ArticleLiterature Review

The Use of Biological Agents in the Treatment of Rheumatoid Arthritis

March 2007
Annals of the Academy of Medicine Singapore 36(2):128-34

March 2007
36(2):128-34

Source
PubMed

Authors:

Rheumatoid arthritis is a common and potentially devastating condition which did not have good treatment options until recently. Pharmacological treatment should not just comprise antiinflammatory agents and corticosteroids. The current therapeutic approach is to start a disease modifying agent early in the illness to prevent eventual joint damage. Older disease modifying anti-rheumatic drugs (DMARDs) include methotrexate, sulphasalazine and hydroxychloroquine. Newer ones such as leflunomide and cyclosporine are also used. A recent advance in the management of rheumatoid arthritis is the use of biological agents which block certain key molecules involved in the pathogenesis of the illness. They include tumour necrosis factor (TNF)- blocking agents such as infliximab, etanercept and adalimumab, the anti-CD 20 agent rituximab and CTLA-4 Ig abatacept. Other agents which are in development include anti-IL6 tocilizumab, anti-CD22 and anti-lymphostat B. In this review, the efficacy and side effects of these agents, their impact on current clinical practice and future trends are discussed.

Peri-Infusional Adverse Reactions to Rituximab in Mexican Patients with Rheumatoid Arthritis

Article

Full-text available

Jun 2019

Background. The treatment of rheumatoid arthritis (RA) has significantly improved since the introduction of biologics like rituximab. Rituximab achieves selective B lymphocyte depletion and, thereby, reduce inflammation. It has adverse reactions related to the immunogenic response. Objective. The aim of this study was to evaluate the frequency and severity of rituximab adverse reactions in Mexican patients with RA. Methods. A prospective, observational, descriptive, open-labeled, multicenter cohort study of intensive pharmacovigilance was conducted during 17 months in 10 hospitals. We included 335 adult patients with RA, 26 male an 309 female. They received two doses of rituximab (1000 mg) on days 1 and 15 in combination with methotrexate. Adverse reactions were graded according to the National Cancer Institute (NCI) scale and causality was established with the Naranjo algorithm. Infusions were classified as fast (0 to 180 minutes) and slow (> 181 minutes). The first and second infusions were compared. Results. The total number of infusion episodes recorded was 631 and 36 adverse reactions were informed in 24 patients (7.1 %). There were no differences between the variances of the first and second infusions. All the adverse reactions were considered mild to moderate (NCI Scale). According to Naranjo algorithm, the adverse reactions to rituximab were possible or probable. The infusion speed did not have an influence on the adverse reactions; whereas the incident rate was lower than that reported by other authors. Conclusions. Rituximab has a favorable safety profile in Mexican patients.

Biological Agents in the Treatment of Rheumatoid Arthritis

Article

Mar 2011

Rheumatoid arthritis (RA) is the commonest joint disease with considerable morbidity and mortality. Conventional disease modifying antirheumatic drugs like methotrexate form the cornerstone of therapy. These drugs have several limitations in terms of slow onset of action, adverse effects and modest remission rates. Several cytokines are involved in the pathogenesis of RA. Biological agents that specifically inhibit the effects of tumour necrosis factor-alpha (TNF-a) or interleukin-1 (IL-1) represent a major advancement in the treatment of RA. By targeting mediators that are directly involved in the pathogenesis of RA, these agents slow the radiological progression of bone and cartilage damage in joints, prevent or delay the onset of disability. These are highly specific and better tolerated. The use of these biological agents needs careful monitoring for side effects, including the development of infection. Additional anti-cytokine agents for the treatment of RA are under further development. Key words: Rheumatoid arthritis; biological agents; inflammatory cytokine. DOI: 10.3329/jbsp.v29i1.7168 J Bangladesh Coll Phys Surg 2011; 29:27-31

Current status and challenges of cytokine pharmacology

Article

May 2009
BRIT J PHARMACOL

The major concern of pharmacology about cytokines has originated from plentiful data showing association between gross changes in their production and pathophysiological processes. Despite the enigmatic role of cytokines in diseases, a number of them have become a subject of cytokine and anti-cytokine immunotherapies. Production of cytokines can be influenced by many endogenous and exogenous stimuli including drugs. Cells of the immune system, such as macrophages and lymphocytes, are richly endowed with receptors for the mediators of physiological functions, such as biogenic amines, adenosine, prostanoids, steroids, etc. Drugs, agonists or antagonists of these receptors can directly or indirectly up- and down-regulate secretion of cytokines and expression of cytokine receptors. Vice versa, cytokines interfere with drug pharmacokinetics and pharmacodynamics through the interactions with cytochrome P450 and multiple drug resistance proteins. The aim of the review is to encourage more intensive studies in these fields of cytokine pharmacology. It also outlines major areas of searching promising candidates for immunotherapeutic interventions.

MEDIA SYSTEM AND EURO-INTEGRATIONS: STATE OF PLAY, CHALLENGES AND PERSPECTIVES

Chapter

Apr 2022

The Republic of Serbia joined the Council of Europe in 2003 and afterwards signed the EU Stabilization and Association Agreement (2007) and became an official candidate for membership in the European Union (2012). Thus, Serbia mapped its strategic European orientation, committing itself to the defined framework for the implementation of reforms for its alignment with the European Union's public policies. When it comes to media as a specific social sub-system, in this chapter we look at the different aspects of the Serbian media system on its way to democratic and professional emancipation in the post-socialist period (following the political changes of 2000, when the coalition of democratic parties ousted the authoritarian socialist regime). The research analyzes and systematizes key current issues confronting the Serbian media sphere and concerning the issues of ownership, regulation, self-regulation, market and ethics in the context of the European media policy. The first strand of our research focuses on reviewing the achievements in the democratic post-socialist transformation of the media system in Serbia. It presents the principles of the European media policy and outlines principal challenges arising from the process of the so-called democratic transformation of the media system through its harmonization with European standards. The second strand of our research unfolds in the context of assumption that mass media play a significant role in the European Union’s image-creation. The study, based on sociological and communication theory knowledge and methods, elucidates the role of media in generating the discourse on EU integrations within the Serbian public sphere.

CONTEMPORARY UNDERSTANDING OF THE PATHOGENESIS OF RHEUMATOID ARTHRITIS.

Article

Sep 2021

Arvinder Singh

Rheumatoid Arthritis (RA) is one of the most common rheumatologic conditions. Dell et al (2013) denes RA as a systemic autoimmune polyarticular arthritis, which can also have extra-articular manifestations that can lead to various systemic complications,. It is more common in women and can present at any age, however, the peak age of onset is the fth decade. RA mainly involves the synovial membrane leading to synovial inammation, proliferation, pannus formation and destruction of the articular cartilage, peri- articular bone and soft tissues.

Globalization Impact on Entrepreneurship in Small Countries

Chapter

Full-text available

May 2019

Mirjana Radovic Markovic

Soluble CD83 Triggers Resolution of Arthritis and Sustained Inflammation Control in IDO Dependent Manner

Article

Full-text available

Apr 2019

Interference with autoimmune-mediated cytokine production is a key yet poorly developed approach to treat autoimmune and inflammatory diseases such as rheumatoid arthritis. Herein, we show that soluble CD83 (sCD83) enhances the resolution of autoimmune antigen-induced arthritis (AIA) by strongly reducing the expression levels of cytokines such as IL-17A, IFNγ, IL-6, and TNFα within the joints. Noteworthy, also the expression of RANKL, osteoclast differentiation, and joint destruction was significantly inhibited by sCD83. In addition, osteoclasts which were cultured in the presence of synovial T cells, derived from sCD83 treated AIA mice, showed a strongly reduced number of multinuclear large osteoclasts compared to mock controls. Enhanced resolution of arthritis by sCD83 was mechanistically based on IDO, since inhibition of IDO by 1-methyltryptophan completely abrogated sCD83 effects on AIA. Blocking experiments, using anti-TGF-β antibodies further revealed that also TGF-β is mechanistically involved in the sCD83 induced reduction of bone destruction and cartilage damage as well as enhanced resolution of inflammation. Resolution of arthritis was associated with increased numbers of regulatory T cells, which are induced in a sCD83-IDO-TGF-β dependent manner. Taken together, sCD83 represents an interesting approach for downregulating cytokine production, inducing regulatory T cells and inducing resolution of autoimmune arthritis.

Chapter: RHEUMATIC MUSCULOSCELETAL DISEASES IN SERBIA. In: Serbia, Current Political, Economic and Social Issues and Challenges

Book

Feb 2019

Mirjana Zlatkovic-Svenda

Rheumatic mucsuloskeletal diseases (RMDs) have been added to non-communicable diseases apart from cardiovascular diseases, diabetes, chronic obstructive respiratory diseases and malignancy. RMDs comprise over 150 diseases and syndromes, broadly categorized as inflammatory and non-inflammatory rheumatic diseases. RMDs are the greatest cause of work loss in Europe along with mental health problems. For most of the countries in 2015, musculoskeletal conditions are the leading cause for Years Living with Disability (YLD) worldwide exhibiting huge impact on economy by direct (medical and nonmedical), indirect (productivity loss) and intangible (pain and disability) cost.RMDs economic burdenin Europe is very heavy: the estimated cost is more than 200 billion Euros per year. This makes RMDs the most expensive group ofdiseases in the European health care system. Because of the above mentioned, the World Health Organisation has shifted its goal from reducing mortality to reducing disease consequences and improving health. Being staggered in the upper middle income economy countries, Serbia is challenged to fight RMDs not only by prevention and early diagnosis strategy, but also by new and potent drugs implementation strategy. New drugs can slow down the inflammation process and prevent joint damage as well as periarticular tissue structural changes, and also inhibit systemic injures and internal organs involvement. The impact of rheumatic diseases in Serbia has been evaluated by several studies. A study conducted in 1989-1990 has determined the Serbian capital town-Belgrade RA prevalence of 0.2%, lower than that in other European population estimates reported for that time. Three additional Serbian studies have confirmed the above result: the Zlatibor region study with RA prevalence of 0,25% [95% CI (0.22-0.29)], Dobanovci 0,22% [95% CI (0.21-0.23)] and Mladenovac 0,22% [95% CI (0.18-0.27)]. Furthermore, similar RA prevalence was found in Turkish part of Istanbul- Sagmalcilar district, which was mainly settled by immigrants from Balkan countries- e.g. former Yugoslav, where it was 0.22%. According to the latest Serbian population study done on 6213 people sample covering two differently-located Serbian regions embracing four towns (the northern town Belgrade and southern towns Cacak, Uzice and Krusevac) with 63,3% response rate, the inflammatory rheumatic diseases representative reumatoid arthritis (RA) prevalence was estimated at 0.35 % [95% Confidence Interval-CI 0.18-0.53], which makes around 20.200 inhabitans older than 18 years, e.g. 0.19 [95%CI 0.00-0.38] males and 0.52 [95%CI 0.27-0.76] females. Considering the fact that impact of patients with rheumatic diseases treated with biologic therapy in Western European countries is about 20%, it would ideally be 4.000 people in Serbia, but in fact is much lower. Another most common inflammatory rheumatic disease spondyloarthritis (SpA), prevalence in Serbia is estimated at 0.35 [95%CI 0.17-0.54], e.g. 0.38 [95%CI 0.06-0.71] for males and 0.32 [95%CI 0.10-0.54] for females, which makes around 18.500 people. Percentage of SpA patients treated with biologics is 30% in America, extrapolated to Serbia it would be around 5.000 persons- but in fact is much lower, as well. Being faced with non-communicable diseases economic impact- specially RMDs, Serbia has experienced big challenge for new and potent therapeutic drugs usage, mostly limited by the country's economic situation. Improving the economic situation in Serbia will bring benefits in many areas, including the health care.

SERBIA: Current Political, Economic and Social Issues and Challenges

Book

Mar 2019

Danijela Spasic

Rheumatoid Arthritis: A Novel Approach in Diagnosis and Treatment

Article

Full-text available

Feb 2018

Marina Kostic

The rheumatoid arthritis is chronic disease with progressive course and deteriorations of joints as well as other organs. The pathogenesis of rheumatoid arthritis is characterized with chronic synovitis and inflammation. The main roles in development of rheumatoid arthritis have auto-reactive T cells and inflammatory cytokines, especially tumor necrosis factor α, interleukin 1 and interleukin 6. The management of rheumatoid arthritis has evolved significantly in the past twenty years, especially with introduction new diagnostic criteria by European League for Rheumatoid Arthritis which are very sensitive for early arthritis. The main goal of treating rheumatoid arthritis is to start with therapy in the phase of the disease when destruction of joints can still be prevented. Therapeutic strategies for rheumatoid arthritis involve wide palette of different drugs which can be divided into conventional and biological Disease Modifying Anthirheumatic Drugs. The use of methotrexate in combination with biological drugs provide targeting not only structural changes in rheumatoid arthritis but also and immunological pathways in development of rheumatoid arthritis. These drugs synergistically provide clinical remission and low activity of rheumatoid arthritis in the majority of patients. The uses of biological drugs are limited due their high costs or safety profile. In order to reduce costs and toxicity in the treatment of rheumatoid arthritis, new treat- to –target concept is established. The new class of drugs which modulate signal pathways and activity of tyrosine kinase are under investigations in post marketing surveys in patients with rheumatoid arthritis as in efficacy as in safety issues.

Automatic identification of bone erosions in rheumatoid arthritis from hand radiographs based on deep convolutional neural network

Article

Full-text available

May 2018
MULTIMED TOOLS APPL

Although radiographic assessment of joint damage is essential in characterizing disease progression and prognosis in patients with rheumatoid arthritis (RA), it is often difficult even for trained radiologists to find radiographic changes on hand and foot radiographs because lesion changes are often subtle. This paper proposes a novel quantitative method for automatically detecting bone erosion on hand radiographs to assist radiologists. First, the proposed method performs with the crude segmentation of phalanges regions from hand radiograph and extracts the detailed phalanges regions by the multiscale gradient vector flow (MSGVF) Snakes method. Subsequently, the region of interest (ROI; 40 × 40 pixels) is automatically set on the contour line of the segmented phalanges by the MSVGF algorithm. Finally, these selected ROIs are identified by the presence or absence of bone erosion using a deep convolutional neural network classifier. This proposed method is applied to the hand radiographs of 30 cases with RA. The true-positive rate and the false-positive rate of the proposed method are 80.5% and 0.84%, respectively. The number of false-positive ROIs is 3.3 per case. We believe that the proposed method is useful for supporting radiologists in imaging diagnosis of RA.

An update of dietary phenolic compounds in prevention and management of rheumatoid arthritis

Article

Jun 2016

Certain nutritional components influence the cellular metabolism and interfere in the pathological inflammatory process, so that they may act as a coadjuvant in the treatment of many chronic inflammatory diseases, including rheumatoid arthritis (RA). Particularly, a wide range of evidence has demonstrated the beneficial roles of dietary phenolic compounds in RA because of their ability to modulate pro-oxidant and pro-inflammatory pathways reducing the onset of arthritic disease progression. These natural phenolic compounds can modulate both the action and the production of inflammatory mediators either directly or indirectly by modulating the action of other molecules involved in RA pathology. Subsequently, the purpose of this article is to review the main in vitro and in vivo studies in RA, which have documented interesting insights into the antioxidant, anti-inflammatory, and immunomodulatory properties of dietary phenolic compounds focusing on their molecular action mechanisms involved in RA. The observations reported above are promising and suggest that the dietary phenolic compounds may influence the course of RA, ameliorating the RA symptoms and downregulating the inflammation at the molecular level; however, most of the studies conducted to date have been preclinical. Thus, future studies should therefore focus more on understanding the efficacy of these phenolic compounds in humans and bringing them to the forefront of the treatment of chronic human diseases.

Análisis de minimización de costos de infusiones endovenosas aplicadas en pacientes hospitalizados y pacientes ambulatorios en el servicio de reumatología en un hospital de Lima, Perú

Article

Full-text available

Oct 2015

Michelle Lozada

Objective: To measure the costs of therapy hospital intravenous infusion. vs outpatient service of Rheumatology, the National Hospital Edgardo Rebagilati Martins (HNERM) in Lima Peru, in 2009. Methods: The study design was a descriptive, retrospective and transversal. The population was comprised of all hospitalized patients (N =42) who received intravenous infusions of rituximab, pamidronate, infliximab, abatacept, tocilizumab, zoledronic acid and cyclophosphamide in the service of Rheumatology. Inclusion criteria were to be of both sexes over thirteen policyholders and / or beneficiaries of EsSalud. Medical and non-medical direct costs are for one year. A chip was developed, in which socioeconomic and demographic information requested type. The marginal costs of the alternatives were identified. Results: The study population was characterized by a greater proportion of female university level higher education, and prevalence of rheumatic diseases in the age group of 42-52 years and up. The total annual cost of hospitalization amounted to S / 472 726,21 (US $ 166 160,355); and for outpatient alternative to S / 416 092,25 (US $ 146 253,867), which make a difference in S / 56 633,96 (US $ 19 906,49) is equivalent to 12% savings. The management of outpatient intravenous infusions (in policyholders who have no hospitalization criteria) allowed reduce costs arising from hospitalization (hotel, food and staff). The biggest difference in this study was established hospitality costs (day bed), personnel costs and cost of lost productivity. Conclusions: The administration of intravenous infusions outpatients had lower costs for the institution and for the insured, thus optimizing resources.

