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Life Extension Magazine March 2010

Arthro Immune Support

Current treatment of rheumatoid arthritis.

Over the past 10 years, the management of rheumatoid arthritis has been revolutionized. Early diagnosis is essential and should allow an early initiation of disease modifying anti-rheumatic drugs (DMARD), if possible within the first 3 three months after disease onset, aiming at disease remission and the best long-term prognosis. Recommendations for the prescription of synthetic and biologic DMARD (mainly anti-TNFalpha agents) are available since September 2007 [6] by HAS in France. The great efficacy of these drugs has been established from many clinical trials including tens of thousands of patients. However, severe adverse side effects may occur (allergy, tuberculosis, opportunistic infections, demyelination) and rheumatologists should remain vigilant. Global care of the patient includes prescription of pharmacologic and non-pharmacologic treatments (education, physical treatment, ergotherapy, psychotherapy, surgery). A good coordination between all specialists is required. Screening and treatment of extra-articular manifestations, prevention of infections, osteoporosis and cardiovascular complications are essential to allow a better long-term prognosis, and reduce disability and mortality of rheumatoid arthritis.

Rev Med Interne. 2009 Dec;30(12):1067-79.

The costs of rheumatoid arthritis: an international long-term view.

OBJECTIVES: To review the literature on the measurable direct and indirect costs of rheumatoid arthritis (RA) in industrialized countries from a societal perspective and to develop a template for international use. METHODS: A literature search using MEDLINE and other sources identified 153 relevant published articles, press releases, and so forth on the costs of RA and rheumatism from the major Organization for Economic Cooperation and Development (OECD) countries in English and other languages. Sixty-eight publications provide some economic data for analysis and are included in the bibliography. Twelve publications provide sufficiently detailed and robust information for inclusion in country overview tables. The concept of varied costs at different disease stages measured by years since diagnosis and Health Assessment Questionnaire (HAQ) scores is used to guide rational decisions in the allocation of scarce health care resources. RESULTS: Direct costs increase overproportionately during the course of the disease. The most important driver of direct costs is hospitalization, especially in moderate and severe RA. Costs of medication represent a comparatively small proportion of direct costs. Indirect costs caused by work disability can be substantially higher than direct costs, particularly in working-age patients. The total costs of RA to society, and the different cost components such as direct and indirect costs, are broadly comparable in industrialized countries by their order of magnitude. Major confounding factors for international comparison are different study methodologies and patient samples. CONCLUSIONS: The cost template developed in this article can be used to estimate the likely costs of RA to society for industrialized countries. It probably will underestimate indirect costs because of their incomplete coverage in the studies examined. A long-term perspective is needed for chronic diseases such as RA to assess the future effects of early interventions. Treatment in the early stages of RA that effectively reduces long-term disability has the potential to save substantial costs to society.

Semin Arthritis Rheum. 2000 Apr;29(5):305-20.

Reporting of patient-reported outcomes in recent trials in rheumatoid arthritis.

OBJECTIVES: Patient-reported outcomes (PROs) have been increasingly recognised as important in rheumatoid arthritis (RA). The objective of this study was to assess the frequency of use of different PROs in recently published RA articles and to compare the tools used through a systemic literature review. METHODS: (1) DATA SOURCE: In PUBMED MEDLINE database, articles reporting any type of clinical study for adult patients with RA, published between February 2005 and February 2007, and reporting any type of PRO. Articles were excluded if they did not concern adult RA or if they did not report any PROs. (2) DATA EXTRACTION: demographic characteristics of patients, study design, treatment assessed and all PROs. (3) Data analysis: descriptive. RESULTS: Of 109 reports, 50 (45%) were randomised controlled trials and 59 were other types of studies. A total of 63 questionnaires or tools for PROs were used, corresponding to 14 domains of health. Frequently reported domains (and most frequent tools) were: function, 83% (most frequent tool, health assessment questionnaire, HAQ); patient global assessment, 61% (most frequent tool, visual analogue scale, VAS); pain, 56% (VAS); and morning stiffness 27%. Domains such as fatigue, coping or sleep disturbance were infrequently reported. CONCLUSIONS: PROs are reported with great heterogeneity in recently published trials in RA. Some domains that appear important from the patient’s perspective are infrequently reported. Further work is needed in this field.

