Biologic Therapy For Rheumatoid Arthritis Research Articles

Predictors of response to biologic therapies in rheumatoid arthritis

The advent of biological therapies has revolutionized the management of rheumatoid arthritis, demonstrating effectiveness in controlling clinical and radiological damage. However, 20% to 40% of the patients will not respond to these therapies, which are associated to a very high cost. In addition, non-responder patients are exposed to possible adverse effects. For these reasons, we need to identify predictors of response to these treatments. These predictors are reviewed in this evidence-based paper and classified into genetic and nongenetic. Despite extensive search, nowadays there are no predictors powerful enough to be used in regular clinical practice. Serum factors, the presence of rheumatoid factor and anti-cyclic citrullinated peptide antibodies, are the only factors currently being used to predict the response to specific biological therapy. In the future, probably thanks to new technologies based on genomics, transcriptomics and proteomics, it will be possible to identify genetic predictors of response to biological drugs that will allow us to select suitable patients for a specific biological therapy.

Applying science in practice: the optimization of biological therapy in rheumatoid arthritis

Most authorities recommend starting biological agents upon failure of at least one disease-modifying agent in patients with rheumatoid arthritis. However, owing to the absence of head-to-head studies, there is little guidance about which biological to select. Still, the practicing clinician has to decide. This review explores the application of published evidence to practice, discussing the goals of treatment, the (in) ability to predict individual responses to therapy, and the potential value of indirect comparisons. We suggest that cycling of biological agents, until remission is achieved or until the most effective agent for that individual patient is determined, deserves consideration in the current stage of knowledge.

Analysis of biologic therapy in rheumatoid arthritis in a southern Spanish hospital population

Material and methods We have reviewed all RA patients treated with biologicals from 1998 to January 2010. We include all patients with at least 6 months of follow up and analyze clinical efficacy as improvement in DAS count. We registered the cause for switch among biologic drugs and the response to a new biologic. Our hospital attends about 350.000 inhabitants and the prevalence of RA in Spain, as settled by Spanish Society for Rheumatology is 0.5%, so we could expect to have about 1800 RA patients, so we are treating about 12% of RA patients with biologicals.

The Japanese experience with biologic therapies for rheumatoid arthritis

The unique genetic, environmental and medical backgrounds of people in Japan might influence the effectiveness and safety of biologic agents in patients with rheumatoid arthritis (RA). Indeed, clinical trials revealed higher response rates to some biologic agents (including infliximab, etanercept and tocilizumab) in patients with RA in Japan than patients treated with the same agents in Western countries, although response rates to adalimumab were comparable in both populations. The reasons why response rates to some biologic agents differ in Japanese individuals is currently under investigation. Post-marketing surveillance data have been collected for all patients with RA who were treated with biologic agents in Japan to monitor drug safety. These data clearly demonstrated that only ∼5% of these patients experienced adverse drug reactions to biologic agents, which were well tolerated. Pneumonia, tuberculosis, Pneumocystis jirovecii pneumonia and interstitial pneumonitis are considered important severe adverse reactions and risk factors for these adverse effects have been identified. Adverse drug reactions could exaggerate the risks associated with biologic therapy in Japanese patients with RA. Attempts have, therefore, been made to predict clinical response and adverse effects to enable personalized therapy with biologic agents and to optimize the outcomes of these patients.

A Genetic Association Study of Serum Acute-Phase C-Reactive Protein Levels in Rheumatoid Arthritis: Implications for Clinical Interpretation