Dual Islet Transplantation Modeling of the Instant Blood-Mediated Inflammatory Reaction

Article

Feb 2015
AM J TRANSPLANT

Islet xenotransplantation is a potential treatment for diabetes without the limitations of tissue availability. Although successful experimentally, early islet loss remains substantial and attributed to an instant blood-mediated inflammatory reaction (IBMIR). This syndrome of islet destruction has been incompletely defined and characterization in pig-to-primate models has been hampered by logistical and statistical limitations of large animal studies. To further investigate IBMIR, we developed a novel in vivo dual islet transplant model to precisely characterize IBMIR as proof-of-concept that this model can serve to properly control experiments comparing modified xenoislet preparations. WT and α1,3-galactosyltransferase knockout (GTKO) neonatal porcine islets were studied in nonimmunosuppressed rhesus macaques. Inert polyethylene microspheres served as a control for the effects of portal embolization. Digital analysis of immunohistochemistry targeting IBMIR mediators was performed at 1 and 24 h after intraportal islet infusion. Early findings observed in transplanted islets include complement and antibody deposition, and infiltration by neutrophils, macrophages and platelets. Insulin, complement, antibody, neutrophils, macrophages and platelets were similar between GTKO and WT islets, with increasing macrophage infiltration at 24 h in both phenotypes. This model provides an objective and internally controlled study of distinct islet preparations and documents the temporal histology of IBMIR. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Cost-effectiveness analysis of tocilizumab in combination with methotrexate for rheumatoid arthritis: A Markov model based on data from Serbia, country in socioeconomic transition

Article

Full-text available

Feb 2014

Recent studies have shown that biological treatments for rheumatoid arthritis can change the course of rheumatoid arthritis and improve functional ability of patients with rheumatoid arthritis. In spite of this fact, use of biological therapy is still limited by high prices of these medicines, especially in countries in socioeconomic transition. The aim of our study was to compare cost-effectiveness of a combination of tocilizumab and methotrexate with methotrexate alone for rheumatoid arthritis in Serbia, a country in socioeconomic transition. For the purpose of our study we designed a Markov model using data on therapy efficacy from the available literature, and data on the costs of health states calculated from records of actual patients treated in the Clinical Center Kragujevac, Serbia. The duration of one cycle in our model was set at one month, and the time horizon was 480 months (40 years). The study was done from the social perspective, and all the costs and outcomes were discounted for 3% per year. Treating rheumatoid arthritis with disease-modifying antirheumatic drugs (DMARDs) alone was more cost-effective in comparison with a combination of biologic treatment with tocilizumab and DMARDs. The total costs for treating a patient with DMARDs for one year were on average 261,945.42 RSD, or 2,497.70 Euro and the total costs for treatment with tocilizimab plus DMARDs were on average 1,959,217.44 RSD, or 18,659.20 Euro. However, these results are susceptible to changes in costs and treatment effects of tocilizumab in patients with more severe forms of rheumatoid arthritis. Our results show that the use of tocilizumab for rheumatoid arthrits in economic environment of Serbia is not cost-effective. Use of tocilizumab for treating rheumatoid arthritis can become affordable, if costs of its use become lower. In order to start using expensive biologic medicines in patients in transitional countries, special strategy and pricing policy of international pharmaceutical companies are necessary, which would include calculation of prices of biologic medicines on the basis of local pharmacoeconomic studies.

Biopharmaceuticals: An overview

Article

Jan 2010

Bhupinder Sekhon

Biopharmaceuticals drugs structurally mimics compounds found within the body and are produced using biotechnologies. These have the potential to cure diseases rather than merely treat symptoms, and have fewer side effects because of their specificity, for example, cytokines, enzymes, hormones, clotting factors, vaccines, monoclonal antibodies, cell therapies, antisense drugs, and peptide therapeutics. Emerging technologies in the area of biopharmaceuticals include manufacture of monoclonal antibodies in protein free media, designing chemically defined cells, genome based technologies, improving vaccine manufacturing processes, a potential cancer treatment and non-ribosomal peptide synthesis. Biopharmaceuticals have changed the treatment ways of many diseases like diabetes, malignant disorders; since these can be tailored for specific medical problems in different individuals. With biotechnology, any drug can be genetically modified using cell fusion or deoxyribonucleic acid (DNA)-recombinant technologies to alter specificities for individual diseases. Some distinct advantages of biotechnological processes include fewer side effects and more potent effect on target cells. Biopharmaceuticalsû greatest potential lies in gene therapy and genetic engineering.

Processing and presentation of the rheumatoid arthritis candidate autoantigen aggrecan, by antigen- specific B cells

Article

Caroline Louise Wilson

Active Compound of Zingiber Cassumunar Roxb. Down-Regulates the Expression of Genes Involved in Joint Erosion in a Human Synovial Fibroblast Cell Line

Article

Oct 2012

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the synovium. It is involved in up-regulation of pro-inflammatory cytokines and matrix metalloproteinases (MMPs), resulting in joint inflammation and erosion. Zingiber cassumunar Roxb. has long been used to reduce joint pain and inflammation. This study aimed to investigate the inhibitory activities of an active compound of Z. cassumunar, (E)-4-(3',4'-dimethoxyphenyl)but-3-en-1-ol (compound D), against cytokine-induced up-regulation of catabolic genes involved in cartilage degradation in RA. Synovial fibroblast cell line, SW982, was cultured in media containing interleukin-1β (IL-1β), in the presence or absence of compound D at the concentration range of 1 to 100 µM. After 24 hours, the cells were analyzed for the expressions of MMPs, IL-1β and interleukin-1β-converting enzyme (ICE) by RT-PCR. MMPs activities in the culture media were analyzed by zymographic techniques. Dexamethasone was used as the positive control. It was found that compound D at the concentration of 10 - 100 µM significantly decreased the mRNA expressions of MMP-1, -2, -3, and -13 which was induced by IL-1β (P<0.05) concomitantly with a decrease in activities of these MMPs in the culture media. An increase in the mRNA expression of IL-1β and ICE was also suppressed by compound D. The results suggest that the potent activities of this compound may be involved in the reduction of IL-1β protein synthesis in both pro-form and active form which played an important role in up-regulation of MMPs. This study first revealed the chondroprotective activity of Z. cassumunar in the transcriptional level by suppressing cytokine-induced catabolic genes which caused cartilage erosion in RA.

Biological Therapies for Rheumatoid Arthritis: Progress to Date

Article

Full-text available

Apr 2013

Biologic drugs for the management of rheumatoid arthritis (RA) have revolutionized the therapeutic armamentarium with the development of several novel monoclonal antibodies, which include murine, chimeric, humanized, fully human antibodies and fusion proteins. These biologics bind to their targets with high affinity and specificity. Since 1998, nine different biologics have been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of RA, and several others are in different stages of clinical trials. This field is in continuous evolution and new biologics are tested every year. Therefore a precise analysis is required in order to have a detailed and updated state of the art of this field. In this review, our main aim is to analyse all available biological therapies that are FDA and EMA approved for the treatment of RA and also those that are in clinical trials for the management of RA patients.

Current imaging strategies in rheumatoid arthritis

Article

Full-text available

Nov 2012

As remission has now become a realistic therapeutic goal in the clinical management of RA due to the introduction and widespread adoption of biologic agents, there is a greater need for earlier diagnoses and objective methods for evaluating disease activity and response to treatment. In this capacity, advanced imaging strategies are assuming an expansive clinical role, particularly as they take advantage of newer imaging technologies and the shift toward imaging at the molecular level. Molecular imaging utilizes target-specific probes to non-invasively visualize molecular, cellular, and physiological perturbations in response to the underlying pathology. Probes for nuclear and MR imaging have been and are being developed that react with discrete aspects of inflammatory and destructive pathways specific to RA. These probes in addition to new MR sequences and contrast agents have the potential to provide an earlier and more reliable assessment of clinical outcome, disease activity, severity, and location, and therapeutic response. Furthermore, these imaging strategies may enable a more fundamental understanding of critical pathophysiological processes and the advent of new molecular therapies. This review will discuss these advances in both nuclear medicine and MRI strategies for imaging RA with a particular emphasis on molecular imaging.

Rheumatoid Arthritis: Refractory to Infliximab, a Tumor Necrosis Factor Inhibitor

Article

Full-text available

Oct 2011
J Clin Med Res

Rheumatoid arthritis is one of the commonest autoimmune diseases. It is a chronic, progressive, systemic inflammatory disorder affecting the synovial joints and typically producing symmetrical arthritis. If left untreated, it leads to joint destruction and thus deformity and disability. In the recent years, advances in molecular biology have led to a variety of new treatment approaches to rheumatoid arthritis and other systemic inflammatory diseases associated with autoimmunity. Anti tumor necrosis factor (TNF) agents are emerging in the frontline management of rheumatoid arthritis (RA) in the current era of biological treatment. We presented a 46-year-old Chinese female with a history of seropositive RA for the past 22 years refractory and intolerant to multiple medications including sulphasalazine (SSZ), leflunomide, hydroxychloroquine (HCQ) and methotrexate (MTX), thus infliximab, a tumor necrosis factor (TNF) inhibitor was initiated. However, despite receiving 6 cycles of infliximab therapy, she still complained of persistent disabled multiple joint pain and swelling. This report will discuss about rheumatoid arthritis, which is refractory to infliximab (a TNF inhibitor) and its alternative. Keywords Rheumatoid arthritis; Biologics treatment; Tumor-necrosis factor inhibitor; Infliximab

I-125-Labeled Gold Nanorods for Targeted Imaging of Inflammation

Article

Nov 2011
ACS NANO

For better examination of inflammation, we designed inflammation-targeted nuclear and optical dual-modality contrast agents prepared by I-125 radiolabeling of gold nanorods (GdNRs) conjugated with anti-intercellular adhesion molecule 1 (ICAM-1) antibody. The bioactivity and specific binding of the PEGylated (125)I-ICAM-GdNR conjugates to the ICAM-1 was validated through ELISA testing. Inflammation-targeted imaging was then conducted on an adjuvant-induced arthritic rat model which demonstrated an elevation of ICAM-1 level in the affected ankle joints. Facilitated by the I-125 radioisotope and the whole-body imaging via the Gamma camera, the time-dependent distribution of the systemically injected agent as well as the uptake of the agent in the inflammatory articular tissues could be examined conveniently and quantitatively. The success in targeted delivery of gold nanoparticles to inflammatory tissue enables both nuclear and optical imaging of inflammation at molecular or cellular level. Other than diagnosis, radiolabeled gold nanoparticles also hold promise for targeted therapy of a variety of disorders.

Molecular imaging of rheumatoid arthritis by radiolabelled monoclonal antibodies: New imaging strategies to guide molecular therapies

Article

Full-text available

Sep 2009
EUR J NUCL MED MOL I

The closing of the last century opened a wide variety of approaches for inflammation imaging and treatment of patients with rheumatoid arthritis (RA). The introduction of biological therapies for the management of RA started a revolution in the therapeutic armamentarium with the development of several novel monoclonal antibodies (mAbs), which can be murine, chimeric, humanised and fully human antibodies. Monoclonal antibodies specifically bind to their target, which could be adhesion molecules, activation markers, antigens or receptors, to interfere with specific inflammation pathways at the molecular level, leading to immune-modulation of the underlying pathogenic process. These new generation of mAbs can also be radiolabelled by using direct or indirect method, with a variety of nuclides, depending upon the specific diagnostic application. For studying rheumatoid arthritis patients, several monoclonal antibodies and their fragments, including anti-TNF-alpha, anti-CD20, anti-CD3, anti-CD4 and anti-E-selectin antibody, have been radiolabelled mainly with (99m)Tc or (111)In. Scintigraphy with these radiolabelled antibodies may offer an exciting possibility for the study of RA patients and holds two types of information: (1) it allows better staging of the disease and diagnosis of the state of activity by early detection of inflamed joints that might be difficult to assess; (2) it might provide a possibility to perform 'evidence-based biological therapy' of arthritis with a view to assessing whether an antibody will localise in an inflamed joint before using the same unlabelled antibody therapeutically. This might prove particularly important for the selection of patients to be treated since biological therapies can be associated with severe side-effects and are considerably expensive. This article reviews the use of radiolabelled mAbs in the study of RA with particular emphasis on the use of different radiolabelled monoclonal antibodies for therapy decision-making and follow-up.

Nano-platform Strategies of Herbal Components for the Management of Rheumatoid Arthritis: A Review on the Battle for Next-Generation Formulations

Article

Aug 2023
Curr Drug Deliv

Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that initially affects small joints and then spreads to the bigger joints. It also affects other organs of the body such as the lungs, eyes, kidneys, heart, and skin. In RA, there is destruction of cartilage and joints, and ligaments and tendons become brittle. Damage to the joints leads to abnormalities and bone degradation, which may be quite painful for the patient. Method: The nano-carriers such as liposomes, phytosomes, nanoparticles, microcapsules, and niosomes are developed to deliver the encapsulated phytoconstituents to targeted sites for the better management of RA. Results: The phytoconstituents loaded nano-carriers have been used in order to increase bioavailability, stability and reduce the dose of an active compound. In one study, the curcumin-loaded phytosomes increase the bioavailability of curcumin and also provides relief from RA symptoms. The drug-loaded nano-carriers are the better option for the management of RA. Conclusion: In conclusion, there are many anti-arthritic herbal and synthetic medicine available in the market that are currently used in the treatment of RA. However, chronic use of these medications may result in a variety of side effects. Because therapy for RA is frequently necessary for the rest of ones life. The use of natural products may be a better option for RA management. These phytoconstituents, however, have several disadvantages, including limited bioavailability, low stability, and the need for a greater dosage. These problems can be rectified by using nano-technology.

Diagnostic Imaging Support System for Rheumatoid Arthritis Using Ultrasound Images

Conference Paper

Jul 2021

Therapeutic and Prophylactic Use of Oral, Low-Dose IFNs in Species of Veterinary Interest: Back to the Future

Article

Full-text available

Jun 2021

Cytokines are important molecules that orchestrate the immune response. Given their role, cytokines have been explored as drugs in immunotherapy in the fight against different pathological conditions such as bacterial and viral infections, autoimmune diseases, transplantation and cancer. One of the problems related to their administration consists in the definition of the correct dose to avoid severe side effects. In the 70s and 80s different studies demonstrated the efficacy of cytokines in veterinary medicine, but soon the investigations were abandoned in favor of more profitable drugs such as antibiotics. Recently, the World Health Organization has deeply discouraged the use of antibiotics in order to reduce the spread of multi-drug resistant microorganisms. In this respect, the use of cytokines to prevent or ameliorate infectious diseases has been highlighted, and several studies show the potential of their use in therapy and prophylaxis also in the veterinary field. In this review we aim to review the principles of cytokine treatments, mainly IFNs, and to update the experiences encountered in animals.

Análisis de minimización de costos de infusiones endovenosas aplicadas en pacientes hospitalizados y pacientes ambulatorios en el servicio de reumatología en un hospital de Lima, Perú

Article

Full-text available

Jun 2015

Objetivo: Medir los costos de la terapia de infusion endovenosa hospitalaria vs ambulatoria en el servicio de Reumatologia, del Hospital Nacional Edgardo Rebagilati Martins (HNERM) de Lima Peru, en el año 2009. Metodos: El diseño corresponde a un estudio de tipo descriptivo, retrospectivo y transversal. La poblacion estuvo comprendida por todos los pacientes hospitalizados (N = 42), que recibieron infusiones endovenosas con rituximab, pamidronato, infliximab, abatacept, tocilizumab, acido zoledronico y ciclofosfamida en el servicio de Reumatologia. Los gastos medicos y no medicos directos corresponden a un atio. Se elaboro una ficha, en la que se solicito informaci6n de tipo socioeconomica y demografica. Se identificaron los costos marginales de las alternativas. Resultados: La poblacion se caracterizo por ser en mayor proporcion de sexo femenino, con nivel de instruccion superior universitaria, y con predominancia de las enfermedades reumaticas en el grupo etareo de 42 a 52 &los en adelante. El costo total anual de la hospitalizacion ascendio a S/.472 726,21 (US$ 166 160,30); y para la alternativa ambulatoria de S/.416 092,25 (US$ 146 253,867), los cuales hacen una diferencia de S/.56 633,96 (US$ 19.906,49) que equivale al 12%. La administraci6n de las infusiones endovenosas ambulatoriamente (en asegurados que no tienen criterios de hospitalizaciOn), permitio disminuir los costos suscitados por la hospitalizacion (hoteleria, alimentacion y personal). La mayor diferencia en este estudio lo establecieron los costos de hoteleria (dia cama), costo de personal y costo de perdida de productividad. Conclusiones: La administracion de infusiones endovenosas ambulatoriamente tuvo un menor costo para la institucion y para el asegurado. Palabras clave: EvaluaciOn economica, costo minimo, costo, infusiones endovenosas, reumatologia.

