anti-TNF Therapy For Rheumatoid Arthritis Research Articles

PMS13 Economic Model of Workplace Impacts of anti-Tnf therapy for Rheumatoid Arthritis in Brazil

PMS13 Economic Model of Workplace Impacts of anti-Tnf therapy for Rheumatoid Arthritis in Brazil

Role of Anti-Tumor Necrosis Factor-α Blockers in Inducing Lupus Erythematosus Tumidus in “Rhupus Syndrome”

To the Editor: We read with interest the case report by Soforo, et al 1 and thoughtful accompanying editorial by Jacob and Jacob2 on anti-tumor necrosis factor (TNF)-induced systemic lupus erythematosus (SLE). They suggest that TNF is proinflammatory in certain disorders and blockade is therapeutically useful, whereas in other disorders, like SLE, it has an immune regulatory role, and blockade can be detrimental2. Anti-TNF treatments are known to induce autoantibodies, particularly antinuclear antibodies (ANA). Hence it is important to check for ANA before initiating anti-TNF treatments. Jacob and Jacob2 have advanced the discussion by mentioning the influence of HLA class II genotype on TNF inducibility. Caucasians possessing HLA-DR3/DR4 have higher levels of TNF in response to activation as compared with subjects who are DR2/DQW1-positive (mostly non-Caucasians) who have lower TNF inducibility3. We describe a patient that developed a rare variant of cutaneous lupus erythematosus several years after anti-TNF therapy for rheumatoid arthritis (RA). Our case reveals the importance of HLA class II genotyping assessment. A 58-year-old woman with a 12-year history of seropositive RA experienced disease progression despite use of triple disease modifying antirheumatic drugs (DMARD) hydroxychloroquine, sulfasalazine, and methotrexate (MTX). In April 2000, she was recruited into a phase IIIB drug trial to assess efficacy and safety of etanercept in RA in a different hospital. She received 177 injections of etanercept 25 mg twice weekly up to November 2001 … Address correspondence to Dr. Chogle; E-mail: archogle{at}vsnl.net

Anti-TNF therapy: what have we learned in 12 years?

Two decades ago, the available treatment options were not effective for many persons with rheumatoid arthritis (RA) and other inflammatory rheumatic diseases. At this time RA patients had a significantly decreased life expectancy due to a relatively incontrolled inflammatory activity of RA combined with an increased incidence of comorbidities and severe treatment-related side effects. After 5 years of disease duration, a considerable percentage of patients became unemployed. The available disease-modifying antirheumatic drugs were able to slow disease progression, but they could not stop it. This unsatisfying situation changed significantly at the beginning of the 1990s, when treatment options for RA patients expanded to include TNF blockers. These blockers were shown to significantly decrease not only the inflammatory activity of RA, but also the radiographic progression. This breakthrough in therapeutic options was fostered by the pioneering research of Prof. Sir Ravinder Maini and Prof. Sir Marc Feldman working at the Kennedy Institute in London, who introduced a chimeric monoclonal antibody against TNFα in the treatment of RA patients. Since these early clinical trials, TNF inhibitors have radically changed the entire therapeutic approach, not only for RA but also for ankylosing spondylitis (AS) and for psoriatic arthritis (PsA). While the focus once was symptom mitigation, rheumatologists now seek control of disease progression. Today, TNF inhibitors effectively suppress and control the inflammation driving these diseases, and thereby prevent irreversible tissue damage and disability. Radiographic studies are showing that progressive joint damage can be halted under certain conditions in some patients. These conditions and patients are currently being elucidated. New frontiers include early diagnosis and referral; optimizing treatment regimens; identifying patients at risk of rapidly progressing disease; and instituting early, rapid TNF blockade in these patients. Using combination therapy with TNF inhibitors and disease-modifying antirheumatic drugs – specifically methotrexate – at an early stage of RA, disease progression can be stopped or at least significantly retarded. The four articles in this supplement present up-to-date information, current data, and the best thinking on anti-TNF therapy in RA, AS, and PsA. Since research over the past decade revealed that these three disorders share an inflammatory mechanism fueled especially by TNF, efforts to produce viable TNF inhibitors have accelerated. Josef S Smolen and Paul Emery, in their article ‘Infliximab: 12 Years of Experience’, expound upon the record of efficacy and safety amassed for this TNF inhibitor. Research on infliximab, which began with the first randomized controlled study in a rheumatic disease, stimulated most of the development of TNF neutralizing therapies. The authors summarize the major trials in RA, AS, and PsA that contributed to this body of evidence. In the second article, ‘Understanding Emerging Treatment Paradigms in Rheumatoid Arthritis’, Ferdinand C Breedveld and Bernard Combe assert that most patients with RA are undertreated. They outline accumulating data showing that intensive treatment in the early stages of RA can slow or stop disease progression, and they describe alternatives to traditional step-up approaches and to sequential monotherapy with disease-modifying antirheumatic drugs. Next, Georg Schett and colleagues focus on bone and cartilage injury in all three diseases, with an emphasis on key knowledge arising from TNF research and how it has paved the way for future advances. Their article, ‘Structural Damage in Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis: Traditional Views, Novel Insights Gained from TNF Blockade, and Concepts for the Future’, explores the different pathologies as well as radiographic data for the interaction between inflammation and structural progression. Lastly, Paul P Tak and I discuss innovative approaches – with TNF inhibitors but also with other biologic agents – to inflammatory arthritides, including new targets within the inflammatory cascade, agents designed to affect associated pathways, and improved management strategies involving early diagnosis and referral. In the article ‘Advances in Rheumatology: New Targeted Therapeutics’, we explore the variable response to targeted therapy and consider how best to integrate these advanced therapies into daily practice. Our goal with the present supplement is to provide a valuable, current resource from which additional dialog may spring. We all agree that optimal treatment, initiated sooner, may reduce costs and risks to patients, and therefore achieve our common ambition – to help the patient and to attain low disease activity or remission in persons with inflammatory arthritis.

