obtain benefit from anti-TNF-α agents.     

Gene therapy targets for rheumatoid arthritis

Rheumatoid arthritis (RA) is the most common chronic systemic autoimmune inflammatory disease whose pathogenesis is not fully understood. The physiology of inflammation has been systematically studied and has provided specific targeted strategies for the modulation of inflammation. A number of biological agents targeted at reducing the inflammatory cascade of pathophysiological reactions have been developed. Some, such as interleukin-1 receptor antagonist (IL-1Ra), antitumour necrosis factor (TNF) α antibodies and TNF soluble receptors, have been tested and are now in use clinically. The clinical effects that have been observed are transient, necessitating repeated treatments. Advances in molecular biology have opened ways for the development of gene therapy in which specific genes are introduced, using either viral or non-viral ex vivo and in vivo gene transfer techniques, to locally enhance in vivo gene expression or suppress gene(s) of interest with a view to downregulating inflammatory responses. The proof of concept has been provided in a number of animal models of inflammatory arthritis. Strategies for production of cytokine inhibitors, such as soluble TNF receptors, or anti-inflammatory cytokines, such as IL-4, IL-10, transforming growth factor β (TGF-β) and interferon β (IFN-β), have been developed. Other approaches involve the regulation of cartilage and bone erosion using IL-1Ra and tissue inhibitors of metalloproteinases, modulating apoptotic pathways in the rheumatoid synovium and the use of decoy oligonucleotides to nuclear factor κB (NF-κB), whose local application has been shown to be effective in downregulating joint inflammation in rat models of arthritis. Cytokines and other mediators play important physiological roles in the host’s defence system against infections and malignancy. Their chronic inhibition or their constitutive expression by gene therapy may lead to the development of side effects. Thus, carefully regulated gene expression during long-term studies will be required to assess the safety of selective targeting of processes involved in inflammation. This review summarises the important developments in gene therapy for RA.     

Combination therapy for early rheumatoid arthritis

Around 1% of adults in the U.K. have rheumatoid arthritis (RA). U.K. national guidelines recommend that such people should receive disease-modifying anti-rheumatic drugs (DMARDs) as soon as possible after diagnosis, as earlier treatment is more effective in reducing disease progression. Also, it has been proposed that combination DMARD therapy may reduce joint damage more than single drugs. In the light of several recently published trials on combination therapy in early RA, here we update our recommendations on such treatment.     

The effect of gene polymorphisms on patient responses to rheumatoid arthritis therapy

Introduction: Rheumatoid arthritis (RA) is a systemic disease leading to joint destruction. The therapy of RA is mainly based on disease-modifying anti-rheumatic drugs (DMARDs) and biological drugs. The response to treatment is different among patients. Therefore, we have searched for factors that may predict the efficacy and toxicity during therapy in individual patients.

Areas covered: This review presents the role of genetic polymorphisms as predictors of the efficacy and toxicity during the therapy of RA patients with DMARDs (methotrexate, leflunomide, sulfasalazine) and biological drugs (anti-TNF-alpha antagonists, Tocilizumab, Rituximab).

Expert opinion: Despite studies having shown an association between genetic polymorphisms and response to therapy in RA patients, the majority of these findings are still inconclusive and inconsistent. We are still far from applying pharmacogenetic tests in routine clinical practice that can predict the outcome of treatment. Several factors, such as small sample size with low statistical power, variability in the outcome definitions and the heterogeneity of the cohorts, limited number of tested single nucleotide polymorphisms (SNPs), small effect for the selected variant, and a lack of consideration of epigenetic factors, may contribute to the inconsistency observed and may lead to limited success in personalizing therapy.     

Flurbiprofen in rheumatoid arthritis therapy

Summary

Preliminary findings are reported from an open study of 300?mg flurbiprofen daily in 24 patients and from 6 out of 30 patients treated so far in a double-blind crossover comparison of 300?mg flurbiprofen daily and 150?mg indomethacin daily in the treatment of rheumatoid arthritis. The results indicate that flurbiprofen is effective in relieving symptoms and is better tolerated than indomethacin. Using an experimental model in rats to assess the anti-inflammatory activity of flurbiprofen, data suggest that flurbiprofen is unable to prevent an immunological type of inflammation but is capable of modifying the type and extent of cellular infiltration.     