The acute-phase increase in serum C-reactive protein (CRP) is used to diagnose and monitor infectious and inflammatory diseases. Little is known about the influence of genetics on acute-phase CRP, particularly in patients with chronic inflammation. We studied two independent sets of patients with chronic inflammation due to rheumatoid arthritis (total 695 patients). A tagSNP approach captured common variation at the CRP locus and the relationship between genotype and serum CRP was explored by linear modelling. Erythrocyte sedimentation rate (ESR) was incorporated as an independent marker of inflammation to adjust for the varying levels of inflammatory disease activity between patients. Common genetic variants at the CRP locus were associated with acute-phase serum CRP (for the most associated haplotype: p = 0.002, p<0.0005, p<0.0005 in patient sets 1, 2, and the combined sets, respectively), translating into an approximately 3.5-fold change in expected serum CRP concentrations between carriers of two common CRP haplotypes. For example, when ESR = 50 mm/h the expected geometric mean CRP (95% confidence interval) concentration was 43.1 mg/l (32.1-50.0) for haplotype 1 and 14.2 mg/l (9.5-23.2) for haplotype 4. Our findings raise questions about the interpretation of acute-phase serum CRP. In particular, failure to take into account the potential for genetic effects may result in the inappropriate reassurance or suboptimal treatment of patients simply because they carry low-CRP-associated genetic variants. CRP is increasingly being incorporated into clinical algorithms to compare disease activity between patients and to predict future clinical events: our findings impact on the use of these algorithms. For example, where access to effective, but expensive, biological therapies in rheumatoid arthritis is rationed on the basis of a DAS28-CRP clinical activity score, then two patients with identical underlying disease severity could be given, or denied, treatment on the basis of CRP genotype alone. The accuracy and utility of these algorithms might be improved by using a genetically adjusted CRP measurement.

Pharmacogénomique et traitement de la polyarthrite rhumatoïde

The development of biological therapies in rheumatoid arthritis leads to develop methods to predict individual response to a given disease modifying anti-rheumatic drug (DMARD). Pharmacogenomics is able to give a part of the answer, with the study of inherited predispositions that influence interindividual variabilities of responses to drugs. The gene polymorphisms that influence metabolic enzymes in the cellular pathway of methotrexate have been intensely studied. The most important studied gene codes for methylenetetrahydrofolate reductase (MTHFR), a very important enzyme of the regeneration of reduced folate. This enzyme is inhibited by methotrexate. The search of predictors of response to biological drugs is another field of the pharmacogenomics in rheumatology. The polymorphism of both TNF gene and immunoglobuline Fc receptors has been studied in patients treated with biologicals. The associations between a single gene and the response to the drugs are not pertinent. The future orientations for pharmacogenomics will concern association between several known genetics polymorphism in a same patient or genome wide association scan studies. Knowledge in pharmacogenomics will lead to the development of new strategies of treatment in rheumatic diseases.

Cost-effectiveness treatment with Rituximab in patients with rheumatoid arthritis in real life

The cost-effectiveness of treatments that have the potential to change the "natural history" of a chronic progressive disease has to be evaluated over the long term. Cost-effectiveness estimates have been based on the concept that, with treatment, patients will not progress to the next level(s) of disease severity or will take a longer time to progress, thus avoiding or delaying the high costs and low utility associated with more severe disease. This analysis focused on the use of Rituximab in treating patients with moderate to severe RA for whom at least one anti-TNFα blocking agent had failed. The aim of our study was to evaluate the cost-effectiveness in 32 patients with rheumatoid arthritis in therapy with a single infusion of Rituximab 1,000 mg given on days 1 and 15 of each month for 1 year. After 6 months of treatment, we observed for all 32 patients a total quality-adjusted life year (QALY) gained of 11,840 with an average of 0.37 QALY for a single patient, a treatment cost of euro 5,610 and a QALY/cost ICER (incremental cost-effectiveness ratio) of euro 15,114. After 1 year of treatment, we observed data for 28 patients with a total QALY gained of 11,480 with an average of 0.41 QALY for a single patient, a treatment cost of euro 9,690 and a QALY/cost ICER (incremental cost-effectiveness ratio) of euro 23,696. The benefit of using Rituximab is cost-effectiveness with a QALY/gained under the acceptable threshold of euro 50,000 in our observational study. These are important data for discussion from the economic point of view when we choose a biologic therapy for rheumatoid arthritis in clinical practice.