The association between the biological disease-modifying anti-rheumatic drugs and the incidence of diabetes: A systematic review and meta-analysis

Article

Nov 2020

Whether the use of biological disease-modifying anti-rheumatic drugs (bDMARDs) would influence the risk of new-onset diabetes remains uncertain. Therefore, we performed a systematic review and meta-analysis to evaluate the association between the use of bDMARDs and the incidence of diabetes in patients with systemic inflammatory conditions. Pubmed, Medline, Embase and the Cochrane Central Register of Controlled Trials were searched for studies published from January 2000 to March 2020. Studies conducted in systemic inflammatory conditions with reports of the incidence of diabetes in subjects treated with bDMARDs were included. With 22 randomized controlled trials and 3 cohort studies included, the overall result indicated that compared with non-bDMARD treatment, the use of bDMARDs was significantly associated with decreased incidence of diabetes in patients with systemic inflammatory conditions (RR = 0.56, 95 % CI, 0.43 to 0.74, P < 0.001, I² = 69 %), especially in patients with in rheumatoid arthritis (RR = 0.54, 95 % CI, 0.38 to 0.76, P = 0.0005, I² = 26). Reduced risk of new-onset diabetes was observed in studies with follow-up more than 1 year (RR = 0.73, 95 % CI, 0.54 to 0.99, P = 0.04, I² = 88). New-onset diabetes was less frequent in patients with TNF-α inhibitor treatment (RR = 0.54, 95 % CI, 0.48 to 0.60, P < 0.001, I² = 42 %) and abatacept treatment (RR = 0.44, 95 % CI, 0.34 to 0.58, P < 0.001, I² = 3 %), which might be associated with the inhibition of TNF-α mediated inflammatory responses and dysregulated T cell activation and immune responses respectively. Further investigations are required to validate the glucose metabolism protective effect of bDMARDs and clarify the underlying mechanisms of the crosstalk between bDMARDs and diabetes.

The Development of a Quantitative Method for the Detection of Periarticular Osteoporosis Using Density Features within ROIs from Computed Radiography Images of the Hand

Chapter

Jan 2013

Periarticular osteoporosis of the hands and feet is one of the major diagnostic criteria for rheumatoid arthritis (RA). However, a quantitative method to detect periarticular osteoporosis using radiographs has not been reported. In this chapter, the authors propose a quantitative method for the detection of periarticular osteoporosis using density features of regions of interest (ROIs) from computed radiography (CR) images of the hand. The proposed method measures the density features of ROIs using histogram analysis, co-occurrence matrices, Fourier analysis, and the extraction of line components. Periarticular osteoporosis is detected using a discernment function based on these measurements. The sensitivity and specificity of the proposed method was assessed using 188 joints from 17 cases, including 6 normal cases (without periarticular osteoporosis) and 11 abnormal cases (with periarticular osteoporosis). The sensitivity of the method was 88.9%, and the specificity was 98.1%. Therefore, the authors consider this method to be potentially useful to radiologists for detecting periarticular osteoporosis in the hands.

Early Barriers to Neonatal Porcine Islet Engraftment in a Dual Transplant Model

Article

Nov 2017

Porcine islet xenografts have the potential to provide an inexhaustible source of islets for β cell replacement. Proof-of-concept has been established in nonhuman primates. However, significant barriers to xenoislet transplantation remain, including, the poorly understood instant blood mediated inflammatory reaction (IBMIR), and a thorough understanding of early xeno-specific immune responses. A paucity of data exist comparing xeno-specific immune responses to allo-islet responses in primates. We recently developed a dual islet transplant model, which enables direct histological comparison of early engraftment immunobiology. In this study, we investigate early immune responses to neonatal porcine islet (NPI) xenografts compared to rhesus islet allografts at 1 hour, 24 hours, and 7 days. Within the first 24 hours after intraportal infusion, we identified greater apoptosis (caspase 3 activity and TUNEL positive cells) of NPIs when compared to alloislets (AIs). Macrophage infiltration was significantly greater at 24 hours compared with 1 hour in both NPI (WT) and AIs. At 7 days, IgM and macrophages were highly specific for NPIs (GTKO) compared to AIs. These findings demonstrate an augmented macrophage and antibody response towards xenografts compared to allografts. These data may inform future immune or genetic manipulations required to improve xenoislet engraftment.

Cholesterol: Biological function and medical implications

Article

Full-text available

Jun 2012

Our body synthesizes its own cholesterol, an extra percentage is obtained from diet. Cholesterol is part of our cell membranes, serves as a precursor of all steroid hormones, bile acids, and vitamin D. Excessive intake of cholesterol and genetic mutations in the rLDL promotes the increase of blood serum cholesterol above recommended levels, which facilitate the genesis of atherosclerosis, that is the main risk factor for developing cardiovascular disease. Healthy lifestyles, dietary and pharmacological treatments are able to reduce plasma cholesterol concentrations, which decreases the probability to suffer a coronary event. Here, we review the biological role of cholesterol, its relationship with cardiovascular disease also discusses dietary and pharmacological aspects help to counteract these conditions.

Rheumatology in Singapore-Moving Forward

Article

Feb 2007
ANN ACAD MED SINGAP

The practice of Rheumatology and Clinical Immunology has made big strides in the last decade. The availability of immune modifiers, e.g. anti-cytokine agents, has changed the therapeutic landscape of arthritis treatment. What is refractory arthritis previously had now become controllable disease. Fan and Leong 1 had in this issue reviewed the use of biological agents in the treatment of rheumatoid arthritis and given us an overview of the evolving treatment regimens over the years. This experience is indeed repeated for other arthritis seen by rheumatologist in their clinics. The advent of biologics agents however do not exclude the need for better understanding of the epidemiology of rheumatological conditions. Howe et al 2 in their article reviewed seronegative spondyloarthropathy studies from the Asia-pacific region, bringing to the fore the collaborative research efforts among Asia-pacific rheumatologists. Thumboo and Strand 3 touched on another important subject for rheumatologists who deal with chronic diseases daily. Treatment of chronic conditions have reached a level in which the question being asked is not "what is the mortality or survival rate" but "what is the effect on quality of life". The importance of using health-related quality of life instruments to measure disease outcomes is paramount. The article dealt with systemic lupus erythematosus but the underlying principles are the same for other chronic rheumatic diseases. Today, information technology is widely harnessed for research and service, and transcends all disciplines. Immunology is no exception. The article by Chan and Kepler 4 on computational immunology gives a snapshot of what's possible and on the horizon. It promises to enhance the pace of immunology research as well as provides directions for new research areas. It is without doubt going to play an increasingly significant role in immunology research. Apart from the review articles, there is a good mix of letters, case reports and original articles dealing with research from the bedside to the bench. Clinical case reports and letters provide insights into particular aspects of rheumatic diseases. Hepatitis B infections are prevalent in Singapore and Thong et al 5 reported the outcomes of chronic hepatitis B infection in local rheumatic diseases patients. It is of particular interest as corticosteroids and immuno-suppressives therapy are used commonly in the treatment of rheumatic diseases, and rightly feared to be a factor in causing hepatitis B infection flares. Xu et al 6 reported on their study of cytokines gene polymorphisms in systemic lupus erythematosus (SLE) and Suppiah et al 7 on cytokines levels in rheumatoid arthritis (RA). IL-18 promoter gene polymorphism (CC genotype) is found to be associated with SLE, while IL-1beta, IL-6, TNF-alpha and IL-18 proteins concentrations are elevated in RA patients. Conversely, TGF-beta levels are reduced in RA patients when compared to normal controls. The articles by Lim et al 8 and Chong et al 9 on patient satisfaction and value of joint aspiration respectively reveal important aspects of clinical management. They provide good insights into simple but important clinical research. The wide spectrum of rheumatic conditions studied as well as the various aspects of pathogenetic factors and clinical management published in this issue makes it a worthwhile effort, and highlights the active rheumatology and immunology research scene in Singapore. REFERENCES 1. Fan PT, Leong KH. The use of biological agents in the treatment of rheumatoid arthritis. Ann Acad Med Singapore 2007;36:128-34. 2. Howe HS, Zhao L, Song YW, Springer L, Edmonds J, Gu J, et al. Seronegative spondyloarthropathy – studies from the Asia Pacific region. Ann Acad Med Singapore 2007;36:135-41. 3. Thumboo J, Strand V. Health-related quality of life in patients with systemic lupus erythematosus: an update. Ann Acad Med Singapore 2007;36:115-22. 4. Chan C, Kepler TB. Computational immunology – from bench to virtual reality. Ann Acad Med Singapore 2007;36:123-7. 5. Thong BYH, Koh ET, Chng HH, Chow WC. Outcomes of chronic hepatitis B infection in Oriental patients with rheumatic diseases. Ann Acad Med Singapore 2007;36:100-5. 6. Xu Q, Tin SK, Sivalingam SP, Thumboo J, Koh DR, Fong KY. Interleukin-18 promoter gene polymorphisms in Chinese patients with systemic lupus erythematosus: association with CC genotype at position –607. Ann Acad Med Singapore 2007;36:91-5. 7. Sivalingam SP, Thumboo J, Vasoo S, Thio ST, Tse C, Fong KY. In vivo pro-and anti-inflammatory cytokines in normal and patients with rheumatoid arthritis. Ann Acad Med Singapore 2007;36:96-9. 8. Lim AYN, Ellis C, Brooksby A, Gaffney K. Patient satisfaction with rheumatology practitioner clinics: can we achieve concordance by meeting patients' information needs and encouraging participatory decision making? Ann Acad Med Singapore 2007;36:110-4. 9. Chong YY, Fong KY, Thumboo J. The value of joint aspirations in the diagnosis and management of arthritis in a hospital-based Rheumatology Service. Ann Acad Med Singapore 2007;36:106-9.

General aspects of biologic agents in rheumatology

Article

Mar 2010

Faruk Sendur

Pharmaceutical vs. alternative treatment in the rheumatoid arthritis patients

Article

Jun 2012

Rheumatoid Arthritis is an autoimmune and progressive disease, of multifactorial etiology and characterized by inflammation, pain and bone erosion in the peripheral joints. The most common therapeutic treatments included the employ of allopathic drugs (AINES, DMARDs and biological), which allow a control of symptoms and development of the disease in patients. However, an elevated number of patients also employ non-conventional or alternative treatments (CAMs), deriving in very different and sometimes undesirable clinical responses. In this review we compare the pharmacologic treatments and alternative treatments according with the scientific evidences of its effect in the RA patients.

Where are we heading to in pharmacological IBD therapy?

Article

Aug 2015
PHARMACOL RES

Gerhard Rogler

After a relatively long time of failed developments and negative clinical trials in pharmacological inflammatory bowel disease (IBD) therapy we now phase a time of a great number of successful studies and new therapy principles that will most likely make it into clinical practice. This will change the landscape of IBD therapy in future markedly. Many new therapeutic principles have been developed and old ones that seemed to have failed such as anti-sense technology suddenly now provide promising results. Some initially promising therapies will need further development or have failed such as Trichuris suis ova therapy (but not helminth therapy in general), CCR9 targeted therapies or recombinant IL-10. In contrast anti-leukocate trafficking therapies appear to be quite promising. Vedolizumab is the first in class anti-integrin antibody that was approved for the therapy of CD and UC recently. Other anti-integrin antibodies and small molecule adhesion inhibitors will most likely be approved in the next years for IBD therapy. Tofacitinib, a small molecule JAK inhibitor, is a promising candidate for the treatment of UC. Phosphatidylcholine may be a future option for patients with 5-ASA refractory UC or 5-ASA intolerance. The preliminary data for Mongersen, a Smad7 antisense oligonucleotide, are promising despite some concerns about long term effect of TGFβ induction. Anti IL6 strategies will hopefully be further evaluated keeping in mind the caveat of a lack of CRP induction in anti-IL6 treated patients. Stem cell transplantation will become an option for patients that have experienced failure of established medications. Fecal microbiota transplantation and also perhaps combined probiotic therapy is a field that will be evaluated in more detail in the near future especially for UC patients. Based on these new developments treatment algorithms need to be updated. This review will reflect these current developments and give a perspective for future IBD therapy.

An Update on the Roles of the Complement System in Autoimmune Diseases and the Therapeutic Possibilities of Anti-Complement Agents

Article

Feb 2011
Curr Drug Ther

Masashi Mizuno

Complement activation plays important roles in innate immunity. However, excessive or unregulated activation of complement can injure host tissues, not only causing local injuries but also systemic reactions. Autoimmune diseases such as rheumatoid arthritis, lupus nephritis and Guillain-Barre syndrome are among the pathological situations caused by aberrant activation of the host immune system and complement activation plays important roles to develop and/or augment these diseases. Recent therapeutic approaches in autoimmune disease have involved biological response modifiers such as anti-TNF, anti- TNF receptor and anti-IL6 agents, in addition to traditional therapies such as corticosteroid, methotrexate, azathioprine, mizoribine and cyclophosphamide in collagen diseases. These new biological reagents have shown promise but sometimes cause severe side effects or complications, including interstitial pneumonia and predispose to other infections such as tuberculosis. New strategies may therefore be required. As an alternative therapeutic approach, anti-complement agents might become a treatment of choice to control autoimmune diseases. This mini-review focuses on recent knowledge of the role of complement activation in human collagen diseases and the other autoimmune diseases, including relevant animal models, and discusses the possibility of using anti-complement therapies. Regulation of the complement system might be a new approach to be considered as an alternative therapeutic strategy.

Pemetrexed Ameliorates Experimental Arthritis in Rats

Article

Aug 2014
INFLAMMATION

Pemetrexed (PMTX) is an anti-folate drug as methotrexate. The purpose of this study was to assess the efficacy of PMTX on collagen-induced arthritis (CIA). Forty Wistar albino rats were randomized into four groups. Arthritis was induced by intradermal injection of chicken type II collagen combined with incomplete Freund's adjuvant. Animals were sacrificed at the 15th day after the onset of arthritis. Tumor necrosis factor alpha (TNF-α), interleukin (IL)-17, and malondialdehyde (MDA) levels were increased, and superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities and the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were decreased in the arthritis group. In the PMTX-treated (0.2 and 1 mg/kg/week i.p.) groups, the levels of TNF-α, IL-17, and MDA were decreased; the activities of SOD, CAT, and GPx and the expressions of Nrf2 and HO-1 were restored, and perisynovial inflammation and cartilage-bone destruction were decreased. PMTX has anti-arthritic potential in the CIA model and may be a therapeutic agent for rheumatoid arthritis.

Targeted therapies for rheumatoid arthritis: A review

Article

Jan 2011

Rheumatoid arthritis (RA) is an aggressive disease that needs to be treated effectively if subsequent deformity and disability are to be reduced. A recent advance in the management of RA is the use of biological agents which block certain key molecules involved in the pathogenesis of the illness. They include tumor necrosis factor (TNF-) -blocking agents, Anti-Interleukin-1receptor (IL-1) antagonist, anti-CD-20 agents, CTLA-4 Ig, anti IL-6 etc. These newer agents proved to be useful for alleviating symptoms and slowing the disease progression in the patients with RA who have failed to respond to conventional disease modifying anti-rheumatic drugs (DMARDs). DMARDs are nonspecific immunomodulators, each of which has substantial drawbacks in terms of effectiveness or adverse effects (AEs). The development of biologic agents has provided more effective therapeutic options. The terms biologic therapies and biologics have emerged to describe agents with biologic properties, including monoclonal antibodies and soluble cytokine receptors etc. The advent of effective biological agents has certainly been a major advance in the treatment of inflammatory arthritis, heralding a new era for rheumatology. In this review the focus is only on pathophysiology of the disease process as well as the recent advances with Biological response modifiers (BRMs) and its impact on current clinical practice in the treatment of RA.

