ABSTRACT
Objective: SB4, SB2, and SB5 are biosimilars of etanercept (ETN), infliximab (INF), and adalimumab (ADA), respectively. This pooled analysis evaluated the immunogenicity of these treatments across three phase III randomized controlled trials of patients with rheumatoid arthritis (RA). Methods: Patients had to have at least one anti-drug antibody (ADAb) assessment up to the time of the primary endpoint from each study (week 24 in SB4 and SB5 studies; week 30 in SB2 study). The effect of ADAbs on American College of Rheumatology 20% (ACR20) response and the incidences of injection-site reactions (ISRs)/infusion-related reactions (IRRs) were evaluated. Results: The study included 1709 patients. The cumulative incidences of ADAbs were 30.3% in the all-treatments-combined group, 29.1% in the biosimilars combined group, and 31.5% in the reference products combined group. ACR20 response rates were significantly lower in ADAb-positive patients in the all-treatments-combined [odds ratio (95% confidence interval) 1.77 (1.37, 2.27), p < 0.0001], biosimilars combined [2.24 (1.53, 3.30), p < 0.0001], and reference products combined [1.49 (1.06, 2.09), p = 0.0225] groups. ADAb-positive patients also had a higher likelihood of developing ISRs/IRRs in the all-treatments-combined group [0.56 (0.31, 1.01), p = 0.0550], predominantly due to the results observed with SB2 + INF combined rather than with SB4 + ETN or SB5 + ADA combined. Conclusion: In this pooled analysis, ADAbs were associated with reduced efficacy in patients with RA treated with biosimilars (SB4, SB2, and SB5) or their reference products (ETN, INF, and ADA). ADAbs were associated with an increased incidence of ISRs/IRRs in those treated with SB2 + INF. Clinical trial registration numbers: NCT01936181 (SB2 study), NCT01895309 (SB4 study), and NCT02167139 (SB5 study).
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Biosimilar Pharmaceuticals/therapeutic use , Etanercept/therapeutic use , Tumor Necrosis Factor Inhibitors/therapeutic use , Adalimumab/adverse effects , Adalimumab/therapeutic use , Adult , Antibodies , Antirheumatic Agents/adverse effects , Biosimilar Pharmaceuticals/adverse effects , Etanercept/adverse effects , Female , Humans , Infliximab/adverse effects , Infliximab/therapeutic use , Male , Middle Aged , Treatment Outcome , Tumor Necrosis Factor Inhibitors/adverse effectsABSTRACT
OBJECTIVES: To assess the efficacy and safety of certolizumab pegol (CZP)+dose-optimised methotrexate (MTX) versus placebo (PBO)+dose-optimised MTX in inducing and sustaining clinical remission in DMARD-naïve patients with moderate-to-severe, active, progressive rheumatoid arthritis (RA), with poor prognostic factors over 52â weeks. METHODS: DMARD-naïve patients with ≤1â year of active RA were randomised (3:1) in a double-blind manner to CZP (400â mg Weeks 0, 2, 4, then 200â mg Q2W to Week 52)+MTX or PBO+MTX (the mean optimised-MTX dose=21 and 22â mg/week, respectively). Sustained remission (sREM) and sustained low disease activity (sLDA; DAS28(ESR)<2.6 and DAS28(ESR)≤3.2, respectively, at both Weeks 40 and 52) were the primary and secondary endpoints. RESULTS: Patients were randomised to CZP+MTX (n=660) and PBO+MTX (n=219). At Week 52, significantly more patients assigned to CZP+MTX compared with PBO+MTX achieved sREM (28.9% vs 15.0%, p<0.001) and sLDA (43.8% vs 28.6%, p<0.001). Inhibition of radiographic progression and improvements in physical functioning were significantly greater for CZP+MTX versus PBO+MTX (van der Heijde modified total Sharp score (mTSS) mean absolute change from baseline (CFB): 0.2 vs 1.8, p<0.001, rate of mTSS non-progressors: 70.3% vs 49.7%, p<0.001; least squares (LS) mean CFB in Health Assessment Questionnaire-Disability Index (HAQ-DI): -1.00 vs -0.82, p<0.001). Incidence of adverse events (AEs) and serious AEs was similar between treatment groups. Infection was the most frequent AE, with higher incidence for CZP+MTX (71.8/100 patient-years (PY)) versus PBO+MTX (52.7/100â PY); the rate of serious infection was similar between CZP+MTX (3.3/100â PY) and PBO+MTX (3.7/100â PY). CONCLUSIONS: CZP+dose-optimised MTX treatment of DMARD-naïve early RA resulted in significantly more patients achieving sREM and sLDA, improved physical function and inhibited structural damage compared with PBO+dose-optimised MTX. TRIAL REGISTRATION NUMBER: NCT01519791.