Etanercept can induce resolution of renal deterioration in patients with amyloid A amyloidosis secondary to rheumatoid arthritis

The benefit of biological therapies in rheumatoid arthritis (RA) treatment is well known, but their role in amyloid A (AA) amyloidosis secondary to RA is unclear. The aim of this study was to clarify the clinical benefit of etanercept in RA patients with AA amyloidosis. We treated 14 RA patients who had serum amyloid A protein (SAA) 1.3 allele, with biopsy-confirmed AA amyloidosis with etanercept and investigated the efficacy of etanercept treatment, focusing on renal function retrospectively. The AA amyloidosis improved and stabilized after 89.1 ± 27.2 weeks. Proteinuria decreased from 2.24 ± 0.81 to 0.57 ± 0.41 g/day (P < 0.01) and SAA fell from 250 ± 129 to 26 ± 15 μg/ml (P < 0.01), respectively. Diarrhea secondary to gastrointestinal AA amyloidosis was less. Overall, the serum creatinine levels did not benefit with treatment, but in those with a creatinine values <2.0 mg/dl the creatinine level continued to fall (P = 0.021). Serum albumin increased following 96 weeks of etanercept treatment (P = 0.003). Etanercept treatment led to clinical improvement in proteinuria and serum albumin levels accompanied by a fall in SAA levels.

Sequential use of biologic therapy in rheumatoid arthritis

With an increasing range of biological therapies available in the management of rheumatoid arthritis, sequencing of such therapies is becoming more frequent, particularly with more ambitious treatment aims. This review will address the evidence to date on use of successive targeted agents. Double-blind, randomized controlled trials have confirmed the role of alternative tumour necrosis factor (TNF) inhibitors (TNFi), rituximab, abatacept and tocilizumab, following TNFi failure with no comparative studies to date. Registry data have demonstrated efficacy of switching from a first to a second TNFi. Observational experience has confirmed benefits of switching from TNFi to TNFi and TNFi to rituximab. Within available randomized controlled trial data, tocilizumab appears effective in TNFi failure group, irrespective of number of TNFi previously failed. Such data are not available for the other agents. No safety signals have been identified thus far with biologic sequencing. Although formal comparative, controlled studies do not exist, type of previous failure to TNFi and disease characteristics (serology, comorbidity, concomitant therapy) can provide a good platform for choosing the next biologic treatment. Although biological sequencing is well established, optimal approach represents a significant knowledge gap; well designed clinical studies with associated mechanistic investigation are necessary to identify disease subgroups that would benefit from one sequence over another.

The Axis of Thrombospondin-1, Transforming Growth Factor Beta and Connective Tissue Growth Factor: An Emerging Therapeutic Target in Rheumatoid Arthritis

Biologic therapy for rheumatoid arthritis (RA) targets specific molecules that mediate and sustain the clinical manifestations of this complex illness. Compared with the general population, patients with RA die prematurely, in part due to associated cardiovascular disease. Even though the mechanisms by which premature atherosclerosis develops in RA is unknown, chronic inflammation may play a major role. This review connects current knowledge of the pathophysiology of RA with data available in the literature related to thrombospondin-1 (TSP1), transforming growth factor beta (TGFbeta and connective tissue growth factor (CTGF) and their relationship with cardiovascular disease in RA. The TSP1/TGFbeta/CTGF axis may contribute in the pro-inflammatory and pro-atherogenic state in patients affected with RA. In fact, increased TSP1 plasma levels are found in patients of RA. TGFbeta is activated by TSP1 through a non-enzymatic mechanism and is constitutively overexpressed by synovial fibroblasts from RA patients. Activation of TGFbeta pathway in synovial fibroblasts and other cells including neutrophils leads to downstream upregulation of CTGF. Overexpression of CTGF is associated with angiogenesis, fibrosis, atherosclerotic blood vessels and erosive arthritis lesions. Recent RA therapies emphasize the need for aggressive control of the activity of the disease to prevent premature atherosclerosis in RA patients. The complexity and heterogeneity of RA as judged by response to a wide spectrum of treatments mandates the elucidation of unknown pro-inflammatory pathways playing a major role in this disease. The TSP1/TGFbeta/CTFG axis represents one of these pro-inflammatory pathways that may result in the development of promising therapeutic strategies to prevent chronic inflammation and thus premature atherosclerosis in RA.