Ann Rheum Dis. 2009 Feb;68(2):183-90.

“TRECID,” TNFalpha related chronic inflammatory diseases - a new multiple diseases bridging concept.

The pro-inflammatory cytokine TNF alpha (TNF) has a key position in the pathogenesis of various infectious and inflammatory diseases. Clarification of its pivotal role in the pathogenesis of rheumatoid arthritis, spondyloarthritis, uveitis, psoriasis and inflammatory bowel disease has resulted in the successful development of TNF- blocking therapies, which have disease-modifying properties that exceed the effects of conventional therapeutic options. For this reason data on the concurrence of several chronic inflammatory diseases have led to the hypothesis of common pathogenetic processes of cytokine dysregulation. The acronym TRECID describes this concept of “TNF RElated Chronic Inflammatory Diseases”. Physicians of different specialties have integrated new therapeutic options with TNF-blocking therapies into their strategies for the management of the affected patients. Thus the concept of TRECID can be regarded as a role model for a dynamic, interdisciplinary cooperation based on shared pathophysiological aspects.

Dtsch Med Wochenschr. 2009 Oct;134(42):2132-6.

Switching between TNFalpha antagonists in rheumatoid arthritis: personal experience and review of the literature.

OBJECTIVE: To evaluate the clinical response after switching to another TNFalpha antagonist in patients with rheumatoid arthritis (RA) and provide a review of the literature on this topic. METHODS: In this ongoing, longitudinal, observational study we have prospectively collected data of patients starting biological treatments since 2000. The present analysis is restricted to RA patients who switched to another anti-TNFalpha due to lack of efficacy (LaE), loss of efficacy (LoE), or adverse events (AEs) by the end of December 2007. Disease activity score (ESR-based DAS28) was calculated and the clinical response (none, moderate, good) was evaluated according to the European League Against Rheumatism (EULAR) criteria. Clinical remission (DAS28 <2.6) and low disease activity (DAS28 </=3.2) were also evaluated. RESULTS: A total of 692 anti-TNFalpha-naïve patients has been registered, of whom 395 with a diagnosis of RA. Thirtyseven RA patients switched to another TNFalpha antagonist. Three months after switching, the proportion of patients with remission, low disease activity, good and moderate/good EULAR responses grew from 0%, 2.7%, 0%, and 5.4% (baseline before switching) to 16.2%, 35.1%, 27%, and 62.2% (p<0.05, p<0.001, p<0.001, p<0.000001, respectively). Of the patients who switched because of LaE, LoE, and AEs a moderate/good EULAR response was achieved in 38.4%, 66.6%, and 88.8% of patients, respectively. Mean treatment duration with the second anti-TNFalpha was significantly longer in patients switching for LoE and AEs than in those switching for LaE (p<0.05). CONCLUSIONS: The findings of this study suggest that RA patients may be successfully treated with another TNFalpha antagonist, especially those withdrawing for LoE or AEs.

Reumatismo. 2009 Apr-Jun;61(2):107-17.

Biologic therapy for rheumatoid arthritis: clinical efficacy and predictors of response.