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Certolizumab Pegol/therapeutic use , Methotrexate/therapeutic use , Adult , Antirheumatic Agents/administration & dosage , Antirheumatic Agents/adverse effects , Arthritis, Rheumatoid/diagnostic imaging , Certolizumab Pegol/adverse effects , Double-Blind Method , Drug Therapy, Combination/adverse effects , Female , Humans , Infections/chemically induced , Male , Methotrexate/administration & dosage , Methotrexate/adverse effects , Middle Aged , Prognosis , Radiography , Remission InductionABSTRACT
OBJECTIVES: We report the incidence of tuberculosis (TB) across certolizumab pegol (CZP) clinical trials in rheumatoid arthritis (RA), psoriasis, psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), before and after the introduction of stricter TB screening. METHODS: TB incidence rates (IRs) were assessed and stratified according to screening guidelines used at the time of CZP trials. Before 2007 (original trials), purified protein derivative (PPD) tuberculin skin test positivity varied according to local standards (induration ≥5 up to ≥20â mm). Since 2007, all CZP trial protocols have been amended, including trials spanning (intermediate) and initiated after 2007 (current), mandating that any patient with PPD≥5â mm receives treatment for latent TB infection (LTBI). All cases of suspected TB or PPD≥5â mm, in pooled data from 5402 CZP patients across all CZP trials up to 2012, underwent blinded central review by independent experts. RESULTS: 44 TB cases were confirmed in pooled CZP RA trials (IR 0.47/100PY, patient-years) with no cases in Japanese RA trials (J-RAPID, HIKARI). Single TB cases were confirmed in psoriasis and axSpA trials (RAPID-axSpA), and no cases in the PsA trial (RAPID-PsA). IR of TB was 0.51/100PY across original or intermediate RA trials and 0.18/100PY in current trials. The majority of TB cases in RA occurred in Eastern (IR 1.02/100PY) and Central Europe (IR 0.58/100PY). Of 242/370 PPD≥5â mm patients who received 9â months isoniazid (INH) treatment for latent TB infection (LTBI), none developed TB, versus 7.8% of 128 untreated PPD≥5â mm patients. CONCLUSIONS: Implementation of more stringent LTBI screening, plus treatment for LTBI, reduced the IR of TB, even when INH was administered after starting CZP therapy.
ABSTRACT
No consensus has previously been formed regarding the types and presentations of infectious pathogens to be considered as 'opportunistic infections' (OIs) within the setting of biologic therapy. We systematically reviewed published literature reporting OIs in the setting of biologic therapy for inflammatory diseases. The review sought to describe the OI definitions used within these studies and the types of OIs reported. These findings informed a consensus committee (infectious diseases and rheumatology specialists) in deliberations regarding the development of a candidate list of infections that should be considered as OIs in the setting of biologic therapy. We reviewed 368 clinical trials (randomised controlled/long-term extension), 195 observational studies and numerous case reports/series. Only 11 observational studies defined OIs within their methods; no consistent OI definition was identified across studies. Across all study formats, the most numerous OIs reported were granulomatous infections. The consensus group developed a working definition for OIs as 'indicator' infections, defined as specific pathogens or presentations of pathogens that 'indicate' the likelihood of an alteration in host immunity in the setting of biologic therapy. Using this framework, consensus was reached upon a list of OIs and case-definitions for their reporting during clinical trials and other studies. Prior studies of OIs in the setting of biologic therapy have used inconsistent definitions. The consensus committee reached agreement upon an OI definition, developed case definitions for reporting of each pathogen, and recommended these be used in future studies to facilitate comparison of infection risk between biologic therapies.