The history of erosions in rheumatoid arthritis: Are erosions history?

Small joint periarticular erosions have occupied center stage in the understanding of the pathogenesis of rheumatoid arthritis (RA) for well over 50 years (1). Such erosions have diagnostic and prognostic significance and have served as a valuable outcome measure in the evaluation of therapeutic responses to drugs for disease (2). The RA erosion paradigm extends well beyond these immediately clinically relevant issues. An understanding of the proinflammatory milieu at the cartilage–pannus junction, the putative site where erosion formation was thought to be initiated, was considered to represent a key event toward the development of biologic therapies in RA (3). Ongoing efforts seek to link the immunopathogenetic basis for erosion formation to emergent genome-wide association studies to further elucidate the basis for joint disease in RA. The importance of erosions in the immunopathogenesis of RA is almost dwarfed by the importance that their early detection has assumed. Erosions represent 1 of the 3 diagnostic criteria for RA when combined with clinical and serologic parameters (2). With the advent of more sophisticated imaging techniques, most notably, magnetic resonance imaging (MRI) and ultrasound (US), rheumatologists are increasingly interested in detecting these seemingly diagnostic and prognostic features in early RA to facilitate a definitive diagnosis and to initiate the most appropriate therapy, at the earliest possible opportunity. Why this is the case and why it merits reconsideration based on work reported by Stach et al in this issue of Arthritis & Rheumatism (4) and based on other recent data are the subjects of this perspective. History of erosion immunopathogenesis

Tocilizumab: a review of its safety and efficacy in rheumatoid arthritis.

Recent years have seen many exciting developments in the treatment of rheumatoid arthritis. Tocilizumab (TCZ) is a monoclonal antibody which inhibits the interleukin-6 receptor. After initial studies in Japan, it has been extensively studied in five multicentre clinical trials. This report summarises the key efficacy and toxicity findings from the major clinical trials. TCZ works quickly and effectively in rheumatoid arthritis either as monotherapy or in combination with other agents in early disease, DMARD inadequate responders, seronegative disease and after anti-TNF failure. The toxicity profile is manageable but includes infections (most notably skin and soft tissue), increases in serum cholesterol, transient decreases in neutrophil count and abnormal liver function tests (especially in combination with methotrexate). In summary, there is sufficient evidence to make TCZ a first line biologic therapy for rheumatoid arthritis especially for those who are unable to take methotrexate or who fail anti-TNF therapy.

Update of the Consensus Statement of the Spanish Society of Rheumatology on the management of biologic therapies in rheumatoid arthritis

ObjectiveTo provide a reference to rheumatologists and to those involved in the treatment of RA who are using, or about to use biologic therapy. MethodsRecommendations were developed following a nominal group methodology and based on systematic reviews. The level of evidence and grade of recommendation were classified according to the model proposed by the Center for Evidence Based Medicine at Oxford. The level of agreement was established through Delphi technique. ResultsWe have produced recommendations on the use of the seven biologic agents available for RA in our country. The objective of treatment is to achieve the remission of the disease as quickly as possible. Indications and nuances regarding the use of biologic therapy were reviewed as well as the evaluation that should be performed prior to administration and the follow up of patients undergoing this therapy. ConclusionsWe present an update on the SER recommendations for the use of biologic therapy in patients with RA.