Genome‐wide association study of genetic predictors of anti–tumor necrosis factor treatment efficacy in rheumatoid arthritis identifies associations with polymorphisms at seven loci

ObjectiveAnti–tumor necrosis factor (anti-TNF) agents are successful therapies in rheumatoid arthritis (RA); however, inadequate response occurs in 30–40% of patients treated. Knowledge of the genetic factors that influence response may facilitate personalized therapy. The purpose of this study was to identify genetic predictors of response to anti-TNF therapy in RA and to validate our findings in independent cohorts.MethodsData from genome-wide association (GWA) studies were available from the Wellcome Trust Case Control Consortium for 566 anti-TNF–treated RA patients. Multivariate linear regression analysis of changes in the Disease Activity Score in 28 joints at 6 months was conducted at each single-nucleotide polymorphism (SNP) using an additive model. Associated markers (P < 10−3) were genotyped in 2 independent replication cohorts (n = 379 and n = 341), and a combined analysis was performed.ResultsOf 171 successfully genotyped markers demonstrating association with treatment response in the GWA data, 7 were corroborated in the combined analysis. The strongest effect was at rs17301249, mapping to the EYA4 gene on chromosome 6: the minor allele conferred improved response to treatment (coefficient −0.27, P = 5.67−05). The minor allele of rs1532269, mapping to the PDZD2 gene, was associated with a reduced treatment response (coefficient 0.20, P = 7.37−04). The remaining associated SNPs mapped to intergenic regions on chromosomes 1, 4, 11, and 12.ConclusionUsing a genome-wide strategy, we have identified and validated the association of 7 genetic loci with response to anti-TNF treatment in RA. Additional confirmation of these findings in further cohorts will be required.

PTPRC mutation associated with response to anti-TNF therapy in rheumatoid arthritis

Genetics: PTPRC mutation associated with response to anti-TNF therapy in rheumatoid arthritis

Etanercept-induced anti-Jo-1-antibody-positive polymyositis in a patient with rheumatoid arthritis: a case report and review of the literature

Antitumor necrosis factor (TNF) therapy has been associated with adverse immunologic events including systemic lupus erythematosus. However, the development of polymyositis (PM)/dermatomyositis (DM) associated with anti-TNF therapy is extremely rare. We experienced a case of a 48-year-old female with rheumatoid arthritis (RA) who had anti-Jo-1 antibodies and interstitial lung disease but no previous history of PM/DM and who developed PM soon after the initiation of etanercept (ETN) therapy for RA. The patient recovered upon withdrawal from ETN and corticosteroid (CS) therapies. Only four reports of PM/DM associated with anti-TNF therapy for RA could be found in the literature. The patients described in three of the four reports were positive for anti-Jo-1 antibodies before the initiation of anti-TNF therapy, and in all the cases, recovery occurred after the cessation of anti-TNF-agent administration and CS therapy. These results suggest a relationship between the onset of PM/DM with anti-Jo-1 antibody and anti-TNF therapy for RA.