Subject(s)
Biological Therapy/methods , Consensus , Immunosuppressive Agents/therapeutic use , Opportunistic Infections , Product Surveillance, Postmarketing/methods , Clinical Trials as Topic , Global Health , Humans , Morbidity/trends , Opportunistic Infections/epidemiology , Opportunistic Infections/immunology , Opportunistic Infections/therapy , Risk FactorsABSTRACT
The objective of this study was to study genetic factors that influence quantitative anticyclic citrullinated peptide (anti-CCP) antibody levels in RA patients. We carried out a genome-wide association study (GWAS) meta-analysis using 1975 anti-CCP+ RA patients from three large cohorts, the Brigham Rheumatoid Arthritis Sequential Study (BRASS), North American Rheumatoid Arthritis Consortium (NARAC) and the Epidemiological Investigation of RA (EIRA). We also carried out a genome-wide complex trait analysis (GCTA) to estimate the heritability of anti-CCP levels. GWAS-meta-analysis showed that anti-CCP levels were most strongly associated with the human leukocyte antigen (HLA) region with a P-value of 2 × 10(-11) for rs1980493. There were 112 SNPs in this region that exceeded the genome-wide significance threshold of 5 × 10(-8), and all were in linkage disequilibrium (LD) with the HLA- DRB1*03 allele with LD r(2) in the range of 0.25-0.88. Suggestive novel associations outside of the HLA region were also observed for rs8063248 (near the GP2 gene) with a P-value of 3 × 10(-7). None of the known RA risk alleles (â¼52 loci) were associated with anti-CCP level. Heritability analysis estimated that 44% of anti-CCP variation was attributable to genetic factors captured by GWAS variants. In summary, anti-CCP level is a heritable trait, and HLA-DR3 and GP2 are associated with lower anti-CCP levels.
Subject(s)
Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/immunology , Autoantibodies/immunology , Peptides, Cyclic/immunology , Case-Control Studies , Cohort Studies , Female , GPI-Linked Proteins/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , HLA-DR3 Antigen/genetics , HLA-DR3 Antigen/immunology , HLA-DRB1 Chains/genetics , HLA-DRB1 Chains/immunology , Humans , Linkage Disequilibrium , Male , Middle Aged , Models, Genetic , Polymorphism, Single Nucleotide , Prospective StudiesABSTRACT
OBJECTIVE: To determine whether certolizumab pegol (CZP) dosage escalation from 200 mg to 400 mg every other week benefits some patients with rheumatoid arthritis (RA). METHODS: In the extension of the Rheumatoid Arthritis Prevention of Structural Damage 1 (RAPID 1) study into an open-label study, all patients received CZP 400 mg every other week in combination with methotrexate (MTX). Before the open-label phase of the study, patients had received CZP 200 mg or 400 mg every other week, or placebo every other week, as add-on therapy to MTX. The open-label study included those who had completed the RAPID 1 study (to week 52) and also those who had been withdrawn from the study (at week 16, due to inadequate response). At 12 weeks and 48 weeks after enrollment in the open-label study, changes in the Disease Activity Score in 28 joints (DAS28) were compared in dose-escalation patients (200 mg increased to 400 mg every other week) versus stable-dosage patients (400 mg every other week), using cumulative probability plots of individual patient-level data. RESULTS: In the group of patients who had completed the RAPID 1 study and had moderate or severe disease activity at entry into the open-label study, and in those who had been withdrawn early from the RAPID 1 study, the median DAS28 improvements 12 weeks after enrollment into the open-label study were similar in the dose-escalation and stable-dose groups. Individual patient-level data revealed no greater likelihood of response in the group of patients who received an increased dosage of CZP versus those in whom a stable dosage was maintained, whether they had completed the RAPID 1 study or had been withdrawn early. CONCLUSION: Although patient heterogeneity in clinical settings is acknowledged, the present results indicate that increasing the dose of CZP from 200 mg to 400 mg offers little additional benefit in RA, even for selected patients.