HIV hollow fiber SCID model for antiviral therapy comparison with SCID/hu model

Severe combined immunodeficient (SCID) mice have been evaluated for applicability as hosts for a human immunodeficiency virus (HIV) animal model, compatible with the pathogenesis of HIV disease and/or for testing compounds for antiviral efficacy. McCune et al. [Science 241 (1988) 1632] described the SCID/hu model and Namikawa et al. [J. Exp. Med. 172 (1990) 1055] and Rabin et al. [Antimicrob. Agents Chemother. 40 (1996) 755] described the SCID/hu (Thy/Liv) model which was developed for the evaluation of HIV pathogenic mechanisms and for the prioritization of antiviral compounds that were efficacious in vitro. Hollingshead et al. [Antiviral Res. 28 (1995) 265] and Xu et al. [Bioorg. Med Chem. Lett. 9 (1999) 133] described the HIV hollow fiber SCID mouse model. This model was developed to be a low cost, high throughput, time efficient, simple in vivo screening system for preliminary anti-HIV efficacy evaluation for the prioritization of antiviral compounds that demonstrated in vitro efficacy. The hollow fiber model is used as a pharmacologic tool to help separate active and inactive agents and direct the best lead compounds into additional animal model testing (e.g. SCID/hu). Compounds that are known to have an antiviral effect in man (e.g. 3'-azo-3'-deoxythymidine (AZT), dideoxyinosine (ddI) and dideoxycytidine (ddC)) were evaluated in both models. The endpoints (e.g. PCR, flow cytometry, MTT, p24, RT) evaluated in both models indicate that HIV-1 virus replicates in both models and infection is suppressed in the SCID/hu and hollow fiber SCID mouse models when treated with approved clinical antiviral agents. While both models are useful for the evaluation of antiviral therapies, there are distinct advantages (e.g. cost, time, material, equipment, expediency) with the hollow fiber assay over the SCID/hu model (Thy/Liv) for antiviral drug evaluations particularly in terms of cost effectiveness.     

Targeted therapy in rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is the most common inflammatory joint disease in adults leading to pain and disability. New drugs, called biologicals, have opened up new possibilities in the treatment of RA. Objective: Targeting pro-inflammatory cytokines such as tumour necrosis factor-α (TNF-α) or interleukin-1 (IL-1) is well established in clinical care of RA patients. However, lack or loss of clinical response occurs in up to 25% of the patients. New strategies beyond these targets, namely blocking T cells by abatacept or B cells by rituximab (RTX), have been introduced recently. Methods: All relevant clinical trials published in peer-reviewed journals are discussed in this article. Data from abstracts presented at congresses have not been included. Conclusion: TNF blocking agents have significantly improved therapy of and outcome in RA patients and, therefore, are still the first choice biologicals for the treatment of RA. Alternatively, abatacept or RTX offer new options in case of inefficacy of or contraindications against anti-TNF therapy. Forthcoming drugs, such as tocilizumab, will extend our armamentarium to treat RA effectively.     

TNF inhibition as therapy for rheumatoid arthritis

The introduction of TNF-α-inhibiting biologicals has been a major therapeutic breakthrough in rheumatoid arthritis therapy. Against a background of conventional disease-modifying antirheumatic drug experience, this review focuses on present experiences and possible future developments. TNF inhibition results in profound improvement in the majority of rheumatoid arthritis patients, but non-response and adverse effects need attention. Adalimumab is being filed for approval. Other monoclonal antibodies or receptor constructs are in late development. Small molecule inhibitors of TNF production or signalling are a hot topic. One emerging target is nuclear factor kappa B and selective inhibition has proved effective in animal models of arthritis. Synovial proliferation in rheumatoid arthritis is characterised by diminished apoptosis of fibroblasts, whereas bone marrow precursor cells undergo accelerated apoptosis in active rheumatoid arthritis. Both abnormalities are seemingly ameliorated by TNF inhibition. Anti-apoptotic strategies will soon go into development for control of unresponsive rheumatoid arthritis.     