Safety of biologic agents after rituximab therapy in patients with rheumatoid arthritis

The safety of other biologic therapies in rheumatoid arthritis (RA) following B cell-depletion therapy with rituximab has not been established. This retrospective chart review of patients attending an outpatient rheumatology clinic aimed to assess the incidence of adverse events in patients receiving biologic agents to treat RA after an inadequate response or intolerance to rituximab. The charts of 22 patients (18 female; mean age 59 years) were reviewed. Duration of RA was >2 years. Before rituximab, patients had failed one (n = 10), two (n = 4) or three (n = 7) biologic therapies: 1 patient started on rituximab as a first-line biologic. Eighteen patients stopped rituximab due to an inadequate clinical response, while four patients stopped due to adverse events. The mean time to starting a new biologic after rituximab was 4 months, although five patients were started within 1 month of the last rituximab infusion. Abatacept (41%) was the most common biologic used after rituximab. The mean follow-up time from the last rituximab infusion was 14 months. Adverse events occurring after rituximab therapy, but before initiation of a new biologic, included disseminated herpes zoster and aseptic meningitis (both required hospitalization). Adverse events recorded after starting a new biologic post-rituximab included rash, carbuncle, upper respiratory tract infection, urinary tract infection, pneumonia, and eczema, but none was classified as serious. Most of these events occurred in patients receiving abatacept. In conclusion, in this retrospective analysis, no serious adverse events were recorded in patients who received biologic agents following rituximab therapy.

The Economic Burden of Biological Therapy in Rheumatoid Arthritis in Clinical Practice: Cost-Effectiveness Analysis of Sub-Cutaneous Anti-TNFα Treatment in Italian Patients

Rheumatoid arthritis (RA), with a prevalence of 0.46%, is found in about 272,004 patients in Italy. The socioeconomic cost of rheumatoid arthritis in Italy in 2002 has been estimated at Euro 1,600 million. Cost-effectiveness evaluations have been based on the concept that, with treatment, patients will not progress to the next level(s) of disease severity or will take a longer time to progress, thus avoiding or delaying the high costs and low utility associated with more severe disease. Many cost-effective studies have been based on the variation of Health Assessment Questionnaire (HAQ) in clinical trials. The objective of this study is to perform a cost-effective analysis of 86 patients with rheumatoid arthritis in therapy with adalimumab 40 mg every other week and etanercept 50 mg/week for two years in a population of patients observed in clinical practice. The group of patients in therapy with adalimumab had also taken methotrexate, mean dose 12.4+/-2.5 mg/week (22 patients) or leflunomide 20 mg/day (16 patients). The group of patients in therapy with etanercept had also taken methotrexate, mean dose 11.7+/-2.6 mg/week (24 patients) or leflunomide 20 mg/day (24 patients). Incremental costs and QALYs (quality adjusted life years) gains are calculated compared with baseline, assuming that without biologic treatment patients would remain at the baseline level through the year. Conversion HAQ scores to utility were based on the Bansback algorithm. The results after two years showed: in the group methotrexate+adalimumab the QALY gained was 0.62+/-0.15 with a treatment cost of Euro 26,517.62 and a QALY/cost of Euro 42,521.13. In the group methotrexate + etanercept the QALY gained was 0.64+/-0.26 with a treatment cost of Euro 25,020.96 and a QALY/cost of Euro 39,171.76. The result of using etanercept in association with methotrexate is cost-effectiveness with a QALY gained under the acceptable threshold of Euro 50,000. These are important data for discussion from an economic point of view when we choose a biologic therapy for rheumatoid arthritis in clinical practice.

Systemic lupus erythematosus clinical trials—an interim analysis

Since the current standards for drug approval were established nearly half a century ago, no drug has been approved for the treatment of systemic lupus erythematosus (SLE). Despite this sobering history, interest in drug development for SLE has heightened in the past few years. This enthusiasm has been fueled in large part by the success of biologic therapy for rheumatoid arthritis and other autoimmune diseases. Unfortunately, despite considerable clinical trial activity, this interest has not yet translated into the discovery of an effective treatment for SLE. This article provides an analysis of the major clinical trials in SLE, and offers an interpretation of the results that could illuminate the path forward.

Biologic Therapy for Rheumatoid Arthritis

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

Synovial tissue and serum biomarkers of disease activity, therapeutic response and radiographic progression: analysis of a proof-of-concept randomised clinical trial of cytokine blockade

ObjectivesTo evaluate synovial tissue and serum biomarkers of disease activity, therapeutic response and radiographic progression during biological therapy for rheumatoid arthritis (RA).MethodsPatients with active RA entered a randomised study of...