Subject(s)
Antirheumatic Agents/administration & dosage , Arthritis, Rheumatoid/drug therapy , Immunoglobulin Fab Fragments/administration & dosage , Polyethylene Glycols/administration & dosage , Adult , Antibodies, Monoclonal, Humanized , Antirheumatic Agents/therapeutic use , Certolizumab Pegol , Dose-Response Relationship, Drug , Humans , Immunoglobulin Fab Fragments/therapeutic use , Polyethylene Glycols/therapeutic use , Treatment OutcomeABSTRACT
OBJECTIVE: The American College of Rheumatology (ACR) hybrid (a modified mean percent response to treatment) was officially recommended by the ACR as a revision to 20%, 50%, and 70% response criteria (ACR20/50/70) scores, but has not been tested in clinical trials. We performed a post hoc analysis of a phase III study of certolizumab pegol (Rheumatoid Arthritis Prevention of Structural Damage 1 [RAPID 1]) using the ACR hybrid. METHODS: Patients with active rheumatoid arthritis were randomized to certolizumab pegol (200 mg or 400 mg every other week) plus methotrexate or placebo plus methotrexate. ACR hybrid scores were compared with ACR20/50/70 outcomes. RESULTS: Differences between active treatment and placebo were significant throughout the study using the ACR20 and ACR hybrid outcomes. In the certolizumab pegol 200 mg group, the median ACR hybrid score at week 52 (last observation carried forward) was 49.99. A total of 258 (65.8%) of 392 and 172 (43.9%) of 392 patients had ACR20 and ACR50 responses, respectively. An additional 55 patients (14.0%) and 59 patients (15.1%) had mean improvements in ACR core measures of ≥ 20% and ≥ 50%, respectively, and therefore had positive ACR hybrid scores, despite lacking ACR20 and ACR50 responses, respectively. In the placebo group, median ACR hybrid scores were <10 at most time points; unlike other measures, the ACR hybrid measure indicated worsening scores for many patients. CONCLUSION: ACR hybrid analysis had greater sensitivity than traditional ACR20/50/70 criteria, demonstrating improvements in ACR20 nonresponders treated with certolizumab pegol. Negligible benefit was observed with placebo using ACR hybrid analysis.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Immunoglobulin Fab Fragments/administration & dosage , Methotrexate/administration & dosage , Polyethylene Glycols/administration & dosage , Rheumatology/standards , Societies, Medical/standards , Adult , Antibodies, Monoclonal, Humanized , Arthritis, Rheumatoid/pathology , Certolizumab Pegol , Drug Therapy, Combination , Female , Humans , Male , United StatesABSTRACT
The development of methotrexate (MTX) as a therapy for rheumatoid arthritis (RA) evolved initially from positive case reports, uncontrolled case series and then several decades later placebo controlled studies followed by active comparator studies. These studies established MTX as a major therapy for RA. The importance of MTX in the treatment paradigm has only been enhanced over the past decade by the increased efficacy observed when small molecules and biologics are added to MTX. Since the first randomised studies were performed in the 1980s, MTX has now become the most well-studied disease modifying therapy to date and the most popular drug worldwide in the treatment of RA. This chapter will review the history of the development of MTX in RA.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Clinical Trials as Topic , Evidence-Based Medicine , Methotrexate/therapeutic use , Antirheumatic Agents/history , Arthritis, Rheumatoid/history , Clinical Trials as Topic/history , Evidence-Based Medicine/history , History, 20th Century , Humans , Methotrexate/history , Treatment OutcomeSubject(s)
Antirheumatic Agents/therapeutic use , Immunosuppressive Agents/therapeutic use , Rheumatic Diseases/drug therapy , Abatacept , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antibodies, Monoclonal, Murine-Derived , Humans , Immunoconjugates/therapeutic use , Rituximab , Tumor Necrosis Factor-alpha/antagonists & inhibitorsSubject(s)