Transference patterns and working alliance during the early phase of psychodynamic psychotherapy Transferni obrasci i radni savez tokom rane faze psihodinamicke psihoterapije

Article

Full-text available

Feb 2014

Working alliance, as a collaborative part of the therapeutic relationship has been proven to be one of the most powerful therapeutic factors in psychotherapy in general, regardless many technical differences between numerous psychotherapeutic modalities. On the other hand, transference is the basic concept of psychodynamic psychotherapy, and, according to the psychoanalytic theory and practice, it forms a major part of the therapeutic relationship. The aim of our paper was to determine the differences between the groups of patients with low, middle, and high working alliance scores and the dropout group in transference patterns, sociodemographic and clinical parameters, during the early phase of psychodynamic psychotherapy. Our sample consisted of 61 non-psychotic patients, randomly selected by the method of consecutive admissions and treated with psychoanalytic psychotherapy in the outpatient clinical setting. The patients were prospectively followed during 5 initial sessions of the therapeutic process. The working alliance inventory and Core conflictual relationship theme method were used for the estimation of working alliance and transference patterns, respectively. According to the Working Alliance Inventory scores, four groups of patients were formed and than compared. Our results show a significant difference between the groups of patients with low, middle, and high working alliance inventory scores and the dropout group on the variable--transference patterns in the therapeutic relationship. Disharmonious transference patterns are more frequent in patients who form poor quality working alliance in the early phase of psychotherapy, or early dropout psychotherapy. It is of great importance to recognize transference patterns of a patient at the beginning of the psychotherapeutic process, because of their potentially harmful influence on the quality of working alliance.

A Pilot Study and Retrospective Chart Review Comparing Adalimumab, Infliximab, and Etanercept in Patients with Active Rheumatoid Arthritis

Article

Jan 2007

Shana Arnhold

Elbow arthritis

Article

Nov 2008

Purpose of review: Improvements in medications, implant design, and arthroscopic techniques have changed the available treatment options for arthritic patients. The purpose of the present review is to explore recent developments and publications discussing the management of elbow arthritis. Recent findings: New medications have greatly reduced the role of surgery in the management of rheumatoid arthritis. Effective arthroscopic treatments are being developed for elbow arthritis, but it is difficult for more than a few surgeons to gain sufficient experience with these complex technical procedures. Several new concepts have influenced total elbow prostheses. Summary: The management of elbow arthritis is based on the type of arthritis and patient factors. The majority of operative treatments are palliative or reconstructive. As with arthritis in other joints, there is a stepladder of treatment options from nonspecific analgesia to arthroscopic or open debridement, interpositional arthroplasty, and ending with prosthetic arthroplasty, which is best reserved for relatively infirm and low-demand patients.

Differential effect of IL-1β and TNF-α on the production of IL-6, IL-8 and PGE2 in fibroblast-like synoviocytes and THP-1 macrophages

Article

Jun 2009

Inflammation in the joint of rheumatoid arthritis is a complex immune reaction facilitated by various factors, such as cytokines, cells and hypoxia. Thus, we evaluated their relative capacity to produce proinflammatory mediators in response to IL-1β, TNF-α or IL-17 under hypoxia or normoxia in fibroblast-like synoviocytes (FLSs) and macrophages. The level of IL-6 expression was strongly increased in both FLSs and THP-1 macrophages in response to IL-1β and TNF-α, but the level by TNF-α was less than that by IL-1β. In contrast, the expression of IL-8 in both cell types was strongly stimulated by both IL-1β and TNF-α. In FLSs, PGE2 production increased only in response to IL-1β; and no effect was observed in THP-1 cells and TNF-α-stimulated FLSs. In addition, the production by IL-17 was extremely low when compared with those induced by IL-1β or TNF-α in FLSs and THP-1 cells. Hypoxia (2% O2) decreased IL-1β-stimulated production of PGE2, even though it increased the expression of mRNA and protein of COX-2. These results suggest that IL-1β and TNF-α differentially regulate gene expression in FLSs and macrophages under hypoxia or normoxia. KeywordsFibroblast-like synoviocyte-Macrophage-Rheumatoid arthritis-COX-2-TNF-α-IL-1β-Hypoxia

Scorpio and Scolopendra attenuate inflammation and articular damage in rats with collagen-induced arthritis

Article

Sep 2011

Scorpio and Scolopendra (SS) are two traditional Chinese medicines, which are generally used to treat rheumatoid arthritis (RA) in China. However, the mechanism is so far unclear. The purpose of this study was to explore the effects and mechanisms of SS in attenuating inflammation and joint injury in collagen-induced arthritis in rats. RA was induced in Wistar rats by injection of collagen, meanwhile, the rats were administrated daily either SS (0.4 g/kg, 0.2 g/kg, and 0.1 g/kg) or vehicle (physiological saline) for 42 days. The therapeutic effect of SS on RA was evaluated by pathological methods. T lymphocyte subsets and anti-collagen type II (CII) antibody were tested in peripheral blood. Tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin-4 (IL-4) and interleukin-10 (IL-10) were assessed in tissue homogenate of fresh joints. The inflammation and articular damage in SS powder-treated rats were attenuated significantly. In addition, SS powder was revealed to modulate the equilibrium of T lymphocyte subsets, down-regulate TNF-α and IL-1β, up-regulate IL-4 and IL-10, and significantly suppress the level of anti-CII antibody. Scorpio and Scolopendra, when used as a combination, reveal desirable effect for treatment of rheumatoid arthritis, and this beneficial effect may be accomplished through normalization of T lymphocyte subsets and the balance of Th1/Th2 cytokines.

CH-1504, a metabolically inert antifolate for the potential treatment of rheumatoid arthritis

Article

Aug 2010

Malini Bajpai

CH-1504, being developed by Chelsea Therapeutics Inc under license from the University of South Alabama, is an orally available, metabolically inert antifolate, for the potential treatment of rheumatoid arthritis (RA). CH-1504 is an analog of methotrexate (MTX) but differs from the classical antifolates because of an improved safety and tolerability profile. A significant proportion of the toxicity profile of MTX can be attributed to its polyglutamylated and hydroxylated metabolites; therefore, metabolism-blocked antifolates, such as CH-1504, have been designed to prevent the accumulation of toxic metabolites. Preclinical studies and phase II clinical trials indicated that CH-1504 and MTX inhibit dihydrofolate reductase activity with equal potency. In a phase II, proof-of-concept trial in patients with RA, CH-1504 was associated with improved tolerability and reduced hepatotoxicity as compared with MTX; in addition, improvements in the American College of Rheumatology response rates were similar following treatment with either CH-1504 or MTX. Furthermore, Chelsea Therapeutics are developing the L-isomer of CH-1504, CH-4051, which displays improved in vitro potency over with racemate and appears to be Chelsea Therapeutics' preferred candidate for future development. Inert antifolates appear to be a promising drug class for the treatment of RA because the disease-modifying properties of MTX are retained, but the therapeutic window of the inert antifolates is improved. However, further trials are required to establish the efficacy and long-term safety in a wider population of patients with RA.

Comparative renal excretion of VX-702, a novel p38 MAPK inhibitor, and methotrexate in the perfused rat kidney model

Article

Mar 2010
DRUG DEV IND PHARM

VX-702 is a novel p38 mitogen-activated protein kinase inhibitor being developed to treat rheumatoid arthritis. To characterize the renal excretion profile of VX-702 using the isolated perfused rat kidney (IPRK) model. Studies were performed to assess the dose linearity of VX-702 excretion and to evaluate the effect of inhibitors of organic anion (probenecid) and organic cation (cimetidine) transport systems on VX-702 disposition. VX-702 excretion was studied over a range of doses targeting concentrations between 100 and 600 ng/mL. VX-702 (600 ng/mL) was also co-perfused with probenecid (1 mM) and cimetidine (2 mM). The results were compared to parallel experiments performed with methotrexate (MTX). VX-702 excretion was linear over the range of doses studied, and clearance data were consistent with net reabsorption by the kidney. Transport inhibition studies indicate that VX-702 is not a substrate for renal organic anion and organic cation transport systems. MTX (500 ng/mL) also displayed net reabsorption in the IPRK, but secretory transport was inhibited upon co-administration with probenecid. This finding is consistent with previous IPRK studies that demonstrated inhibitory effects of NSAIDS on MTX excretion. Overall, this study suggests that a renal drug-drug interaction between VX-702 and MTX would be unlikely if these medications were co-administered.

Mouse Models of Autoimmune Diseases

Article

Full-text available

Dec 2009

Significant progress has been made in past decades in our understanding of the basic mechanisms underlying autoimmune diseases. Nevertheless, many questions remain unanswered, in particular regarding the mechanisms at very early stages of these diseases. Reliable animal models are of crucial importance in basic research and may help us to understand central disease pathways. They are also indispensable for pre-clinical drug testing. Here we present and discuss two mouse models of rheumatoid arthritis and multiple sclerosis, respectively. In experimental studies using the models of collagen-induced arthritis and experimental autoimmune encephalomyelitis, the efficacy of new biological agents has been tested, which paved the way for clinical trials. A further interesting field where mouse models may provide valuable informations, is the identification of susceptibility genes for autoimmune diseases. Overall, in some instances studies with inbred strains may have an advantage over human studies, because environmental factors may easily be controlled and the genetic differences between different mouse strains are better characterized.

Atacicept, a novel B cell-targeting biological therapy for the treatment of rheumatoid arthritis

Article

Aug 2009
EXPERT OPIN BIOL TH

Recent data suggest a key role for B cells in the pathogenesis of many autoimmune diseases including rheumatoid arthritis (RA), and biological therapies targeting B cells are promising treatments for patients with RA. Atacicept inhibits B cell maturation, differentiation and survival, and immunoglobulin production by depriving B cells of growth and development signals. Therefore, atacicept may represent an effective strategy in RA treatment. To evaluate the potential value of atacicept in RA treatment based on preclinical and clinical studies. Preclinical and clinical data on atacicept were identified using PubMed and systematically reviewed. Preclinical and clinical studies show that atacicept is well tolerated, with no increased incidence of infections. Atacicept displays non-linear pharmacokinetics, with a more than dose-proportional increase in free drug and less than dose-proportional, saturated increase in atacicept-ligand complex. Overall, the pharmacokinetic profiles of atacicept were consistent, dose-related and predictable. Dose-dependent reductions in immunoglobulins and other biomarkers, including rheumatoid factor, occurred rapidly but returned to baseline after discontinuation. There was a biphasic response in B cell number, but no effect on other leucocytes. Atacicept improved the signs and symptoms of RA, although larger studies are needed to confirm its efficacy and its optimal use.

CTLA-4Ig: uses and future directions

Article

Feb 2009

Moshe Ben-Shoshan

Cytotoxic lymphocyte-associated molecule-4 (CTLA-4, CD152) is a member of the CD28 receptor family. Blocking CD28 interaction with its ligands through the use of CTLA-4Ig might contribute to better control of dysregulated immune response processes. The ligands binding to CTLA-4 are the B7 family members, B7-1 (CD80) and B7-2 (CD86). CTLA-4Ig is now a Food and Drug Administration-approved drug for use treating patients with Rheumatoid arthritis (RA) but its use is explored also in other autoimmune diseases, transplantation as well as allergic diseases. Patents related to CTLA-4 function as well as possible clinical applications are discussed in this paper.

Rituximab - In rheumatoid arthritis

Article

Feb 2007

An important role for B cells in the immunopathogenesis of rheumatoid arthritis (RA) is recognized. ▴ Rituximab is a chimeric murine/human anti-CD20 monoclonal antibody that transiently depletes CD20+ B cells. ▴ A single course of rituximab (two intravenous infusions of 1000mg given two weeks apart) with a stable dose of methotrexate significantly improved all measures of disease activity, fatigue, and health-related quality of life relative to placebo with methotrexate. This was demonstrated in the REFLEX trial, a 24-week, randomized, double-blind, double-dummy, international, phase III study in 520 patients who had active RA despite ongoing treatment with methotrexate and had experienced an inadequate response to antitumor necrosis factor (TNF) therapy. ▴ Patients in REFLEX (or other studies) who responded to, and required further treatment after, an initial course of rituximab continued to respond to subsequent courses of the drug. ▴ A small subgroup of patients in REFLEX continued to respond to their first course of rituximab through 48 weeks of follow-up. ▴ Long-term treatment (up to 56 weeks) with one or more courses of rituximab in REFLEX significantly inhibited joint structural damage, the first time this effect has been reported in patients with an inadequate response to TNF inhibitors. ▴ Rituximab was generally well tolerated; the majority of adverse events were related to the first infusion of the drug, were mild to moderate in severity, and were easily managed. The adverse event profile of rituximab was unchanged after repeat courses.

Erratum: Treatment with SI000413, a New Herbal Formula, Ameliorates Murine Collagen-Induced Arthritis [Biol. Pharm. Bull. 31(7): 1337—1342]

Article

Aug 2008

We tested the effects of SI000413, a new formula, consisting of Pyrolae herba and Trachelospermi caulis, on type II collagen-induced arthritis (CIA). CIA was induced in DBA/1J mice by immunization with bovine type II collagen (CII) on days 1 and 21. SI000413 was orally administered 3 times per week throughout the experiment and indomethacin was served as a positive control. Clinical scores, the count of arthritic legs, levels of interleukin 6 (IL-6) and anti-CII antibody, and lymphocyte subsets in blood were examined. SI000413 suppressed CIA development in a dose dependent manner and reduced the incidence of arthritic legs in mice. Histological analysis showed administration of SI000413 reduced inflammatory signs and cartilage destruction. Serum levels of IL-6 and anti-CII antibody were significantly decreased in SI000413-treated mice and the percentages of CD4 T cell, CD8 T cell and B cell in blood were restored to normal levels. In conclusion, we demonstrate that SI000413 ameliorates CIA both clinically and histologically and inhibits the production of anti-CII antibody and pro-inflammatory cytokine in the CIA mouse. These findings suggest that SI000413 is a potential new therapeutic herbal formula for the treatment of RA.

Denosumab in Postmenopausal Women With Low Bone Mineral Density

Article

Full-text available

Feb 2006
NEW ENGL J MED

Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for osteoclast differentiation, activation, and survival. The fully human monoclonal antibody denosumab (formerly known as AMG 162) binds RANKL with high affinity and specificity and inhibits RANKL action. The efficacy and safety of subcutaneously administered denosumab were evaluated over a period of 12 months in 412 postmenopausal women with low bone mineral density (T score of -1.8 to -4.0 at the lumbar spine or -1.8 to -3.5 at the proximal femur). Subjects were randomly assigned to receive denosumab either every three months (at a dose of 6, 14, or 30 mg) or every six months (at a dose of 14, 60, 100, or 210 mg), open-label oral alendronate once weekly (at a dose of 70 mg), or placebo. The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Changes in bone turnover were assessed by measurement of serum and urine telopeptides and bone-specific alkaline phosphatase. Denosumab treatment for 12 months resulted in an increase in bone mineral density at the lumbar spine of 3.0 to 6.7 percent (as compared with an increase of 4.6 percent with alendronate and a loss of 0.8 percent with placebo), at the total hip of 1.9 to 3.6 percent (as compared with an increase of 2.1 percent with alendronate and a loss of 0.6 percent with placebo), and at the distal third of the radius of 0.4 to 1.3 percent (as compared with decreases of 0.5 percent with alendronate and 2.0 percent with placebo). Near-maximal reductions in mean levels of serum C-telopeptide from baseline were evident three days after the administration of denosumab. The duration of the suppression of bone turnover appeared to be dose-dependent. In postmenopausal women with low bone mass, denosumab increased bone mineral density and decreased bone resorption. These preliminary data suggest that denosumab might be an effective treatment for osteoporosis. (ClinicalTrials.gov number, NCT00043186.).

Disease activity and risk of lymphoma in patients with rheumatoid arthritis: Nested case-control study

Article

Full-text available

Aug 1998

A Comparison of Etanercept and Methotrexate in Patients with Early Rheumatoid Arthritis

Article

Full-text available

Dec 2000

Etanercept, which blocks the action of tumor necrosis factor, reduces disease activity in patients with long-standing rheumatoid arthritis. Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown. We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept (10 or 25 mg) or weekly oral methotrexate (mean, 19 mg per week) for 12 months. Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology. Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale. On this scale, an increase of 1 point represents one new erosion or minimal narrowing. As compared with patients who received methotrexate, patients who received the 25-mg dose of etanercept had a more rapid rate of improvement, with significantly more patients having 20 percent, 50 percent, and 70 percent improvement in disease activity during the first six months (P<0.05). The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group (P= 0.001), and the respective increases during the first 12 months were 0.47 and 1.03 (P=0.002). Among patients who received the 25-mg dose of etanercept, 72 percent had no increase in the erosion score, as compared with 60 percent of patients in the methotrexate group (P=0.007). This group of patients also had fewer adverse events (P=0.02) and fewer infections (P= 0.006) than the group that was treated with methotrexate. As compared with oral methotrexate, subcutaneous [corrected] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis.