Rheumatoid arthritis (RA) is a chronic, disabling disease of the synovial joints, thought to be autoimmune in origin. The emergence of biologic therapies has proven to be highly successful in effectively treating RA in the majority of cases. However, the cost of these agents is high and some patients do not respond to these drugs, or they suffer from adverse events. This article will review the currently available data on efficacy and the clinical, genetic, and biomarkers of response to these biologic therapies in RA. The anti-tumour necrosis factor-alpha (anti-TNFalpha) agents, adalimumab, etanercept and infliximab, act to neutralize the pro-inflammatory cytokine. Response to these agents is higher in patients receiving concurrent disease modifying anti-rheumatic drugs or non-steroidal anti-inflammatory drugs, in those with lesser disability, and in non-smokers. Many genetic predictors of response have been investigated, such as the shared epitope, the TNF gene and its receptors, but none have been absolutely confirmed. Synovial expression of TNFalpha has been suggested as a biomarker of response, while anti-cyclic citrullinated peptide antibody and rheumatoid factor (RF)-positivity predict poor response. Newer biologic agents include the interleukin (IL)-1 receptor antagonist anakinra, the B-cell depleting agent rituximab, the selective costimulation modulator abatacept, and the anti-IL-6 receptor monoclonal antibody tocilizumab. No genetic studies of response to these agents have been performed to date. However, it has been reported that low synovial infiltration of B cells and complete B-cell depletion after the first rituximab infusion are predictors of good response to this agent.

BioDrugs. 2009;23(2):111-24.

Treatment of very early rheumatoid arthritis with symptomatic therapy, disease-modifying antirheumatic drugs, or biologic agents: a cost-effectiveness analysis.

BACKGROUND: Long-term control or remission of rheumatoid arthritis (RA) may be possible with very early treatment. However, no optimal first therapeutic strategy has been determined. OBJECTIVE: To assess the potential cost-effectiveness of major therapeutic strategies for very early RA. DESIGN: Decision analytic model with probabilistic sensitivity analyses. DATA SOURCES: Published data, the National Data Bank for Rheumatic Diseases, and actual 2007 hospital costs. TARGET POPULATION: U.S. adults with very early RA (symptom duration <or=3 months). TIME HORIZON: Lifetime. PERSPECTIVE: Health care provider and societal. INTERVENTION: 3 management strategies were compared: a symptomatic or “pyramid” strategy with initial nonsteroidal anti-inflammatory drugs, patient education, pain management, and low-dose glucocorticoids, and disease-modifying antirheumatic drugs (DMARDs) at 1 year for nonresponders; early DMARD therapy with methotrexate; and early therapy with biologics and methotrexate. OUTCOME MEASURES: Cost per quality-adjusted life-year (QALY) gained. RESULTS OF BASE-CASE ANALYSIS: By reducing the progression of joint erosions and subsequent functional disability, both early intervention strategies increase quality-adjusted life more than the pyramid strategy and save long-term costs. When the cost of very early intervention is factored in, the cost-effectiveness ratio of the early DMARD strategy is $4849 per QALY (95% CI, $0 to $16 354 per QALY) compared with the pyramid strategy, whereas the benefits gained through the early biologic strategy come at a substantial incremental cost. The early DMARD strategy maximizes the effectiveness of early DMARDs and reserves the use of biologics for patients with more treatment-resistant disease of longer duration, for which the incremental benefit of biologics is greater.Results of Sensitivity Analysis: The early biologic strategy becomes more cost-effective if drug prices are reduced, risk for death is permanently lowered through biologic therapy, patients experience drug-free remission, responders can be selected before therapy initiation, or effective alternative antirheumatic agents are available for patients for whom several biologics have failed. LIMITATIONS: Data on the long-term effect of very early therapeutic interventions on the natural progression in disability and joint erosions are limited. The study considered only tumor necrosis factor inhibitors and not the newer biologics. CONCLUSION: According to the most objective measures of RA progression, very early intervention with conventional DMARDs is cost-effective. The cost-effectiveness of very early intervention with biologics remains uncertain.

Ann Intern Med. 2009 Nov 3;151(9):612-21.

Inhibitory effects of ethyl acetate extract of Andrographis paniculata on NF-{kappa}B trans-activation activity and LPS-induced acute inflammation in mice.