Antirheumatic Agents/therapeutic use , Immunologic Factors/therapeutic use , Rheumatic Diseases/drug therapy , Abatacept , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Murine-Derived , Antirheumatic Agents/adverse effects , Arthritis/drug therapy , Evidence-Based Medicine , Humans , Immunoconjugates/adverse effects , Immunoconjugates/therapeutic use , Immunologic Factors/adverse effects , Interleukin-1/antagonists & inhibitors , Interleukin-2/antagonists & inhibitors , Opportunistic Infections/chemically induced , Rituximab , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
OBJECTIVE: To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: The project followed the EULAR standardized operating procedures, which use a three-step approach: 1) expert-based definition of relevant research questions (November 2006); 2) systematic literature search (November 2006 to May 2007); and 3) expert consensus on recommendations based on the literature search results (May 2007). In addition, since this is the first joint EULAR/ACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group (August 2007). RESULTS: Eleven relevant questions were identified for the literature search. Based on the evidence from the literature, the expert panel recommended that each trial should report the following items: 1) disease activity response and disease activity states; 2) appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; 3) baseline disease activity levels (in general); 4) the percentage of patients achieving a low disease activity state and remission; 5) time to onset of the primary outcome; 6) sustainability of the primary outcome; 7) fatigue. CONCLUSION: These recommendations endorsed by EULAR and ACR will help harmonize the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in meta-analyses.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Clinical Trials as Topic/standards , Evidence-Based Medicine/methods , Cooperative Behavior , HumansABSTRACT
OBJECTIVE: To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: The project followed the EULAR standardised operating procedures, which use a three-step approach: (1) expert-based definition of relevant research questions (November 2006); (2) systematic literature search (November 2006 to May 2007); and (3) expert consensus on recommendations based on the literature search results (May 2007). In addition, since this is the first joint EULAR/ACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group (August 2007). RESULTS: Eleven relevant questions were identified for the literature search. Based on the evidence from the literature the expert panel recommended that each trial should report the following items: (1) disease activity response and disease activity states; (2) appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; (3) baseline disease activity levels (in general); (4) the percentage of patients achieving a low disease activity state and remission; (5) time to onset of the primary outcome; (6) sustainability of the primary outcome; (7) fatigue. CONCLUSIONS: These recommendations endorsed by EULAR and ACR will help harmonise the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in meta-analyses.
Subject(s)
Arthritis, Rheumatoid/diagnosis , Arthritis, Rheumatoid/drug therapy , Clinical Trials as Topic/standards , Severity of Illness Index , Arthritis, Rheumatoid/complications , Clinical Trials as Topic/methods , Evidence-Based Medicine/methods , Fatigue/diagnosis , Fatigue/etiology , Humans , International Cooperation , Remission Induction , Research Design/standards , Societies, Medical , Treatment OutcomeABSTRACT