Screening of tuberculosis by interferon-γ assay before biologic therapy for rheumatoid arthritis

Infection with Mycobacterium tuberculosis (M. tuberculosis) is a critical complication in anti-TNF therapies. In 141 BCG vaccinated healthy individuals and 71 rheumatoid arthritis (RA) patients as screening before anti-TNF therapies, M. tuberculosis specific immune responses were evaluated by tuberculin skin test (TST) and enzyme-linked immunospot assay (ELISPOT), which detected antigen specific IFN-gamma secreting cells in peripheral blood mononuclear cells simulated with either purified protein derivative (PPD), early secretory antigen target 6 (ESAT-6) or culture filtrate protein 10 (CFP-10). Induration over 5 mm in TST was found in 87.9% of controls and 21.4% of RA patients. Erythema size in TST was significantly suppressed in RA patients, especially those receiving prednisolone (PSL), whereas the PPD specific IFN-gamma secretion was less attenuated. Significant responses to either ESAT-6 or CFP-10 in ELISPOT were detected in 14.1% of RA patients including those having positive TST, while the ELISPOT assay was negative in all healthy individuals and 73.3% of RA patients having positive TST. Of ELISPOT positive RA patients, mean dosage of PSL was 4.58 mg and 1.25 mg in TST negative and positive patients, respectively. Thus, ELISPOT is useful for screening of tuberculosis in RA patients, even in those receiving corticosteroids.

Anakinra for rheumatoid arthritis

In the past decade, a novel class of therapies directed against specific cytokines implicated in the disease process of rheumatoid arthritis (RA), called the 'Biologics' have greatly improved and expanded treatment for RA. Anakinra is an interleukin-1 receptor antagonist that is currently FDA-approved for moderate-severe RA that has been unresponsive to initial disease-modifying anti-rheumatic drugs (DMARD) therapy. To evaluate the clinical effectiveness and safety of anakinra in adult patients with rheumatoid arthritis. We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2008), MEDLINE (1950 to Week 4 2008) , EMBASE (1980 to Week 5 2008), CINAHL (1982 to November 2007) and reference lists of articles. Randomized controlled trials comparing anakinra alone or in combination with DMARDs or biologics to placebo or other DMARDs or biologics in patients >18 years old with rheumatoid arthritis. Two review authors independently assessed trial quality and extracted data. We contacted study authors for additional information. Five trials involving 2876 patients, 781 randomized to placebo and 2065 to anakinra, were included. There was a significant improvement in number of participants achieving ACR20 (38% versus 23%) who were treated with anakinra 50 to 150 mg daily versus placebo after 24 weeks. This 15% increase in patients achieving ACR20 with anakinra versus placebo is felt to be a clinically meaningful, though modest, outcome. Other efficacy data - including ACR50 (18% versus 7%), ACR70 (7% versus 2%), HAQ, visual analog score (VAS), Larsen radiographic scores, and change in erythrocyte sedimentation rate (ESR) - all demonstrated significant improvement with anakinra 50 to 150 mg daily versus placebo as well. There were no statistically significant differences noted in most safety outcomes with treatment with anakinra versus placebo - including number of withdrawals, deaths, adverse events (total and serious), and infections (total and serious). Injection site reactions were significantly increased, occurring in 1235/1729 (71%) versus 204/729 (28%) of patients treated with anakinra versus placebo, respectively. The incidence of serious infections was clinically higher, but not statistically different, in the anakinra (25/1366 patients, 1.8%) versus placebo group (3/534 patients, 0.6%). Anakinra is a relatively safe and modestly efficacious biologic therapy for rheumatoid arthritis. Although head to head comparison trials have not been carried out, the amount of improvement is notably less when compared to studies using other biologic therapies. More studies are needed to evaluate safety and efficacy, especially in comparison to other therapies, and adverse event data for the long-term use of Anakinra has yet to be assessed.