An acutely erythematous, oedematous penis and antecubital fossae rash in a patient taking etanercept: a case report

IntroductionAcute erythema and oedema of the genitalia is an alarming complaint for any patient. Diagnosis can be complicated by atypical presentation and the use of concurrent immuno-modulatory drugs.Case presentationWe present a case report of a man on anti-TNF therapy for rheumatoid arthritis presenting with an acutely red, swollen, non-tender penis and scrotum presumed to be infective. The discovery of erythematous plaques in both antecubital fossae alerted the clinicians to consider alternative dermatological diagnoses.ConclusionThe accepted adjuncts to confirming or excluding infectious aetiology were complicated by the use of immuno-modulatory medication in this case. This patient's unusual presentation may have been associated with and was complicated by the use of etanercept. The case illustrates the need to consider other diagnoses and obtain appropriate advice when the clinical course is not progressing as anticipated.

Employer Model of Workplace Impacts of Anti-TNF Therapy for Rheumatoid Arthritis

Rheumatoid arthritis (RA) greatly affects patients' abilities to perform work, which can translate into substantial employer costs. We developed a customizable model that allows employers to calculate workplace impacts of RA therapies in employees with RA. Costs of medical leave (absenteeism)/disability, reduced productivity, job turnover, and work-equipment adaptations for employees with RA were calculated. Costs of the tumor necrosis factor antagonist adalimumab were compared with those of other RA treatments. Default parameters were based on literature, clinical trials, government sources, and employers' data. Annual per-employee workplace cost was $9071 for adalimumab versus $16,335 for other RA therapies. Costs included reduced productivity (57%), absenteeism/disability (21%), and job turnover (21%). RA imposes a large financial burden on employers, predominantly owing to lost productivity. When compared with other RA therapies, adalimumab substantially reduced employers' costs.

Workplace impacts of anti-TNF therapies in rheumatoid arthritis: review of the literature

Background: Rheumatoid arthritis (RA) causes pain and serious functional impacts and substantially affects patients' daily lives, including their ability to work. Objective: This review examines recent studies of patients with RA treated with TNF antagonists and the impacts these therapies have on the workplace. Methods: A total of 133 articles and 14 poster abstracts were reviewed that matched specific criteria. Results/conclusion: The results of early studies of TNF antagonists varied regarding their effects on patients with RA in the workplace. However, recent studies of adalimumab showed positive impacts across a range of workplace burdens. Treatments such as adalimumab may help employees with RA to remain in the workforce and lead to reduced workplace costs to the employers and employees.

Pericardial effusions on anti-TNF therapy for rheumatoid arthritis--a drug side effect or uncontrolled systemic disease?

Pericardial effusions on anti-TNF therapy for rheumatoid arthritis--a drug side effect or uncontrolled systemic disease?

Power doppler ultrasonographic monitoring of response to anti–tumor necrosis factor therapy in patients with rheumatoid arthritis

To evaluate the validity, responsiveness, and predictive value of power Doppler ultrasonography (PDUS) monitoring of response to tumor necrosis factor (TNF) blocking agents in rheumatoid arthritis (RA). Three hundred sixty-seven RA patients were prospectively recruited at 25 Spanish centers; complete clinical, laboratory, and PDUS data were obtained on 278 patients. The patients underwent clinical, laboratory, and PDUS assessment at baseline and after 1, 3, 6, and 12 months of anti-TNF treatment, and radiographic assessment of the hands and feet at baseline and 12 months. The Disease Activity Score in 28 joints (DAS28) was recorded at each visit. PDUS examination included 86 intraarticular and periarticular sites in 28 joints. US synovial fluid (SF), synovial hypertrophy (SH), and PD signal were scored in all synovial sites. US count and index for SF, SH, and PD signal were obtained. Sensitivity to change of the PDUS variables was assessed by estimating the smallest detectable difference (SDD) from the intraobserver variability. A significant parallel improvement in DAS28 and PDUS parameters was found at followup assessment (P < 0.0005 for within-subject between-visit changes). The SDD for PDUS parameters was lower than the mean changes throughout followup. Time-integrated values of US joint count for PD signal and rheumatoid factor (RF) showed predictive value in relation to progression of radiographic erosion (R = 0.64), and time-integrated values of US joint count for PD signal, RF, and erythrocyte sedimentation rate were predictors of progression of the total radiographic score (R = 0.59). These findings indicate that PDUS is a valid method for monitoring response to anti-TNF therapy in RA; results obtained by PDUS are reproducible and sensitive to change. PDUS findings may have predictive value in relation to radiologic outcome.