OBJECTIVES: There is a lack of agreement on assessing disease activity in patients with RA and determining when the RA treatment should be changed or continued. A panel of rheumatologists was convened to develop guidelines to assess adequacy of disease control, focusing on the use of disease-modifying anti-rheumatic drugs. METHODS: The Research and Development/University of California in Los Angeles (RAND/UCLA) Appropriateness Method was used to evaluate disease control adequacy. After a literature review, 108 scenarios were developed to simulate situations most likely to be encountered in clinical practice and rated on a 9-point scale by a 10-member expert panel. RESULTS: Final appropriateness rankings for the scenarios were as follows: 37% 'appropriate', 48% 'inappropriate', and 16% 'neutral'. The panelists felt that patients with disease control in the 'appropriate' range have adequate control with their current therapy, whereas those in the 'inappropriate' range should be considered for a change in therapy. Those in 'neutral' areas should have their therapy reviewed carefully. The panelists recommended that the clinically active joint count should be considered the most important decision factor. In patients with no clinically active joints, regardless of other factors no change in therapy was felt to be warranted. Patients with five or more active joints should be considered inadequately treated, and in patients with one to four active joints other variables must be considered in the decision to change therapy. CONCLUSION: These preliminary guidelines will assist the clinician in determining when a patient's clinical situation warrants therapy escalation and when continuing the current regimen would be appropriate.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antirheumatic Agents/classification , Antirheumatic Agents/standards , Clinical Trials as Topic/standards , Delivery of Health Care , Evaluation Studies as Topic , Evidence-Based Medicine , Humans , Predictive Value of Tests , Reproducibility of Results , Treatment OutcomeABSTRACT
BACKGROUND: HLA-DRB1 shared epitope (HLA-SE), PTPN22 and CTLA4 alleles are associated with cyclic citrullinated peptide (CCP) and rheumatoid arthritis (RA). OBJECTIVE: We examined associations between HLA-SE, PTPN22, CTLA4 genotypes and RA phenotypes in a large cohort to (a) replicate prior associations with CCP status, and (b) determine associations with radiographic erosions and age of diagnosis. METHODS: A total of 689 RA patients from the Brigham RA Sequential Study (BRASS) were genotyped for HLA-SE, PTPN22 (rs2476601) and CTLA4 (rs3087243). Association between genotypes and CCP, rheumatoid factor (RF) erosive phenotypes and age at diagnosis were assessed with multivariable models adjusting for age, sex and disease duration. Novel causal pathway analysis was used to test the hypothesis that genetic risk factors and CCP are in the causal pathway for predicting erosions. RESULTS: In multivariable analysis, presence of any HLA-SE was strongly associated with CCP+ (odds ratio (OR) 3.05, 95% CI 2.18-4.25), and RF+ (OR 2.53, 95% CI 1.83-3.5) phenotypes; presence of any PTPN22 T allele was associated with CCP+ (OR 1.81, 95% CI 1.24-2.66) and RF+ phenotypes (OR 1.84, 95% CI 1.27-2.66). CTLA4 was not associated with CCP or RF phenotypes. While HLA-SE was associated with erosive RA phenotype (OR 1.52, 95% CI 1.01-2.17), this was no longer significant after conditioning on CCP. PTPN22 and CTLA4 were not associated with erosive phenotype. Presence of any HLA-SE was associated with an average 3.6 years earlier diagnosis compared with absence of HLA-SE (41.3 vs 44.9 years, p = 0.002) and PTPN22 was associated with a 4.2 years earlier age of diagnosis (39.5 vs 43.6 years, p = 0.002). CTLA4 genotypes were not associated with age at diagnosis of RA. CONCLUSIONS: In this large clinical cohort, we replicated the association between HLA-SE and PTPN22, but not CTLA4 with CCP+ and RF+ phenotypes. We also found evidence for associations between HLA-SE, and PTPN22 and earlier age at diagnosis. Since HLA-SE is associated with erosive phenotype in unconditional analysis, but is not significant after conditioning on CCP, this suggests that CCP is in the causal pathway for predicting erosive phenotype.