Evaluation and documentation of rheumatoid arthritis disease status in the clinic: Which variables best predict change in therapy

Article

Full-text available

Aug 2001

To determine in clinical practice which rheumatoid arthritis (RA) clinical status variables are most associated with a change in disease modifying antirheumatic drug (DMARD) therapy, we studied 26,240 observations from 1905 RA patients occurring over 25 years. Variables included tender joint count, erythrocyte sedimentation rate (ESR), grip strength, visual analog scale for pain, global severity, fatigue and sleep, Health Assessment Question functional disability scale (HAQ), anxiety, depression and morning stiffness. Only the tender joint count required a physician. Observations at which a change in DMARD therapy occurred were compared to those where a change did not occur using generalized estimating equations (GEE) and classification and regression tree analysis (CART). Tender joint count, pain, global severity, and ESR were the 4 variables most strongly predictive of DMARD change. CART modeling indicated a special role for fatigue and sleep disturbance in some patients. These data add support in clinical practice for the ACR core set and the DAS set of variables. In addition, they validate the use of these variables in a practice setting. We suggest a minimum set of evaluations comprising: joint count, ESR or CRP, measures of pain and/or severity, a fatigue scale (fatigue being a surrogate for sleep disturbance), and a measure of function such as the HAQ or modified HAQ. Because only joint count requires physician participation, these evaluations are practical for the clinic, and allow quantitative measurement of RA status. With the use of quantile charts, the comparative status of RA and the change in RA status can be determined easily.

Tuberculosis Associated with Infliximab, a Tumor Necrosis Factor α–Neutralizing Agent

Article

Full-text available

Nov 2001

Infliximab is a humanized antibody against tumor necrosis factor alpha (TNF-alpha) that is used in the treatment of Crohn's disease and rheumatoid arthritis. Approximately 147,000 patients throughout the world have received infliximab. Excess TNF-alpha in association with tuberculosis may cause weight loss and night sweats, yet in animal models it has a protective role in the host response to tuberculosis. There is no direct evidence of a protective role of TNF-alpha in patients with tuberculosis. We analyzed all reports of tuberculosis after infliximab therapy that had been received as of May 29, 2001, through the MedWatch spontaneous reporting system of the Food and Drug Administration. There were 70 reported cases of tuberculosis after treatment with infliximab, for a median of 12 weeks. In 48 patients, tuberculosis developed after three or fewer infusions. Forty of the patients had extrapulmonary disease (17 had disseminated disease, 11 lymph node disease, 4 peritoneal disease, 2 pleural disease, and 1 each meningeal, enteric, paravertebral, bone, genital, and bladder disease). The diagnosis was confirmed by a biopsy in 33 patients. Of the 70 reports, 64 were from countries with a low incidence of tuberculosis. The reported frequency of tuberculosis in association with infliximab therapy was much higher than the reported frequency of other opportunistic infections associated with this drug. In addition, the rate of reported cases of tuberculosis among patients treated with infliximab was higher than the available background rates. Active tuberculosis may develop soon after the initiation of treatment with infliximab. Before prescribing the drug, physicians should screen patients for latent tuberculosis infection or disease.

Treatment of psoriatic arthritis and psoriasis vulgaris with the tumor necrosis factor blocker infliximab

Article

Full-text available

Dec 2002

The aim was to evaluate the efficacy and safety of multiple infusions with achimeric, anti-tumor necrosis factor (TNF)alpha monoclonal antibody (infliximab) in patients with psoriatic arthritis (PsA) and psoriasis vulgaris. Over 22 weeks, nine patients with both active psoriasis and PsA received five infusions of 3 mg/kg infliximab. The endpoints included changes in the swollen and tender joints counts, American College of Rheumatology (ACR) preliminary criteria for improvement response rates 20, 50, and 70, and improvement in the psoriasis area and severity index (PASI). The swollen count (SJC) and tender joint count (TJC) fell from means of 5.33+/-2.22 and 17.80+/-4.21 to 1.44+/-1.09 and 9.77+/-0.92, respectively, by week 2 ( P=0.02, P=0.02). This benefit was sustained through week 22 (2.00+/-1.12/7.77+/-3.68, P=0.05/ P=0.002). The ACR 20/50/70 response was achieved in 89%/56%/22% of cases. The mean PASI score improved from 19.04+/-5.41 to 4.91+/-2.51 ( P=0.002). Multiple infusions of infliximab were effective and well tolerated in patients with active psoriasis and PsA.

Effect of tumour necrosis factor alpha antagonists on serum transaminases and viraemia in patients with rheumatoid arthritis and chronic hepatitis C infection

Article

Full-text available

Dec 2003

Tumour necrosis factor alpha (TNF alpha) antagonists are effective for the treatment of rheumatoid arthritis (RA), but concerns remain about the safety of these agents in the presence of chronic infections, including hepatitis C virus (HCV) infection. To examine the influence of treatment with TNF alpha antagonists on levels of HCV viraemia and serum transaminases in patients with RA and HCV. In a retrospective survey the course of 16 HCV infected patients with RA who had received the TNF alpha antagonists etanercept or infliximab was analysed. Eight additional patients with RA and HCV were also enrolled into a three month prospective trial of etanercept. Serum concentrations of albumin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and HCV were followed. Viraemia was measured in 22 patients receiving a TNF alpha antagonist at the start of treatment and after 1-34 months (median 9 months follow up). Twenty four patients had serial tests of liver related enzymes and albumin. None of the differences between liver related tests at baseline and at follow up achieved significance (p>0.05). Similarly, the mean HCV measurement at 1-3, 4-6, 7-12, and 13-34 months did not differ significantly from baseline (p>0.05). In this study, liver related blood tests and HCV viral load measurements did not change substantially. These findings suggest that TNF alpha antagonists merit further study for the treatment of RA in HCV infected patients. Larger and longer term studies are still needed.

Treatment of Rheumatoid Arthritis by Selective Inhibition of T-Cell Activation with Fusion Protein CTLA4Ig

Article

Full-text available

Nov 2003
NEW ENGL J MED

Effective new therapies are needed for rheumatoid arthritis. Current therapies target the products of activated macrophages; however, T cells also have an important role in rheumatoid arthritis. A fusion protein--cytotoxic T-lymphocyte-associated antigen 4-IgG1 (CTLA4Ig)--is the first in a new class of drugs known as costimulation blockers being evaluated for the treatment of rheumatoid arthritis. CTLA4Ig binds to CD80 and CD86 on antigen-presenting cells, blocking the engagement of CD28 on T cells and preventing T-cell activation. A preliminary study showed that CTLA4Ig may be effective for the treatment of rheumatoid arthritis. We randomly assigned patients with active rheumatoid arthritis despite methotrexate therapy to receive 2 mg of CTLA4Ig per kilogram of body weight (105 patients), 10 mg of CTLA4Ig per kilogram (115 patients), or placebo (119 patients) for six months. All patients also received methotrexate therapy during the study. The clinical response was assessed at six months with use of the criteria of the American College of Rheumatology (ACR), which define the response according to its extent: 20 percent (ACR 20), 50 percent (ACR 50), or 70 percent (ACR 70). Additional end points included measures of the health-related quality of life. Patients treated with 10 mg of CTLA4Ig per kilogram were more likely to have an ACR 20 than were patients who received placebo (60 percent vs. 35 percent, P<0.001). Significantly higher rates of ACR 50 and ACR 70 responses were seen in both CTLA4Ig groups than in the placebo group. The group given 10 mg of CTLA4Ig per kilogram had clinically meaningful and statistically significant improvements in all eight subscales of the Medical Outcomes 36-Item Short-Form General Health Survey. CTLA4Ig was well tolerated, with an overall safety profile similar to that of placebo. In patients with active rheumatoid arthritis who were receiving methotrexate, treatment with CTLA4Ig significantly improved the signs and symptoms of rheumatoid arthritis and the health-related quality of life. CTLA4Ig is a promising new therapy for rheumatoid arthritis.

Infliximab Therapy for Rheumatic Diseases in Patients with Chronic Hepatitis B or C

Article

Full-text available

Feb 2004

To describe the safety of tumor necrosis factor-a blockade in 2 patients with inflammatory rheumatic disease with chronic hepatitis B and C. We used infliximab therapy in 2 patients with chronic inflammatory joint disease and chronic hepatitis B or C. We describe the clinical and laboratory test data obtained in these patients during the first year of treatment. Disease activity, liver function tests, and HCV and HBV status were evaluated before infliximab therapy was started and were reevaluated before each infusion. Liver biopsy was performed in both patients before infliximab therapy. After more than one year of treatment, no worsening in liver function or virological status was observed, while a dramatic clinical improvement of joint disease was observed in both patients. These cases suggest that infliximab therapy may be safe in some quiescent or controlled chronic HBV or HCV infection.

Infliximab in active early rheumatoid arthritis

Article

Full-text available

Mar 2004

To examine the impact of the combination of infliximab plus methotrexate (MTX) on the progression of structural damage in patients with early rheumatoid arthritis (RA). Subanalyses were carried out on data for patients with early RA in the Anti-TNF Therapy in RA with Concomitant Therapy (ATTRACT) study, in which 428 patients with active RA despite MTX therapy received placebo with MTX (MTX-only) or infliximab 3 mg/kg or 10 mg/kg every (q) 4 or 8 weeks with MTX (infliximab plus MTX) for 102 weeks. Early RA was defined as disease duration of 3 years or less; 82 of the 428 patients (19%) met this definition. Structural damage was assessed with the modified van der Heijde-Sharp score. The changes from baseline to week 102 in total modified van der Heijde-Sharp score were compared between the infliximab plus MTX groups and the MTX-only group. The erosion and joint space narrowing scores from baseline to week 102 in the cohort of patients with early RA decreased significantly in each infliximab dose regimen compared with the MTX-only regimen. Consistent benefit was seen in the joints of both hands and feet. Infliximab combined with MTX inhibited the progression of structural damage in patients with early RA during the 2 year period of treatment. Early intervention with infliximab in patients with active RA despite MTX therapy may provide long term benefits by preventing radiographic progression and preserving joint integrity.

Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed

Article

Full-text available

May 2004

To evaluate the efficacy and safety of monotherapy with adalimumab in patients with RA for whom previous DMARD treatment has failed. In a 26 week, double blind, placebo controlled, phase III trial, 544 patients with RA were randomised to monotherapy with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, 40 mg weekly, or placebo. The primary efficacy end point was > or =20% improvement in the ACR core criteria (ACR20 response). Secondary efficacy end points included ACR50, ACR70, EULAR responses, and the Disability Index of the Health Assessment Questionnaire (HAQ DI). After 26 weeks, patients treated with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, and 40 mg weekly had significantly better response rates than those treated with placebo: ACR20 (35.8%, 39.3%, 46.0%, 53.4%, respectively v 19.1%; p< or =0.01); ACR50 (18.9%, 20.5%, 22.1%, 35.0% v 8.2%; p< or =0.05); ACR70 (8.5%, 9.8%, 12.4%, 18.4% v 1.8%; p< or =0.05). Moderate EULAR response rates were significantly greater with adalimumab than with placebo (41.5%, 48.2%, 55.8%, 63.1% v 26.4%; p< or =0.05). Patients treated with adalimumab achieved better improvements in mean HAQ DI than those receiving placebo (-0.29, -0.39, -0.38, -0.49 v -0.07; p< or =0.01). No significant differences were found between adalimumab and placebo treated patients for serious adverse events, serious infections, or malignancies. Injection site reaction occurred in 10.6% and 0.9% of adalimumab and placebo treated patients, respectively (p< or =0.05). Among patients with RA for whom previous DMARD treatment had failed, adalimumab monotherapy achieved significant, rapid, and sustained improvements in disease activity and improved physical function and was safe and well tolerated.

Efficacy of B-Cell-Targeted Therapy With Rituximab in Patients With Rheumatoid Arthritis

Article

Full-text available

Jun 2004
NEW ENGL J MED

An open-label study indicated that selective depletion of B cells with the use of rituximab led to sustained clinical improvements for patients with rheumatoid arthritis. To confirm these observations, we conducted a randomized, double-blind, controlled study. We randomly assigned 161 patients who had active rheumatoid arthritis despite treatment with methotrexate to receive one of four treatments: oral methotrexate (> or =10 mg per week) (control); rituximab (1000 mg on days 1 and 15); rituximab plus cyclophosphamide (750 mg on days 3 and 17); or rituximab plus methotrexate. Responses defined according to the criteria of the American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) were assessed at week 24 (primary analyses) and week 48 (exploratory analyses). At week 24, the proportion of patients with 50 percent improvement in disease symptoms according to the ACR criteria, the primary end point, was significantly greater with the rituximab-methotrexate combination (43 percent, P=0.005) and the rituximab-cyclophosphamide combination (41 percent, P=0.005) than with methotrexate alone (13 percent). In all groups treated with rituximab, a significantly higher proportion of patients had a 20 percent improvement in disease symptoms according to the ACR criteria (65 to 76 percent vs. 38 percent, P< or =0.025) or had EULAR responses (83 to 85 percent vs. 50 percent, P< or =0.004). All ACR responses were maintained at week 48 in the rituximab-methotrexate group. The majority of adverse events occurred with the first rituximab infusion: at 24 weeks, serious infections occurred in one patient (2.5 percent) in the control group and in four patients (3.3 percent) in the rituximab groups. Peripheral-blood immunoglobulin concentrations remained within normal ranges. In patients with active rheumatoid arthritis despite methotrexate treatment, a single course of two infusions of rituximab, alone or in combination with either cyclophosphamide or continued methotrexate, provided significant improvement in disease symptoms at both weeks 24 and 48.

Chronic hepatitis B reactivation following infliximab therapy in Crohn's disease patients: Need for primary prophylaxis

Article

Full-text available

Oct 2004

There is little information about the effect of infliximab on the clinical course of liver disease in Crohn's disease patients with concomitant hepatitis B virus (HBV) infection. Theoretically, immunosuppression induced by infliximab will facilitate viral replication which could be followed by a flare or exacerbation of disease when therapy is discontinued. There are no specific recommendations on surveillance and treatment of HBV before infliximab infusion. Two cases of severe hepatic failure related to infliximab infusions have been described in patients with rheumatic diseases. Hepatitis markers (C and B) and liver function tests were prospectively determined to 80 Crohn's disease patients requiring infliximab infusion in three hospitals in Spain. Three Crohn's disease patients with chronic HBV infection were identified. Two of the three patients with chronic HBV infection suffered severe reactivation of chronic hepatitis B after withdrawal of infliximab therapy and one died. A third patient, who was treated with lamivudine at the time of infliximab therapy, had no clinical or biochemical worsening of liver disease during or after therapy. From the remaining 80 patients, six received the hepatitis B vaccine. Three patients had antibodies to both hepatitis B surface antigen (anti-HBs) and hepatitis B core protein (anti-HBc) with normal aminotransferase levels, and one patient had positive anti-hepatitis C virus (HCV) antibodies, negative HCV RNA, and normal aminotransferase levels. Except for the patients with chronic HBV infection, no significant changes in hepatic function were detected. Patients with Crohn's disease who are candidates for infliximab therapy should be tested for hepatitis B serological markers before treatment and considered for prophylaxis of reactivation using antiviral therapy if positive.

THU0237 Enbrel® (etanercept) in patients with psoriatic arthritis and psoriasis

Conference Paper

Jun 2001

Background Results have been previously presented from a 12-week, double-blind placebo-controlled study of 60 patients with psoriatic arthritis (PsA) and psoriasis.¹ ENBREL was well tolerated and provided clinically significant benefit to patients with PsA and psoriasis. All patients could receive open-label ENBREL in a 24-week extension study. Objectives Observe the safety and clinical benefit of ENBREL in a longer-term open-label study. Methods In the extension study, as in the blinded study, we evaluated improvements in patients with PsA according to PsA response criteria (PsARC) and ACR criteria. Patients with psoriasis were evaluated using the Psoriasis Area and Severity Index (PASI). Results Fifty-eight patients from the 12-week study received open-label ENBREL in the 24-week extension study and were evaluated according to PsARC and ACR criteria. Thirty-seven patients with psoriasis were evaluated using the PASI. The original ENBREL patients sustained their improvement in both PsA and psoriasis in the extension study. The original placebo patients demonstrated similar improvements once they began receiving ENBREL. At 36 weeks of therapy, 81% of all patients achieved the PsARC, 74% achieved the ACR 20, and 55% achieved the ACR 50. The patients with psoriasis (n = 37) achieved median improvements of 62% in the PASI and 50% in the target lesion response. Of the 28 patients who were taking concomitant methotrexate (MTX) at baseline, 43% (12/28) have decreased their MTX dose and 25% (7/28) patients have discontinued MTX. Similarly, of 18 patients on corticosteroids at baseline, 67% (12/18) have decreased their steroid dose and 44% (8/18) have discontinued steroids. At 36 weeks, 28% of patients had zero tender joints, 41% had zero swollen joints, and 40% had a disability score of zero. ENBREL continued to be well tolerated, with no serious adverse events or infections and no increases in adverse events with extended exposure. Conclusion ENBREL continues to be safe and effective in reducing the clinical signs and symptoms of PsA and psoriasis for up to 36 weeks. Reference • Mease PJ, Goffe BS, Metz J, et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomized trial. Lancet 2000;356:385–90

FRI0063 Anakinra reduces the rate of joint destruction after 1 year of treatment in a randomised controlled cohort of patients with rheumatoid arthritis

Conference Paper

Jun 2001

Objectives To assess the effect of ankinra on progressive joint damage in patients with rheumatoid arthritis after 12 months of treatment. Methods 472 patients were randomised to a 24 week study. On completing the 24 week, placebo-controlled, randomised clinical trial, patients receiving anakinra 30, 75 or 150 mg daily continued blinded treatment for a further 24 weeks. Patients originally randomised to placebo were re-randomised to blinded treatment with one of the 3 anakinra doses for an additional 24 weeks resulting in a blinded cohort of patients (N = 309) followed for up to 1 year by radiographic assessments, using a modified Sharp method (Genant A&R, 41:1583, 98). Results Treatment with 75 or 150 mg anakinra was significantly superior in terms of reducing joint destruction after 1 year, when compared to the group of patients originally randomised to placebo. This analysis demonstrated a dose proportional relationship with increasing doses of anakinra providing superior reduction of joint destruction when measured by a modified Sharp score.View this table: • View inline • View popup Abstract FRI0063 Table 1 p-values for pairwise comparisons vs placebo are the result of an analysis using a repeated measures mixed model. Conclusion Anakinra provides a statistically significant reduction in joint destruction, compared with patients originally randomised to placebo after 1 year of treatment. The reduction in joint destruction was dose proportional.

Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas. (vol 65, pg 699, 2005)

Article

Oct 2006

Clinical and radiological outcomes after one-year follow-up of the BeSt study, a randomized trial comparing four different treatment strategies in early rheumatoid arthritis (RA).

Conference Paper

Dec 2003

Improved quality of life with rituximab plus methotrexate in patients with active rheumatoid arthritis who experienced inadequate response to one or more anti-TNF alpha therapies

Conference Paper

Apr 2006

Reply [2]

Article

Jul 2006

Inhibition of tumor necrosis factor alpha and ankylosing spondylitis - Reply

Article

Jan 2003

RANKL inhibition with denosumab reduces progression of bone erosions in patients with rheumatoid arthritis: Month 6 MRI results

Article

Jan 2006
ARTHRIT RHEUM-ARTHR

Effects of Abatacept in Patients with Methotrexate-Resistant Active Rheumatoid Arthritis

Article

Jun 2006

Joel M. Kremer

Background: The selective co-stimulation modulator abatacept demonstrated efficacy for treating rheumatoid arthritis in early clinical studies. Objective: To evaluate the effects of abatacept in patients with persistent, active rheumatoid arthritis despite methotrexate treatment. Design: One-year, multicenter, randomized, double-blind, placebo-controlled trial (November 2002 to October 2004). Setting: 116 centers worldwide. Patients: 652 patients with active rheumatoid arthritis despite methotrexate treatment. Intervention: Once-monthly infusion of a fixed dose of abatacept, approximately 10 mg/kg of body weight, or placebo. Measurements: Co-primary end points were a 20% improvement in American College of Rheumatology (ACR) response criteria (ACR 20) at 6 months, clinically meaningful improvements in physical function, and change from baseline in joint erosion score at 1 year. Results: Four hundred thirty-three and 219 patients were randomly assigned to abatacept or placebo, respectively, and 385 (89%) and 162 (74%), respectively, completed 1 year of treatment. In a modified intention-to-treat analysis, 6-month ACR 20, ACR 50, and ACR 70 responses were 67.9% for abatacept versus 39.7% for placebo (difference, 28.2 percentage points [95% Cl, 19.8 to 36.7 percentage points]), 39.9% for abatacept versus 16.8% for placebo (difference, 23.0 percentage points [Cl, 15.0 to 31.1 percentage points]), and 19.8% for abatacept versus 6.5% for placebo (difference, 13.3 percentage points [CI, 7.0 to 19.5 percentage points]), respectively. At 1 year, the responses increased to 73.1 % for abatacept versus 39.7% for placebo (difference, 33.4 percentage points [Cl, 25.1 to 41.7 percentage points]), 48.3% for abatacept versus 18.2% for placebo (difference, 30.1 percentage points [Cl, 21.8 to 38.5 percentage points]), and 28.8% for abatacept versus 6.1 % for placebo (difference, 22.7 percentage points [Cl, 15.6 to 29.8 percentage points]), respectively (P < 0.001 for all). Physical function significantly improved in 63.7% versus 39.3% of patients (P< 0.001). At 1 year, abatacept statistically significantly slowed the progression of structural joint damage compared with placebo. Abatacept-treated patients had a similar incidence of adverse events (87.3% vs. 84.0%; difference, 3.3 percentage points [Cl, -2.5 to 9.1 percentage points]) and a higher incidence of prespecified serious infections (2.5% vs. 0.9%; difference, 1.6 percentage points [Cl, -0.3 to 3.6 percentage points]) and infusion reactions (acute, 8.8% vs. 4.1%; difference, 4.7 percentage points [Cl, 0.9 to 8.4 percentage points]; peri-infusional, 24.5% vs. 16.9%; difference, 7.6 percentage points [Cl, 1.2 to 14.0 percentage points]) compared with placebo recipients. Limitations: The study involved only 1 group of patients over 1 year. Conclusions: Abatacept statistically significantly reduced disease activity in patients with rheumatoid arthritis and an inadequate response to methotrexate. Longer treatment in different patient populations is needed to establish its appropriate role in rheumatoid arthritis.

Treatment of psoriatic arthritis with antitumour necrosis factor – antibody clears skin lesions of psoriasis resistant to treatment with methotrexate

Article

Mar 2001

Background In inflamed skin, keratinocytes and inflammatory cells both produce large amounts of tumour necrosis factor (TNF) -α, a cytokine with broad effects that are relevant to inflammation. Blockade of this proinflammatory cytokine by a monoclonal anti-TNF-α antibody might be effectively used in the treatment of inflammatory skin diseases. Objectives To gather information about the efficacy of an anti-TNF-α antibody (infliximab) in the treatment of skin lesions of psoriatic arthritis. Methods Six patients with progressive joint disease and psoriatic skin lesions unresponsive to methotrexate therapy were treated with anti-TNF-α antibody. The Psoriasis Area and Severity Index was determined before and 10 weeks after initiation of therapy. Results Improvement of psoriatic skin lesions was observed in all patients. In addition, a marked improvement of the joint disease was noted. Conclusions Therapy with anti-TNF-α antibody may be an effective treatment regimen for both psoriatic arthritis and psoriatic skin lesions.

Reduction in long-term disability in patients with rheumatoid arthritis by disease-modifying antirheumatic drug-based treatments

Article

Apr 1996
ARTHRIT RHEUM-ARTHR

Objective. Therapeutic strategies for rheumatoid arthritis (RA) have been evolving from the traditional “pyramid” approach toward one based upon early and sustained use of disease-modifying antirheumatic drugs (DMARDs), in the hope of improving long-term health outcomes. However, few data to have been presented to document the effects of this approach. We sought to directly assess associations between consistent DMARD use and long-term functional outcomes. Methods. We studied 2,888 RA patients who were followed up prospectively for up to 20 years (average 9 years) at 8 databank centers. The independent variable was the proportion of patient encounters that resulted in treatment with ⩾1 DMARD (hydroxychloroquine, sulfasalazine, auranofin, intramuscular gold, D-penicillamine, methotrexate, and/or azathioprine). The dependent variable was each patient's last recorded Disability Index value from the Health Assessment Questionnaire (HAQ). Results. Increased DMARD use was strongly associated with better long-term Disability Index values (P < 0.0001). The association was strengthened when restricted to more seriously affected (rheumatoid factor (RF)–positive) patients. The magnitude of the effect, unadjusted, was a difference of 0.53 HAQ Disability units (scale 0–3) between 100% DMARD use and 0%. Correlation coefficients ranged up to 0.26. Effects were similar for all disease duration periods (0–4, 5–9, 10–14, 15–19, and 20+ years). “Control” correlations, with variables computed to represent the proportion of time in which patients were taking either nonsteroidal antiinflammatory drugs or prednisone, failed to show positive associations. A multiple linear regression model, which controlled for age, disease duration, sex, RF positivity, proportion of visits under a prednisone regimen, and initial disability level, included the proportion of time in which patients were taking DMARDs (P < 0.0001), with a model R2 of 0.54. These results were obtained despite an adverse selection bias in which more severely affected individuals were given DMARDs more frequently, and despite absence of data on drug use early in the disease course of many patients. Thus, these results, which suggest up to a 30% reduction in longterm disability with consistent DMARD use, are most likely conservative. Conclusion. An association between consistent DMARD use and improvement in long-term functional outcomes in RA is supported by these data.

Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis

Article

Aug 1997

The value of intensive combination therapy in early rheumatoid arthritis is unproven. In a multicentre, double-blind, randomised trial (COBRA), we compared the combination of sulphasalazine (2 g/day), methotrexate (7.5 mg/week), and prednisolone (initially 60 mg/day, tapered in 6 weekly steps to 7.5 mg/day) with sulphasalazine alone. 155 patients with early rheumatoid arthritis (median duration 4 months) were randomly assigned combined treatment (76) or sulphasalazine alone (79). Prednisolone and methotrexate were tapered and stopped after 28 and 40 weeks, respectively. The main outcomes were the pooled index (a weighted change score of five disease activity measures) and the Sharp/Van der Heijde radiographic damage score in hands and feet. Independent health-care professionals assessed the main outcomes without knowledge of treatment allocation. At week 28, the mean pooled index was 1.4 (95% CI 1.2-1.6) in the combined treatment group and 0.8 (0.6-1.0) in the sulphasalazine group (p < 0.0001). At this time, 55 (72%) and 39 (49%) patients, respectively, were improved according to American College of Rheumatology criteria. The clinical difference between the groups decreased and was no longer significant after prednisolone was stopped, and there were no further changes after methotrexate was stopped. At 28 weeks, the radiographic damage score had increased by a median of 1 (range 0-28) in the combined-therapy group and 4 (0-44) in the sulphasalazine group (p < 0.0001). The increases at week 56 (2 [0-43] vs 6 [0-54], p = 0.004), and at week 80 (4 [0-80] vs 12 [0-72], p = 0.01) were also significant. Further analysis suggests that combined therapy immediately suppressed damage progression, whereas sulphasalazine did so less effectively and with a lag of 6 to 12 months. There were fewer withdrawals in the combined therapy than the sulphasalazine group (6 [8%] vs 23 [29%]), and they occurred later. This combined-therapy regimen offers additional disease control over and above that of sulphasalazine alone that persists for up to a year after corticosteroids are stopped. Although confirmatory studies and long-term follow-up are needed, this approach may prove useful in the treatment of early rheumatoid arthritis.

Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis

Article

Sep 1998

To evaluate the efficacy, pharmacokinetics, immunogenicity, and safety of multiple infusions of a chimeric monoclonal anti-tumor necrosis factor alpha antibody (cA2) (infliximab; Remicade, Centocor, Malvern, PA) given alone or in combination with low-dose methotrexate (MTX) in rheumatoid arthritis (RA) patients. In a 26-week, double-blind, placebo-controlled, multicenter trial, 101 patients with active RA exhibiting an incomplete response or flare of disease activity while receiving low-dose MTX were randomized to 1 of 7 groups of 14-15 patients each. The patients received either intravenous cA2 at 1, 3, or 10 mg/kg, with or without MTX 7.5 mg/week, or intravenous placebo plus MTX 7.5 mg/week at weeks 0, 2, 6, 10, and 14 and were followed up through week 26. Approximately 60% of patients receiving cA2 at 3 or 10 mg/kg with or without MTX achieved the 20% Paulus criteria for response to treatment, for a median duration of 10.4 to >18.1 weeks (P < 0.001 versus placebo). Patients receiving cA2 at 1 mg/kg without MTX became unresponsive to repeated infusions of cA2 (median duration 2.6 weeks; P=0.126 versus placebo). However, coadministration of cA2 at 1 mg/kg with MTX appeared to be synergistic, prolonging the duration of the 20% response in >60% of patients to a median of 16.5 weeks (P < 0.001 versus placebo; P=0.006 versus no MTX) and the 50% response to 12.2 weeks (P < 0.001 versus placebo; P=0.002 versus no MTX). Patients receiving placebo infusions plus suboptimal low-dose MTX continued to have active disease, with a Paulus response lasting a median of 0 weeks. A 70-90% reduction in the swollen joint count, tender joint count, and C-reactive protein level was maintained for the entire 26 weeks in patients receiving 10 mg/kg of cA2 with MTX. In general, treatment was well tolerated and stable blood levels of cA2 were achieved in all groups, except for the group receiving 1 mg/kg of cA2 alone, at which dosage antibodies to cA2 were observed in approximately 50% of the patients. Multiple infusions of cA2 were effective and well tolerated, with the best results occurring at 3 and 10 mg/kg either alone or in combination with MTX in approximately 60% of patients with active RA despite therapy with low-dose MTX. When cA2 at 1 mg/kg was given with low-dose MTX, synergy was observed. The results of the trial provide a strategy for further evaluation of the efficacy and safety of longer-term treatment with cA2.

Etanercept therapy in rheumatoid arthritis: A randomized, controlled trial

Article

Apr 1999

In a phase II study, etanercept (recombinant human tumor necrosis factor receptor [p75]:Fc fusion protein) safely produced rapid, dose-dependent improvement in rheumatoid arthritis over 3 months. To confirm the benefit of etanercept therapy of longer duration and simplified dosing in patients with rheumatoid arthritis. Randomized, double-blind, placebo-controlled trial with blinded joint assessors. 13 North American centers. 234 patients with active rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs. Twice-weekly subcutaneous injections of etanercept, 10 or 25 mg, or placebo for 6 months. The primary end points were 20% and 50% improvement in disease activity according to American College of Rheumatology (ACR) responses at 3 and 6 months. Other end points were 70% ACR responses at 3 and 6 months and other measures of disease activity at 3 and 6 months. Etanercept significantly reduced disease activity in a dose-related fashion. At 3 months, 62% of the patients receiving 25 mg of etanercept and 23% of the placebo recipients achieved 20% ACR response (P < 0.001). At 6 months, 59% of the 25-mg group and 11% of the placebo group achieved a 20% ACR response (P < 0.001); 40% and 5%, respectively, achieved a 50% ACR response (P < 0.01). The respective mean percentage reduction in the number of tender and swollen joints at 6 months was 56% and 47% in the 25-mg group and 6% and -7% in the placebo group (P < 0.05). Significantly more etanercept recipients achieved a 70% ACR response, minimal disease status (0 to 5 affected joints), and improved quality of life. Etanercept was well tolerated, with no dose-limiting toxic effects. Etanercept can safely provide rapid, significant, and sustained benefit in patients with active rheumatoid arthritis.

The Pediatric Rheumatology Collaborative Study Group. Etanercept in Children with Polyarticular Juvenile Rheumatoid Arthritis

Article

Mar 2000

We evaluated the safety and efficacy of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein, in children with polyarticular juvenile rheumatoid arthritis who did not tolerate or had an inadequate response to methotrexate. Patients 4 to 17 years old received 0.4 mg of etanercept per kilogram of body weight subcutaneously twice weekly for up to three months in the initial, open-label part of a multicenter trial. Those who responded to treatment then entered a double-blind study and were randomly assigned to receive either placebo or etanercept for four months or until a flare of the disease occurred. A response was defined as an improvement of 30 percent or more in at least three of six indicators of disease activity, with no more than one indicator worsening by more than 30 percent. At the end of the open-label study, 51 of the 69 patients (74 percent) had had responses to etanercept treatment. In the double-blind study, 21 of the 26 patients who received placebo (81 percent) withdrew because of disease flare, as compared with 7 of the 25 patients who received etanercept (28 percent) (P=0.003). The median time to disease flare with placebo was 28 days, as compared with more than 116 days with etanercept (P<0.001). In the double-blind study, there were no significant differences between the two treatment groups in the frequency of adverse events. Treatment with etanercept leads to significant improvement in patients with active polyarticular juvenile rheumatoid arthritis. Etanercept is well tolerated by pediatric patients.

Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B & Burge DJ. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet356: 385-390

Article

Jul 2000

Etanercept, a tumour-necrosis-factor inhibitor, has shown efficacy in the treatment of rheumatoid arthritis. Psoriatic arthritis and psoriasis are disease states in which tumour necrosis factor, a proinflammatory cytokine, is present in increased concentrations in joints and in the skin. Therefore, psoriatic arthritis and psoriasis may be appropriate therapeutic targets for etanercept. This randomised, double-blind, placebo-controlled, 12 week study assessed the efficacy and safety of etanercept (25 mg twice-weekly subcutaneous injections) or placebo in 60 patients with psoriatic arthritis and psoriasis. Psoriatic arthritis endpoints included the proportion of patients who met the Psoriatic Arthritis Response Criteria (PsARC) and who met the American College of Rheumatology preliminary criteria for improvement (ACR20). Psoriasis endpoints included improvement in the psoriasis area and severity index (PASI) and improvement in prospectively-identified individual target lesions. In this 12 week study, 26 (87%) of etanercept-treated patients met the PsARC, compared with seven (23%) of placebo-controlled patients. The ARC20 was achieved by 22 (73%) of etanercept-treated patients compared with four (13%) of placebo-treated patients. Of the 19 patients in each treatment group who could be assessed for psoriasis (> or = 3% body surface area), five (26%) of etanercept-treated patients achieved a 75% improvement in the PASI, compared with none of the placebo-treated patients (p=0.015). The median PASI improvement was 46% in etanercept-treated patients versus 9% in placebo-treated patients; similarly, median target lesion improvements were 50% and 0, respectively. Etanercept was well tolerated. Etanercept offers patients with psoriatic arthritis and psoriasis a new therapeutic option for control of their disease.

Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group

Article

Dec 2000

Neutralization of tumor necrosis factor a (TNF-alpha) for three to six months reduces the symptoms and signs of rheumatoid arthritis. However, the capacity of this approach to effect a more sustained benefit and its effect on joint damage are not known. We treated 428 patients who had active rheumatoid arthritis despite methotrexate therapy with placebo or infliximab, a chimeric monoclonal antibody against TNF-alpha, in intravenous doses of 3 or 10 mg per kilogram of body weight every 4 or 8 weeks in combination with oral methotrexate for 54 weeks. We assessed clinical responses with use of the criteria of the American College of Rheumatology, the quality of life with a health-status questionnaire, and the effect on joint damage radiographically. The combination of infliximab and methotrexate was well tolerated and resulted in a sustained reduction in the symptoms and signs of rheumatoid arthritis that was significantly greater than the reduction associated with methotrexate therapy alone (clinical response, 51.8 percent vs. 17.0 percent; P<0.001). The quality of life was also significantly better with infliximab plus methotrexate than with methotrexate alone. Radiographic evidence of joint damage increased in the group given methotrexate, but not in the groups given infliximab and methotrexate (mean change in radiographic score, 7.0 vs. 0.6, P<0.001). Radiographic evidence of progression of joint damage was absent in infliximab-treated patients whether or not they had a clinical response. In patients with persistently active rheumatoid arthritis despite methotrexate therapy, repeated doses of infliximab in combination with methotrexate provided clinical benefit and halted the progression of joint damage.

Treatment of Ankylosing Spondylitis by Inhibition of Tumor Necrosis Factor ??

Article

May 2002
NEW ENGL J MED

There are few effective treatments for ankylosing spondylitis, which causes substantial morbidity. Because of the central role of tumor necrosis factor alpha in the spondyloarthritides, we performed a randomized, double-blind, placebo-controlled trial of etanercept, a recombinant human tumor necrosis factor receptor (p75):Fc fusion protein, in patients with ankylosing spondylitis. Forty patients with active, inflammatory ankylosing spondylitis were randomly assigned to receive twice-weekly subcutaneous injections of etanercept (25 mg) or placebo for four months. The primary end point was a composite of improvements in measures of morning stiffness, spinal pain, functioning, the patient's global assessment of disease activity, and joint swelling. Patients were allowed to continue taking nonsteroidal antiinflammatory drugs, oral corticosteriods (< or =10 mg per day), and disease-modifying antirheumatic drugs at stable doses during the trial. Treatment with etanercept resulted in significant and sustained improvement. At four months, 80 percent of the patients in the etanercept group had a treatment response, as compared with 30 percent of those in the placebo group (P=0.004). Improvements over base-line values for various measures of disease activity, including morning stiffness, spinal pain, functioning, quality of life, enthesitis, chest expansion, erythrocyte sedimentation rate, and C-reactive protein, were significantly greater in the etanercept group. Longitudinal analysis showed that the treatment response was rapid and did not diminish over time. Etanercept was well tolerated, with no significant differences in rates of adverse events between the two groups. Treatment with etanercept for four months resulted in rapid, significant, and sustained improvement in patients with ankylosing spondylitis.

Frequency of infection in patients with rheumatoid arthritis compared with controls: A population-based study

Article

Sep 2002

A high frequency of infections complicating rheumatoid arthritis (RA) has been described in reports of case series. This retrospective longitudinal cohort study was undertaken to compare the frequency of infections in a population-based incidence cohort of RA patients with that in a group of individuals without RA from the same population. RA patients included all members of an incidence cohort of Rochester, Minnesota residents ages >or=18 years who were first diagnosed as having RA between 1955 and 1994. One age- and sex-matched subject without RA was selected for each patient with RA. Study subjects were followed up by review of their entire medical record until death, migration from the area, or study end (January 1, 2000), and details of all documented infections, along with information on potential risk factors for infection, were recorded. Hazard ratios for infections were estimated using stratified Andersen-Gill proportional hazards models, with adjustment for potential confounders. The 609 RA patients and 609 non-RA study subjects (mean age 58.0 years; 73.1% female) were followed up for a mean of 12.7 years and 15.0 years, respectively, reflecting higher mortality among the group with RA. Hazards ratios for objectively confirmed infections, infections requiring hospitalization, and any documented infection in patients with RA were 1.70 (95% confidence interval [95% CI] 1.42-2.03), 1.83 (95% CI 1.52-2.21), and 1.45 (95% CI 1.29-1.64), respectively, after adjustment for age, sex, smoking status, leukopenia, corticosteroid use, and diabetes mellitus. Sites of infection with the highest risk ratios were bone, joints, skin, soft tissues, and the respiratory tract. In this study, patients with RA were at increased risk of developing infections compared with non-RA subjects. This may be due to immunomodulatory effects of RA, or to agents with immunosuppressive effects used in its treatment.

Long-term efficacy and safety of etanercept in children with polyarticular-course juvenile rheumatoid arthritis: Interim results from an ongoing multicenter, open-label, extended-treatment trial

Article

Jan 2003

To evaluate the long-term efficacy and safety of etanercept in children with juvenile rheumatoid arthritis (JRA) participating in an ongoing multicenter, open-label, extended-treatment trial. All patients had been participants in an initial randomized efficacy and safety trial of etanercept. Etanercept was administered at a dosage of 0.4 mg/kg (maximum 25 mg) subcutaneously twice each week. Safety and efficacy evaluations were performed every 3-4 months. The JRA 30% definition of improvement (DOI) was defined as improvement of > or =30% in at least 3 of 6 response variables used to assess disease activity, with no more than 1 variable worsening by more than 30%. At the time of analysis, 48 of the 58 patients (83%) were still enrolled in the study; 43 of them (74%) had completed 2 years of treatment. Of these 43 patients, 81% met the JRA 30% DOI, 79% met the JRA 50% DOI, and 67% met the JRA 70% DOI. Ten children started low-dose methotrexate after year 1. Of the 32 children taking prednisone, the dosage was decreased to <5 mg/day in 26 (81%). Two children had serious infections (varicella with aseptic meningitis in one and complicated sepsis in the other). In general, adverse events were of the types seen in a general pediatric patient population. Children with severe, longstanding, methotrexate-resistant polyarticular JRA demonstrated sustained clinical improvement with >2 years of continuous etanercept treatment. Etanercept was generally well-tolerated. There were no increases in the rates of adverse events over time. However, children taking etanercept should be monitored closely for infections.

A Simplified Disease Activity Index for rheumatoid arthritis for use in clinical practice

Article

Mar 2003

Fleischmann RM, Schechtman J, Bennett R, Handel ML, Burmester GR, Tesser J, Modafferi D, Poulakos J, Sun GAnakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: a large, international, multicenter, placebo-controlled trial. Arthritis Rheum 48:927-934

Article

Apr 2003

To evaluate the safety of anakinra (a recombinant human interleukin-1 receptor antagonist) in a large population of patients with rheumatoid arthritis (RA), typical of those seen in clinical practice. A total of 1,414 patients were randomly assigned to treatment with 100 mg of anakinra or placebo, administered daily by subcutaneous injection. Background medications included disease-modifying antirheumatic drugs, corticosteroids, and nonsteroidal antiinflammatory drugs, alone or in combination. The primary end point was safety, which was evaluated by adverse events (including infections), discontinuation from study due to adverse events, and death. Safety was evaluated in 1,399 patients (1,116 in the anakinra group and 283 in the placebo group; 15 patients were randomized but did not receive any study drug) during the initial 6-month, double-blind, placebo-controlled phase of this long-term safety study. Baseline demographics, disease characteristics, and concomitant medications were similar between the 2 groups. The study group included patients with numerous comorbid conditions and a wide range of RA disease activity. Serious adverse events occurred at a similar rate in the anakinra group and the placebo group (7.7% and 7.8%, respectively). Serious infectious episodes were observed more frequently in the anakinra group (2.1% versus 0.4% in the placebo group). The rate of withdrawal due to adverse events was 13.4% in the anakinra group and 9.2% in the placebo group. Results from this large, placebo-controlled safety study demonstrate that anakinra is safe and well tolerated in a diverse population of patients with RA, including those with comorbid conditions and those using multiple combinations of concomitant therapies. Although the frequency of serious infection was slightly higher in the anakinra group, no infection was attributed to opportunistic microorganisms or resulted in death.

Efficacy of infliximab in resistant psoriatic arthritis

Article

Aug 2003

To evaluate the efficacy and safety of the anti-tumor necrosis factor alpha monoclonal antibody infliximab in the treatment of active psoriatic arthritis (PsA) resistant to previous symptom modifying antirheumatic drugs. Sixteen patients with peripheral active PsA with at least 6 months of methotrexate (MTX) therapy at a stable dosage were treated with infliximab administered at a dosage of 3 mg/kg at 0, 2, 6, 14, 22, and 30 weeks while continuing to receive MTX. Intake of nonsteroidal antiinflammatory drugs and corticosteroids was stable during the study period. Standard clinical assessments, erythrocyte sedimentation rate (ESR), and C reactive protein (CRP) were determined at baseline and at weeks 2, 6, 14, 22, and 30. By week 2, significant improvements were registered in the number of swollen and tender joints, visual analog scale for pain, patient and doctor global disease assessment scores, Health Assessment Questionnaire, Dougados functional index, ESR, and CRP. At week 30, the percentages of patients satisfying American College of Rheumatology (ACR) 20%, ACR 50%, and ACR 70% response rates were 64%, 57%, and 57%, respectively. In the 3 patients with active axial disease, spinal stiffness and pain resolved almost completely at week 2 and the improvement did not diminish over time. Psoriasis Area Severity Index improvement was 37% at week 2 and 86% at week 30. No patients dropped out for treatment failure. Side effects were observed in 4 of 16 patients, 2 of whom suspended the therapy due to a severe allergic reaction. In patients with resistant PsA, infliximab is an effective therapy without major side effects.

Recombinant Human Tumor Necrosis Factor Receptor (Etanercept) for Treating Ankylosing Spondylitis: A Randomized, Controlled Trial

Article

Nov 2003

To determine the safety and efficacy of etanercept in a multicenter, randomized, placebo-controlled, double-blind trial of adults with moderate to severe active ankylosing spondylitis (AS). Patients (n = 277) were treated with either etanercept 25 mg (n = 138) or placebo (n = 139) subcutaneously twice weekly for 24 weeks. The primary outcome measures were the percentages of patients achieving the Assessments in Ankylosing Spondylitis 20% response (ASAS20) at weeks 12 and 24. Other outcome measures included the percentage of patients achieving higher ASAS responses, and the safety of etanercept in patients with AS. All outcome measures were assessed at 2, 4, 8, 12, and 24 weeks. Treatment with etanercept resulted in dramatic improvement. The ASAS20 was achieved by 59% of patients in the etanercept group and by 28% of patients in the placebo group (P < 0.0001) at week 12, and by 57% and 22% of patients, respectively, at week 24 (P < 0.0001). All individual ASAS components, acute-phase reactant levels, and spinal mobility measures were also significantly improved. The safety profile of etanercept was similar to that reported in studies of patients with rheumatoid arthritis or psoriatic arthritis. The only adverse events that occurred significantly more often in the etanercept group were injection-site reactions, accidental injuries, and upper respiratory tract infections. Etanercept is a highly effective and well tolerated treatment in patients with active AS.

Etanercept as Monotherapy in Patients with Plaque-Psoriasis

Article

Dec 2003
NEW ENGL J MED

Inflammatory cytokines such as tumor necrosis factor (TNF) have been implicated in the pathogenesis of psoriasis. We evaluated the safety and efficacy of etanercept, a TNF antagonist, for the treatment of plaque psoriasis. In this 24-week, double-blind study, 672 patients underwent randomization and 652 either received placebo or received etanercept subcutaneously at a low dose (25 mg once weekly), a medium dose (25 mg twice weekly), or a high dose (50 mg twice weekly). After 12 weeks, patients in the placebo group began twice-weekly treatment with 25 mg of etanercept. The primary measure of clinical response was the psoriasis area-and-severity index. At week 12, there was an improvement from base line of 75 percent or more in the psoriasis area-and-severity index in 4 percent of the patients in the placebo group, as compared with 14 percent of those in the low-dose--etanercept group, 34 percent in the medium-dose--etanercept group, and 49 percent in the high-dose-etanercept group (P<0.001 for all three comparisons with the placebo group). The clinical responses continued to improve with longer treatment. At week 24, there was at least a 75 percent improvement in the psoriasis area-and-severity index in 25 percent of the patients in the low-dose group, 44 percent of those in the medium-dose group, and 59 percent in the high-dose group. The responses as measured by improvements in the psoriasis area-and-severity index were paralleled by improvements in global assessments by physicians and the patients and in quality-of-life measures. Etanercept was generally well tolerated. The treatment of psoriasis with etanercept led to a significant reduction in the severity of disease over a period of 24 weeks.

Adalimumab, a Fully Human Anti-Tumor Necrosis Factor-?? Monoclonal Antibody, and Concomitant Standard Antirheumatic Therapy for the Treatment of Rheumatoid Arthritis: Results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis)

Article

Jan 2004

This study, known as STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis), evaluated the safety and efficacy of adalimumab (Humira), a fully human monoclonal tumor necrosis factor-alpha (TNF-a) antibody, when given with standard antirheumatic therapy in patients with active rheumatoid arthritis (RA) not adequately responding to such therapies. Standard antirheumatic therapy included traditional disease modifying antirheumatic drugs (DMARD), low dose corticosteroids, nonsteroidal antiinflammatory drugs (NSAID), and/or analgesics. In this 24-week, double-blind, placebo-controlled study, 636 patients with RA were randomly assigned to receive adalimumab 40 mg subcutaneously (sc) every other week (n = 318) or placebo (n = 318) while continuing standard antirheumatic therapy. The frequencies of adverse events, serious adverse events, severe or life-threatening adverse events, adverse events leading to withdrawal, infection, or serious infection were the primary endpoints. Secondary endpoints were determined by American College of Rheumatology (ACR) response criteria. During the study, the majority of patients received concomitant traditional DMARD (83.5%) and/or corticosteroids, NSAID, and/or analgesics (97.3%). Overall, 56.0% of patients continued treatment with one, 23.6% with 2, and 3.9% with > or = 3 traditional DMARD. At 24 weeks, there were no statistically significant differences between the adalimumab and placebo groups in their respective rates of adverse events (86.5% vs 82.7%), serious adverse events (5.3% vs 6.9%), severe or life-threatening adverse events (11.9% vs 15.4%), or those leading to withdrawal (2.8% vs 2.2%). There were also no statistically significant differences in the rates of infections (52.2% vs 49.4%) or serious infections (1.3% vs 1.9%) between the groups. The incidence and types of adverse events did not vary between adalimumab- and placebo-treated patients by the number of concomitant traditional DMARD (0, 1, or 2). Adalimumab-treated patients compared with placebo-treated patients achieved statistically superior ACR20 (52.8% vs 34.9%), ACR50 (28.9% vs 11.3%), and ACR70 (14.8% vs 3.5%) response rates at Week 24 (p < or = 0.001). This study demonstrated that addition of adalimumab 40 mg given sc every other week to concomitant standard antirheumatic therapy is well tolerated and provides significant improvements in signs and symptoms of RA. The data indicate that adalimumab is a safe and effective therapeutic option in patients with active RA who have an inadequate response to standard antirheumatic therapy, including one or more traditional DMARD, corticosteroids, NSAID, and analgesics.

Assessment of Patients with Psoriatic Arthritis: A Review of Currently Available Measures

Article

Jan 2004

To date, specific measures to assess disease activity in PsA have not been validated. The tools used for assessment of psoriatic peripheral joint disease have been "borrowed" from the assessment of RA. While, in general, some of these outcome measures perform well in PsA, the distinct distribution of joint involvement coupled with the unique patterns of synovitis and periarticular inflammation demand that these measures be appropriately and carefully adapted. In order to capture the wide variation that characterizes the clinical presentation seen among patients with PsA, a larger number of joints should be assessed. Moreover, because of the frequency and severity of back involvement in PsA, assessment of spinal mobility and pain is required. Many clinical methods used to assess axial disease in AS have not proven to be reliable, and even measures deemed appropriate in AS require validation in PsA. Specific assessment of common features of PsA, including dactylitis, enthesitis, and tendonitis, requires further study. In addition, available techniques for radiographic evaluation of patients with RA may not fully record the specific changes noted among patients with PsA. Moreover, the utility of newer imaging techniques in the assessment of joint and spinal inflammation in patients with PsA requires further study. Finally, it is important to evaluate whether the same instruments can be used for the various patterns of PsA. Rigorous validation of currently used techniques, combined with the development of new assessment tools, is urgently required to fully assess the therapeutic response in PsA. In our view, a consensus development of a core set of outcome domains, psychometric evaluation of candidate instruments in patients with PsA, and construction of response criteria from clinical trials that have used such instruments constitute the research agenda for PsA.