Treatment of Inflammatory Immunologic Disease 3. Anti-TNF Therapy in Rheumatoid Arthritis

Treatment of Inflammatory Immunologic Disease 3. Anti-TNF Therapy in Rheumatoid Arthritis

Association of TNF-alpha –308 G/A polymorphism with responsiveness to TNF-α-blockers in rheumatoid arthritis: a meta-analysis

Tumor necrosis factor (TNF) antagonists are among the most effective therapies for rheumatoid arthritis (RA), yet not all patients show a response. Using meta-analysis, this present study was designed to investigate whether or not the TNF-alpha promoter -308 A/G polymorphism is associated with responsiveness to anti-TNF therapy in RA patients. We performed an exhaustive search for studies that examined the association of the TNF-alpha promoter -308 A/G polymorphism and responsiveness of anti-TNF therapy in RA using MEDLINE citations and manual review. Meta-analysis was performed for A allele carrier (genotypes A/A + A/G) between responders to anti-TNF therapy and a non-responder group in a random effects model. A total of 6 studies met the inclusion criteria. The number of patients in individual studies ranged from 33 to 123. There were 311 RA patients who were included in this meta-analysis. There was no heterogeneity between studies (I (2) = 0%, P = 0.42). The overall OR for the A allele carrier status was significantly decreased in the responder group (OR = 0.33, 95% confidence interval = 0.17-0.63, P = 0.0008). The frequency of the A allele carrier was 53/240 (22.1%) in responders and 32/71 (45.1%) in non-responders. Patients not responding to anti-TNF therapy showed an increased frequency of the A allele. The meta-analysis of the available data shows a significant association between the TNF-alpha promoter -308 A/G polymorphism and responsiveness to anti-TNF therapy, suggesting that the individuals with RA who carry the A allele have a poorer response to anti-TNF therapy than those with the G allele.

Smoldering and polarized inflammation in the initiation and promotion of malignant disease

Smoldering and polarized inflammation in the initiation and promotion of malignant disease

Anti-tumor necrosis factor agents for rheumatoid arthritis in the setting of chronic hepatitis C infection.

To examine the safety of using anti-tumor necrosis factor (TNF) therapy in patients with rheumatoid arthritis (RA) in the setting of hepatitis C virus (HCV) infection. The charts of 5 patients known to have RA requiring anti-TNF therapy as well as established HCV infection were reviewed retrospectively for laboratory data of hepatic parenchymal inflammation and viral proliferation while taking these agents. In a mean +/- SD followup period of 41 months (+/- 28.2 months), no patient displayed evidence of sustained elevation of serum aminotransferases during therapy with anti-TNF. Additionally, 1 patient was observed to have a decreased HCV viral load after extended treatment with only anti-TNF (no therapy for HCV). Anti-TNF therapy for RA in the setting of HCV appears to be safe and well tolerated without apparent influence on the underlying HCV infection. Therefore, this approach should be further evaluated prospectively for longterm safety.

Patients' perceptions of treatment with anti-TNF therapy for rheumatoid arthritis: a qualitative study.

Anti-tumour necrosis factor (anti-TNF) therapy is a highly effective treatment for rheumatoid arthritis (RA), as documented using standard outcome measures in clinical trials. Anecdotal experience suggests health benefits for patients other than those measured in this way. We wished to explore Patients' experience of and views about this treatment and the British Society for Rheumatology Biologics Registry (BSR BR) process. Separate focus groups for patients treated with infliximab (n = 7) and etanercept (n = 12) were undertaken. They were taped and transcribed verbatim, analysed and subjected to peer review and themes were identified. Five main themes were identified: expectations of treatment, experience of treatment and its effects, concerns about taking a new class of drug, views about the BSR Biologics Registry process and costs. Patients' experience of anti-TNF therapy was good, particularly in terms of physical function and well-being, although it did not live up to the very high expectations of some patients. The BSR BR process caused initial apprehension but patients had personal and altruistic reasons for being happy to comply with monitoring requirements. Qualitative methods add to our understanding of the effects of anti-TNF therapy for people with RA.