Subject(s)
Arthritis, Rheumatoid/genetics , Autoantibodies/blood , Genetic Predisposition to Disease , Adult , Age Factors , Aged , Antigens, CD/genetics , Antigens, Differentiation/genetics , Arthritis, Rheumatoid/immunology , Biomarkers/blood , CTLA-4 Antigen , Cohort Studies , Female , Genotype , HLA-DR Antigens/genetics , HLA-DRB1 Chains , Humans , Male , Middle Aged , Peptides, Cyclic/blood , Phenotype , Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics , Rheumatoid Factor/bloodSubject(s)
Antirheumatic Agents/therapeutic use , Arthritis/drug therapy , Abatacept , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Murine-Derived , Antirheumatic Agents/adverse effects , Arthritis, Juvenile/drug therapy , Arthritis, Psoriatic/drug therapy , Arthritis, Rheumatoid/drug therapy , Humans , Immunoconjugates/adverse effects , Immunoconjugates/therapeutic use , Interleukin-1/antagonists & inhibitors , Neoplasms/chemically induced , Rituximab , Spondylitis, Ankylosing/drug therapy , Tuberculosis/chemically induced , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
The CAMERA study shows that using methotrexate in a tight control setting might lead to considerable improvement in disease activity in early rheumatoid arthritis See linked article p 1443.
Subject(s)
Antirheumatic Agents/administration & dosage , Arthritis, Rheumatoid/drug therapy , Methotrexate/administration & dosage , Dose-Response Relationship, Drug , Drug Administration Schedule , Humans , Remission InductionABSTRACT
BACKGROUND: Certain sequences present in the hypervariable region of human leucocyte antigen (HLA)-DRB1 known as the shared epitope (SE) are hypothesised to increase the risk of rheumatoid arthritis (RA), whereas alleles encoding aspartic acid at position 70 (D70 alleles) may have a protective effect. METHODS: Patient HLA-DRB1 serotypes were assessed and the genotypes encoding the SE motif or the putatively protective D70 motif identified in a large RA cohort. Logistic regression was used to analyse associations of genotype with presence of disease, comorbidities and disease severity, and association between genotype and change in disease activity over time. RESULTS: The 689 patients enrolled had a mean (SD) age of 57.9 (13.7) years and mean (SD) disease duration of 15.3 (12.7) years. In a comparison with 482 ethnicity matched population-based controls, the D70 sequence exerted a strong protective effect (OR = 0.52, p<0.001) that remained significant when the SE at the same locus was accounted for (OR = 0.72, 95% CI 0.60 to 0.86, p<0.001). The SE assessed on all HLA-DRB1 serotypic backgrounds except DR1 was associated with RA susceptibility (additive OR = 2.43, p<0.001). Associations were found between SE and serum levels of rheumatoid factor (p<0.001, with correlation of 0.18) and anti-cyclic citrullinated peptide antibodies (p<0.001, with correlation of 0.25) but not with serum C-reactive protein. CONCLUSION: The D70 allele has a significant protective effect that is mitigated but still significant when the risk effect of the SE at the same locus is taken into account. The presence of the SE on DR4 is associated with greater RA susceptibility and certain disease-activity measures.
Subject(s)
Arthritis, Rheumatoid/genetics , HLA-DR4 Antigen/genetics , Mutation , Adult , Aged , Alleles , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/prevention & control , Biomarkers/blood , Complementarity Determining Regions/genetics , Disease Progression , Epitopes/genetics , Female , Genetic Predisposition to Disease , HLA-DR4 Antigen/immunology , Histocompatibility Testing/methods , Humans , Male , Middle Aged , Phenotype , Severity of Illness Index , Time FactorsABSTRACT
Over the past decade, biological immunotherapy has revolutionised the treatment of rheumatoid arthritis (RA). The most widely used of these therapies targets tumour necrosis factor-alpha (TNF-alpha). Approximately 20% of patients fail to respond to TNF-alpha antagonism, however, and a significant number of additional patients become refractory to anti-TNF-alpha therapy over time. Thus investigators have sought to target other pathogenic elements of RA using novel biological therapies. Abatacept is the first immunotherapy directed against the process of T-cell costimulation. Abatacept has shown clinical effectiveness in RA by improving disease activity, quality of life measures and radiographic progression of disease. In this article, we review the immunology of T-cell activation and costimulation, define the role of abatacept in this process, and discuss the clinical trials that led to the approval of abatacept as the latest biological therapy in RA in the USA and Canada. We also address the role of abatacept in the greater context of biological therapy for RA.