Combination Therapy with Etanercept and Anakinra in the Treatment of Patients with Rheumatoid Arthritis Who Have Been Treated Unsuccessfully with Methotrexate

Article

May 2004

To determine the potential for additive or synergistic effects of combination therapy with the selective anti-tumor necrosis factor alpha agent etanercept and the anti-interleukin-1 agent anakinra. Two hundred forty-four patients in whom rheumatoid arthritis (RA) was active despite methotrexate therapy were treated with subcutaneous etanercept only (25 mg twice weekly), full-dosage etanercept (25 mg twice weekly) plus anakinra (100 mg/day), or half-dosage etanercept (25 mg once weekly) plus anakinra (100 mg/day) for 6 months in a double-blind study at 41 centers in the US. Patients had never previously received anticytokine therapy. Patient response was measured with the American College of Rheumatology (ACR) core set criteria, a health-related quality-of-life questionnaire, and the Disease Activity Score. Safety was assessed by the number of adverse events and clinical laboratory values. Plasma concentrations of both agents and antibody formation against both agents were also assessed. Combination therapy with etanercept plus anakinra provided no treatment benefit over etanercept alone, regardless of the regimen, but was associated with an increased safety risk. Thirty-one percent of the patients treated with full-dosage etanercept plus anakinra achieved an ACR 50% response, compared with 41% of the patients treated with etanercept only. This result was not statistically significant (P = 0.914). The incidence of serious infections (0% for etanercept alone, 3.7-7.4% for combination therapy), injection-site reactions, and neutropenia was increased with combination therapy. Combination therapy had no effect on the pharmacokinetics or immunogenicity of either agent. Combination therapy with etanercept and anakinra provides no added benefit and an increased risk compared with etanercept alone and is not recommended for the treatment of patients with RA.

Radiographic, Clinical, and Functional Outcomes of Treatment with Adalimumab (a Human Anti-Tumor Necrosis Factor Monoclonal Antibody) in Patients with Active Rheumatoid Arthritis Receiving Concomitant Methotrexate Therapy: A Randomized, Placebo-Controlled, 52-Week Trial

Article

May 2004

Tumor necrosis factor (TNF) is an important proinflammatory cytokine that mediates inflammatory synovitis and articular matrix degradation in rheumatoid arthritis (RA). We investigated the ability of adalimumab, a human anti-TNF monoclonal antibody, to inhibit the progression of structural joint damage, reduce the signs and symptoms, and improve physical function in patients with active RA receiving concomitant treatment with methotrexate (MTX). In this multicenter, 52-week, double-blind, placebo-controlled study, 619 patients with active RA who had an inadequate response to MTX were randomized to receive adalimumab 40 mg subcutaneously every other week (n = 207), adalimumab 20 mg subcutaneously every week (n = 212), or placebo (n = 200) plus concomitant MTX. The primary efficacy end points were radiographic progression at week 52 (total Sharp score by a modified method [TSS]), clinical response at week 24 (improvements of at least 20% in the American College of Rheumatology core criteria [ACR20]), and physical function at week 52 (disability index of the Health Assessment Questionnaire [HAQ]). At week 52, there was statistically significantly less radiographic progression, as measured by the change in TSS, in the patients receiving adalimumab either 40 mg every other week (mean +/- SD change 0.1 +/- 4.8) or 20 mg weekly (0.8 +/- 4.9) as compared with that in the placebo group (2.7 +/- 6.8) (P < or = 0.001 for each comparison). In addition, there were statistically significant changes in the components of the TSS. At week 24, ACR20 responses were achieved by 63% and 61% of patients in the adalimumab 40 mg every other week and 20 mg weekly groups, respectively, versus 30% of patients in the placebo group (P < or = 0.001 for each comparison). At week 52, ACR20 responses were achieved by 59% and 55% of patients taking adalimumab 40 mg every other week and 20 mg weekly, respectively, versus 24% of patients taking placebo (P < or = 0.001 for each comparison). At week 52, physical function as measured by the HAQ demonstrated statistically significant improvement with adalimumab 40 mg every other week and 20 mg weekly compared with placebo (mean change in HAQ score -0.59 and -0.61, respectively, versus -0.25; P < or = 0.001 for each comparison). A total of 467 patients (75.4%) completed 52 weeks of treatment. Adalimumab was generally well tolerated. Discontinuations occurred in 22.0% of adalimumab-treated patients and in 30.0% of placebo-treated patients. The rate of adverse events (both serious and nonserious) was comparable in the adalimumab and placebo groups, although the proportion of patients reporting serious infections was higher in patients receiving adalimumab (3.8%) than in those receiving placebo (0.5%) (P < or = 0.02), and was highest in the patients receiving 40 mg every other week. In this 52-week trial, adalimumab was more effective than placebo at inhibiting the progression of structural joint damage, reducing the signs and symptoms, and improving physical function in patients with active RA who had demonstrated an incomplete response to MTX.

Effects of anakinra monotherapy on joint damage in patients with rheumatoid arthritis. Extension of a 24-Week randomized, placebo-controlled trial

Article

Jun 2004

To determine the effects of treatment on the radiologic manifestations of joint damage in patients with rheumatoid arthritis (RA) who participated in a 24-week extension study of a randomized, placebo-controlled clinical trial of anakinra, a recombinant human interleukin 1 receptor antagonist. The patients had entered a 24-week, randomized, double-blind, placebo-controlled study. Anakinra was self-administered by subcutaneous injection of 30, 75, or 150 mg/day. Upon completion of the placebo-controlled phase, the patients entering the extension study who had received placebo were randomized to one of the 3 treatment dosages for a further 24 weeks, and the patients who had been initially randomized to one of the 3 anakinra dosages continued to receive the same dosage. Radiographs of the hands were obtained at baseline and at 24 and 48 weeks. The radiographs were evaluated using a modified Sharp method. A total of 472 patients were recruited. The mean change in the total modified Sharp score of 178 patients who completed 48 weeks treatment, including all dosages, was significantly less than the change observed in 58 patients who received placebo for 24 weeks and anakinra for 24 weeks (p = 0.015). A significant reduction in the change of the total modified Sharp score was observed in the patients who received anakinra 75 and 150 mg/day. The total modified Sharp score was reduced significantly more during the second 24-week treatment period, compared to the first (p < 0.001). Significant reductions in the second 24-week period were observed following anakinra 75 mg/day (p = 0.006) and 150 mg/day (p = 0.008). Patients with RA who received anakinra for 48 weeks demonstrated significant slowing of radiographic joint damage. The treatment effect observed after the first 24-week period appeared to increase when anakinra was continued for 48 weeks.

Etanercept Treatment of Psoriatic Arthritis: Safety, Efficacy, and Effect on Disease Progression

Article

Jul 2004

Etanercept has been shown to improve the articular and cutaneous manifestations of psoriatic arthritis (PsA). In this study, we further evaluated the safety, efficacy, and effect on radiographic progression of etanercept in patients with PsA. Patients with PsA (n = 205) were randomized to receive placebo or 25 mg etanercept subcutaneously twice weekly for 24 weeks. Patients continued to receive blind-labeled therapy in a maintenance phase until all had completed the 24-week phase, then could receive open-label etanercept in a 48-week extension. Efficacy and safety were evaluated at 4, 12, and 24 weeks and at 12-week intervals thereafter. Radiographs of the hands and wrists were assessed at baseline and 24 weeks, at entry to the open-label phase, and after 48 weeks in the study. Etanercept significantly reduced the signs and symptoms of PsA and psoriasis. At 12 weeks, 59% of etanercept patients met the American College of Rheumatology 20% improvement criteria for joint response, compared with 15% of placebo patients (P < 0.0001), and results were sustained at 24 and 48 weeks. At 24 weeks, 23% of etanercept patients eligible for psoriasis evaluation achieved at least 75% improvement in the Psoriasis Area and Severity Index, compared with 3% of placebo patients (P = 0.001). Radiographic disease progression was inhibited in the etanercept group at 12 months; the mean annualized rate of change in the modified total Sharp score was -0.03 unit, compared with +1.00 unit in the placebo group (P = 0.0001). Etanercept was well tolerated. Etanercept reduced joint symptoms, improved psoriatic lesions, inhibited radiographic progression, and was well tolerated in patients with PsA.

Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): A single-blind randomised controlled trial

Article

Jul 2004
LANCET

Present treatment strategies for rheumatoid arthritis include use of disease-modifying antirheumatic drugs, but a minority of patients achieve a good response. We aimed to test the hypothesis that an improved outcome can be achieved by employing a strategy of intensive outpatient management of patients with rheumatoid arthritis--for sustained, tight control of disease activity--compared with routine outpatient care. We designed a single-blind, randomised controlled trial in two teaching hospitals. We screened 183 patients for inclusion. 111 were randomly allocated either intensive management or routine care. Primary outcome measures were mean fall in disease activity score and proportion of patients with a good response (defined as a disease activity score <2.4 and a fall in this score from baseline by >1.2). Analysis was by intention-to-treat. One patient withdrew after randomisation and seven dropped out during the study. Mean fall in disease activity score was greater in the intensive group than in the routine group (-3.5 vs -1.9, difference 1.6 [95% CI 1.1-2.1], p<0.0001). Compared with routine care, patients treated intensively were more likely to have a good response (definition, 45/55 [82%] vs 24/55 [44%], odds ratio 5.8 [95% CI 2.4-13.9], p<0.0001) or be in remission (disease activity score <1.6; 36/55 [65%] vs 9/55 [16%], 9.7 [3.9-23.9], p<0.0001). Three patients assigned routine care and one allocated intensive management died during the study; none was judged attributable to treatment. A strategy of intensive outpatient management of rheumatoid arthritis substantially improves disease activity, radiographic disease progression, physical function, and quality of life at no additional cost.

Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: Double-blind randomised controlled trial

Article

Feb 2004
LANCET

Etanercept and methotrexate are effective in the treatment of rheumatoid arthritis but no data exist on concurrent initiation or use of the combination compared with either drug alone. We aimed to assess combination treatment with etanercept and methotrexate versus the monotherapies in patients with rheumatoid arthritis. In a double-blind, randomised, clinical efficacy, safety, and radiographic study, 686 patients with active rheumatoid arthritis were randomly allocated to treatment with etanercept 25 mg (subcutaneously twice a week), oral methotrexate (up to 20 mg every week), or the combination. Clinical response was assessed by criteria of the American College of Rheumatology (ACR). The primary efficacy endpoint was the numeric index of the ACR response (ACR-N) area under the curve (AUC) over the first 24 weeks. The primary radiographic endpoint was change from baseline to week 52 in total joint damage and was assessed with the modified Sharp score. Analysis was by intention to treat. Four patients did not receive any drug; thus 682 were studied. ACR-N AUC at 24 weeks was greater for the combination group compared with etanercept alone and methotrexate alone (18.3%-years [95% CI 17.1-19.6] vs 14.7%-years [13.5-16.0], p<0.0001, and 12.2%-years [11.0-13.4], p<0.0001; respectively). The mean difference in ACR-N AUC between combination and methotrexate alone was 6.1 (95% CI 4.5-7.8, p<0.0001) and between etanercept and methotrexate was 2.5 (0.8-4.2, p=0.0034). The combination was more efficacious than methotrexate or etanercept alone in retardation of joint damage (mean total Sharp score -0.54 [95% CI -1.00 to -0.07] vs 2.80 [1.08 to 4.51], p<0.0001, and 0.52 [-0.10 to 1.15], p=0.0006; respectively). The mean difference in total Sharp score between combination and methotrexate alone was -3.34 (95% CI -4.86 to -1.81, p<0.0001) and between etanercept and methotrexate was -27 (-3.81 to -0.74, p=0.0469). The number of patients reporting infections or adverse events was similar in all groups. The combination of etanercept and methotrexate was significantly better in reduction of disease activity, improvement of functional disability, and retardation of radiographic progression compared with methotrexate or etanercept alone. These findings bring us closer to achievement of remission and repair of structural damage in rheumatoid arthritis.

Tuberculosis following the Use of Etanercept, a Tumor Necrosis Factor Inhibitor

Article

Sep 2004
CLIN INFECT DIS

Infliximab, a tumor necrosis factor (TNF) antagonist, is associated with tuberculosis (TB), but it is unknown whether this phenomenon is true of all TNF antagonists. We reviewed 25 cases of TB due to another TNF antagonist, etanercept, that were reported to the US Food and Drug Administration (FDA) between November 1998 and March 2002. Such cases are sometimes incomplete and are subject to underreporting. Fifteen patients received other immunosuppressive medications. The median interval between the receipt of the first dose of etanercept and the diagnosis of TB was 11.5 months. Thirteen patients had extrapulmonary TB at the time of diagnosis. Diagnosis was made on the basis of culture results for 12 patients, biopsy findings for 9, and sputum staining for 4. There were 2 deaths, 1 of which was directly attributed to TB. The estimated number of TB cases reported to the FDA for each person-year of treatment with etanercept (i.e., the “reporting rate”) among patients with rheumatoid arthritis (RA) was ∼10 cases/100,000 patient-years of exposure. Clinicians considering etanercept for patients with RA should be alert to the possibility of the occurrence of TB, sometimes with an unusual extrapulmonary presentation. It is unclear whether etanercept therapy increases the risk of TB beyond the elevated TB rates already documented for patients with RA.

Effective use of the recombinant interleukin 1 receptor antagonist anakinra in therapy resistant systemic onset juvenile rheumatoid arthritis

Article

Nov 2004

Systemic onset juvenile rheumatoid arthritis (SOJRA) is a multisystem disease characterized by high fever, rash, arthritis, serositis, splenomegaly, and laboratory evidence of systemic inflammation. Anticytokine therapies show promise in the treatment of chronic arthritides in children. We describe the use of the recombinant interleukin 1 receptor antagonist anakinra in 2 patients with therapy resistant SOJRA. Both patients experienced immediate and sustained resolution of symptoms and laboratory markers of inflammation, in one case after years of treatment with other immunosuppressive therapies.

Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group: Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: A randomized, controlled trial

Article

Nov 2004

To compare the benefits of initiating treatment with methotrexate (MTX) and infliximab (anti-tumor necrosis factor alpha [anti-TNFalpha] monoclonal antibody) with those of MTX treatment alone in patients with rheumatoid arthritis (RA) of < or =3 years' duration. RA patients were eligible if they had active disease and no prior treatment with MTX or a TNFalpha inhibitor. One thousand forty-nine patients were randomly assigned in a 4:5:5 ratio to 3 treatment groups: MTX-placebo, MTX-3 mg/kg infliximab, and MTX-6 mg/kg infliximab. MTX dosages were rapidly escalated to 20 mg/week, and infliximab or placebo infusions were given at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46. At week 54, the median percentage of American College of Rheumatology improvement (ACR-N) was higher for the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than for the MTX-placebo group (38.9% and 46.7% versus 26.4%, respectively; P < 0.001 for both comparisons). Patients in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups also showed less radiographic progression than those receiving MTX alone (mean +/- SD changes in van der Heijde modification of the total Sharp score at week 54: 0.4 +/- 5.8 and 0.5 +/- 5.6 versus 3.7 +/- 9.6, respectively; P < 0.001 for each comparison). In addition, physical function improved significantly more in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than in the MTX-placebo group. Infliximab therapy was associated with a significantly higher incidence of serious infections, especially pneumonia. For patients with active RA in its early stages, combination therapy with MTX and infliximab provides greater clinical, radiographic, and functional benefits than treatment with MTX alone.

Switching between biological agents

Article

Sep 2004

Ronald van Vollenhoven

The TNF-alpha antagonists infliximab, etanercept and adalimumab have similar efficacies in clinical trials in the rheumatic diseases, and this efficacy may be related primarily to their neutralizing free TNF-alpha. Thus, a reasonable question for clinicians is whether patients who have failed one TNF-alpha antagonist could reasonably be given a trial with another such agent, or whether this is simply a waste of time and money. Several published studies have addressed this important practical issue and are reviewed in this paper. Data from the Stockholm TNF-alpha follow-up registry "STURE" that address this issue are described in detail. The overall conclusion appears to be that such switches of biologicals can be effective. Nonetheless, further attention should be paid to the details of various clinical scenarios in which this question can arise and the methods by which comparisons are made of treatment effects occurring during sequential therapies.

The Use of Biological Agents in the Treatment of Rheumatoid Arthritis

Abstract

No full-text available

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