Development of anti-TNF therapy for rheumatoid arthritis.

The aetiology of systemic, autoimmune, chronic inflammatory diseases--such as rheumatoid arthritis--is not known, and their pathogenesis is complex and multifactorial. However, progress in the characterization of intercellular mediators--proteins that are now known as cytokines--has led to the realization that one cytokine, tumour-necrosis factor (TNF; previously known as TNF-alpha), has an important role in the pathogenesis of rheumatoid arthritis. This discovery heralded a new era of targeted and highly effective therapeutics for rheumatoid arthritis and, subsequently, other chronic inflammatory diseases.

Anti-TNF therapy for rheumatoid arthritis and other inflammatory diseases.

The availability of agents that block the biological activity of tumor necrosis factor alpha (TNF alpha) in rheumatoid arthritis (RA) has permitted studies that confirm the key role of this cytokine in the pathogenesis of this disease. To date, two anti-TNF agents, infliximab and etanercept, have been approved for use in treatment. Clinical trials of these agents demonstrate efficacy for the control of symptoms and signs and acceptable safety in patients who have failed to respond adequately to conventional therapy. Combination with methotrexate appears to be particularly effective and may provide the main initial indication for clinical application in the first instance. Repeated administration of anti-TNF therapies over a one year period results in sustained reduction in symptoms and signs of RA in the majority of patients. It has recently become apparent that anti-TNF therapy protects joints from structural damage. These findings imply that TNF alpha has a critical role in the bone and cartilage damage associated with RA. Evidence to date support the hypothesis that there are 2 particularly important mechanisms of action; deactivation of the proinflammatory cytokine cascade at the site of inflammation and diminished recruitment of inflammatory cells from blood to the rheumatoid joint.

Anti-TNF therapies in rheumatoid arthritis, Crohn's disease, sepsis, and myelodysplastic syndromes.

An attempt has been made in this article to summarize the state-of-the-art clinical experience with the use of anti-TNF therapies in four diseased states with special emphasis on myelodysplastic syndromes. Given the central role of TNF-alpha in initiating and perpetuating the chronic damage produced in the diseased organs by controlling a cascade of pro-inflammatory cytokines, as well as its acute role in sepsis, theoretically speaking, neutralization of this peptide was a natural therapeutic choice. Results of the initial clinical trials appear encouraging and sometimes dramatic in their efficacy. The mechanism of response however, is interesting in that even when TNF-alpha is directly targeted by a monoclonal antibody, the resulting benefits can frequently not be attributed to TNF suppression alone. Rather, it appears that a more general effect on the T-lymphocytes is also contributing to the responses being seen. This raises the new possibility of combining anti-cytokine and anti-T-cell strategies to treat at least the more chronic diseases such as Crohn's disease and myelodysplastic syndromes. Continued clinical trials testing these strategies are clearly warranted.

TNF blockade in rheumatoid arthritis: implications for therapy and pathogenesis.

The role of the immune response in rheumatoid arthritis (RA) is a subject of debate, although it is widely believed to be a T-cell-driven disease. Progress is being hindered by lack of convincing evidence of a defined specific antigen initiating or perpetuating the response. Clinical trials using monoclonal antibodies directed against T-cell surface molecules such as CD4. CD5, and CD7 have thus far not provided evidence of efficacy. The negative data may reflect inadequate dosing or could suggest that indiscriminate depletion of T cells is insufficient by itself as a therapeutic strategy. Blocking proinflammatory cytokines (e.g. TNF alpha, IL-1) or augmenting anti-inflammatory cytokines (e.g. IL-10) offers an alternative approach to therapy. Clinical trials using monoclonal anti-TNF alpha have been particularly successful in controlling inflammation and markedly reducing acute phase proteins and cellular ingress. However, because disease invariably relapses, repeated therapy is necessary. Preliminary experience suggests that this is possible. Anti-TNF therapy for RA has defined a molecular target and new approach for treating immuno-inflammatory disorders.