TNF inhibition as therapy for rheumatoid arthritis

The introduction of TNF- alpha -inhibiting biologicals has been a major therapeutic breakthrough in rheumatoid arthritis therapy. Against a background of conventional disease-modifying antirheumatic drug experience, this review focuses on present experiences and possible future developments. TNF inhibition results in profound improvement in the majority of rheumatoid arthritis patients, but non-response and adverse effects need attention. Adalimumab is being filed for approval. Other monoclonal antibodies or receptor constructs are in late development. Small molecule inhibitors of TNF production or signalling are a hot topic. One emerging target is nuclear factor kappa B and selective inhibition has proved effective in animal models of arthritis. Synovial proliferation in rheumatoid arthritis is characterised by diminished apoptosis of fibroblasts, whereas bone marrow precursor cells undergo accelerated apoptosis in active rheumatoid arthritis. Both abnormalities are seemingly ameliorated by TNF inhibition. Anti-apoptotic strategies will soon go into development for control of unresponsive rheumatoid arthritis.     

The anti-inflammatory effect of A3 adenosine receptor agonists: a novel targeted therapy for rheumatoid arthritis

Targeting the A₃ adenosine receptor (A₃AR) to combat inflammation is a new concept based on two findings. First, A₃AR is highly expressed in inflammatory cells, whereas low expression is found in normal tissues. This receptor was also found to be overexpressed in peripheral blood mononuclear cells, reflecting receptor status in the remote inflammatory process. Second, A₃AR activation with a specific agonist induces de-regulation of the NF-κB signaling pathway in inflammatory cells, as well as initiation of immunomodulatory effects. The A₃AR agonist CF-101 (known generically as IB-MECA) induces anti-inflammatory effects in experimental animal models of collagen- and adjuvant-induced arthritis. Combined therapy with CF-101 and methotrexate in adjuvant-induced arthritis rats yielded an additive anti-inflammatory effect. Methotrexate induced upregulation of A₃AR, rendering the inflammatory cells more susceptible to CF-101. In Phase I and in Phase IIa human studies, CF-101 was safe, well tolerated and showed strong evidence of an anti-inflammatory effect in rheumatoid arthritis patients. In peripheral blood mononuclear cells withdrawn from the patients at base line, a statistically significant correlation between A₃AR expression level and response to the drug was noted. It is suggested that A₃AR may serve as a biologic marker to predict patient response to the drug. Taken together, this information suggests that A₃AR agonists may be a new family of orally bioavailable drugs to be developed as potent inhibitors of autoimmune–inflammatory diseases.     

The anti-inflammatory effect of A3 adenosine receptor agonists: a novel targeted therapy for rheumatoid arthritis

Targeting the A(3) adenosine receptor (A(3)AR) to combat inflammation is a new concept based on two findings. First, A(3)AR is highly expressed in inflammatory cells, whereas low expression is found in normal tissues. This receptor was also found to be overexpressed in peripheral blood mononuclear cells, reflecting receptor status in the remote inflammatory process. Second, A(3)AR activation with a specific agonist induces de-regulation of the NF-kappaB signaling pathway in inflammatory cells, as well as initiation of immunomodulatory effects. The A(3)AR agonist CF-101 (known generically as IB-MECA) induces anti-inflammatory effects in experimental animal models of collagen- and adjuvant-induced arthritis. Combined therapy with CF-101 and methotrexate in adjuvant-induced arthritis rats yielded an additive anti-inflammatory effect. Methotrexate induced upregulation of A(3)AR, rendering the inflammatory cells more susceptible to CF-101. In Phase I and in Phase IIa human studies, CF-101 was safe, well tolerated and showed strong evidence of an anti-inflammatory effect in rheumatoid arthritis patients. In peripheral blood mononuclear cells withdrawn from the patients at base line, a statistically significant correlation between A(3)AR expression level and response to the drug was noted. It is suggested that A(3)AR may serve as a biologic marker to predict patient response to the drug. Taken together, this information suggests that A(3)AR agonists may be a new family of orally bioavailable drugs to be developed as potent inhibitors of autoimmune-inflammatory diseases.     

Abatacept: a novel treatment for rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, autoimmune disease that has traditionally been treated with non-biologic and biologic disease-modifying antirheumatic drugs (DMARDs). Although these agents have become firmly established as effective RA treatments, some patients do not have an adequate response. The recent approval of abatacept, a first-in-class agent that selectively modulates the activation of T cells, offers an alternative therapeutic option. As reflected in pharmacokinetic analyses, abatacept 10 mg/kg has been shown to be effective in treating patients with established RA. Demonstrating safety, efficacy and quality of life improvements in a wide range of RA patients, including those with inadequate response to methotrexate or tumor necrosis factor antagonists, abatacept is seen as a valuable addition to the RA treatment armamentarium.