This study was to investigate anti-inflammatory effect of Andrographis paniculata (Burm. f.) Nees (Acanthaceae) (AP). The effects of ethyl acetate (EtOAc) extract from AP on the level of inflammatory mediators were examined first using nuclear factor kappa B (NF-kappaB) driven luciferase assay. The results showed that AP significantly inhibited NF-kappaB luciferase activity and tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), macrophage inflammatory protein-2 (MIP-2) and nitric oxide (NO) secretions from lipopolysaccharide (LPS)/interferon-gamma stimulated Raw264.7 cells. To further evaluate the anti-inflammatory effects of AP in vivo, BALB/c mice were tube-fed with 0.78 (AP1), 1.56 (AP2), 3.12 (AP3) and 6.25 (AP4) mg kg(-1) body weight (BW)/day in soybean oil, while the control and PDTC (pyrrolidine dithiocarbamate, an anti-inflammatory agent) groups were tube-fed with soybean oil only. After 1 week of tube-feeding, the PDTC group was injected with 50 mg kg(-1) BW PDTC and 1 h later, all of the mice were injected with 15 mg kg(-1) BW LPS. The results showed that the AP1, AP2, AP3 and PDTC groups, but not AP4, had significantly higher survival rate than the control group. Thus, the control, AP1, AP2, AP3 and PDTC groups were repeated for in vivo parameters. The results showed that the AP and PDTC groups had significantly lower TNF-alpha, IL-12p40, MIP-2 or NO in serum or peritoneal macrophages and infiltration of inflammatory cells into the lung of mice. The AP1 group also had significantly lower MIP-2 mRNA expression in brain. This study suggests that AP can inhibit the production of inflammatory mediators and alleviate acute hazards at its optimal dosages.

Evid Based Complement Alternat Med. 2009 Sep 10.

Transcription factor NF-kappaB: a sensor for smoke and stress signals.

Nuclear factor-kappa B (NF-kappaB) is a transcription factor that resides in the cytoplasm of every cell and translocates to the nucleus when activated. Its activation is induced by a wide variety of agents including stress, cigarette smoke, viruses, bacteria, inflammatory stimuli, cytokines, free radicals, carcinogens, tumor promoters, and endotoxins. On activation, NF-kappaB regulates the expression of almost 400 different genes, which include enzymes (e.g., COX-2, 5-LOX, and iNOS), cytokines (such as TNF, IL-1, IL-6, IL-8, and chemokines), adhesion molecules, cell cycle regulatory molecules, viral proteins, and angiogenic factors. The constitutive activation of NF-kappaB has been linked with a wide variety of human diseases, including asthma, atherosclerosis, AIDS, rheumatoid arthritis, diabetes, osteoporosis, Alzheimer’s disease, and cancer. Several agents are known to suppress NF-kappaB activation, including Th2 cytokines (IL-4, IL-13, and IL-10), interferons, endocrine hormones (LH, HCG, MSH, and GH), phytochemicals, corticosteroids, and immunosuppressive agents. Because of the strong link of NF-kappaB with different stress signals, it has been called a “smoke-sensor” of the body.

Ann N Y Acad Sci. 2005 Nov;1056:218-33.

Andrograpanin, isolated from Andrographis paniculata, exhibits anti-inflammatory property in lipopolysaccharide-induced macrophage cells through down-regulating the p38 MAPKs signaling pathways.

Andrographis paniculata Nees is an official herbal medicine for treatment of infection and inflammation in China. Andrograpanin, the one of diterpene lactones in A. paniculata, is a hydrolysate from neoandrographolide in vivo and in vitro. The goal of the present study was to investigate andrograpanin which effects on over production of nitric oxide (NO) and pro-inflammatory cytokines (TNF-alpha, IL-6 and IL-12p70) and the key signaling pathways involved in lipopolysaccharide (LPS)-activated macrophage cells. The results showed that NO and all three pro-inflammatory cytokines were inhibited by andrograpanin (15-90 microM) in a dose-dependent manner. The RT-PCR and western blotting assays showed that andrograpanin inhibited productions of NO and pro-inflammatory cytokines through down-regulating iNOS and pro-inflammatory cytokines gene expression levels. Further studies suggested that down-regulation of p38 mitogen-activated protein kinase (MAPKs) signaling pathways were involved in the anti-inflammatory activities of andrograpanin. This study provided evidences that andrograpanin might be useful as a potential anti-inflammatory leading compound for inflammatory drug development.

Int Immunopharmacol. 2008 Jul;8(7):951-8

In vivo and in vitro anti-inflammatory activities of neoandrographolide.

Neoandrographolide, one of the principal diterpene lactones, isolated from a medicinal herb Andrographis paniculata Nees, was tested in vivo and in vitro for its anti-inflammatory activities and mechanism. Oral administration of neoandrographolide (150 mg/kg) significantly suppressed ear edema induced by dimethyl benzene in mice. Oral administration of neoandrographolide (100-150 mg/kg) also reduced the increase in vascular permeability induced by acetic acid in mice. In vitro studies were performed using the macrophage cell line RAW264.7 to study the effect of neoandrographolide on suppressing phorbol-12-myristate-13-acetate (PMA)-stimulated respiratory bursts and lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha). Respiratory bursts were quantified by chemiluminescence (CL) measurements. Results showed that neoandrographolide suppressed PMA-stimulated respiratory bursts dose-dependently from 30 muM to 150 muM. Neoandrographolide also inhibited NO and TNF-alpha production in LPS-induced macrophages, contributing to the anti-inflammatory activity of A. paniculata. These results indicate that neoandrographolide possesses significant anti-inflammatory effects, which implies that it would be one of the major contributing components to participate in the anti-inflammatory effect of A. paniculata. and a potential candidate for further clinical trial.

Am J Chin Med. 2007;35(2):317-28.

Inhibitory effects of neoandrographolide on nitric oxide and prostaglandin E2 production in LPS-stimulated murine macrophage.

Activated macrophages express inducible isoforms of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), produce excessive amounts of nitric oxide (NO) and prostaglandin E(2) (PGE(2)), which play key roles in the processes of inflammation. Andrographis paniculata Nees is a traditional Chinese herb commonly used for treatment of infection, inflammation, and diarrhea. However, the mechanism of its therapeutic function is not well known. In the present study, the effect of neoandrographolide, one of bioactive components in A. paniculata, on iNOS-mediated NO production and COX-2-mediated PGE(2) in bacterial lipopolysaccharide (LPS) stimulated-murine macrophages was investigated. Neoandrographolide at concentrations (30-90 microM) significantly (p<0.05) inhibited the productions of NO and PGE(2) in LPS stimulated macrophages without inducing cytotoxicity. The effect of neoandrographolide also has been investigated on iNOS and COX-2 expression in activated macrophage by using RT-PCR and immunoblotting. The inhibition of NO release by neoandrographolide can be attributed to the block of iNOS mRNA transcription followed by inhibiting protein expression. However, neoandrographolide inhibited COX-2 protein expression only but without inhibiting COX-2 mRNA expression, which was involved in the inhibitory activity against the PGE(2) overproduction. This suggests that the effect of neoandrographolide on iNOS expression may occur at the transcriptional level and the inhibition of COX-2 expression occurs at the translational level. Furthermore, we have found that the addition of neoandrographolide inhibited the activation of p38 mitogen-activated protein kinase (MAPKs) instead of JNK, ERK1/2, or NF-kappaB. These results indicated that the anti-inflammatory properties of neoandrographolide might result from the inhibition of iNOS and COX-2 expression through inhibiting p38 MAPKs activation. Therefore, neoandrographolide isolated from A. paniculata could be offered as a leading compound for anti-inflammation.

Mol Cell Biochem. 2007 Apr;298(1-2):49-57.

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