ABSTRACT
This study investigates the association of CRP (C-reactive protein) single-nucleotide polymorphisms (SNPs) with plasma CRP levels and radiographic severity in African Americans with early and established rheumatoid arthritis (RA). Using a cross-sectional case-only design, CRP SNPs were genotyped in two independent sets of African Americans with RA: Consortium for the Longitudinal Evaluation of African Americans with RA (CLEAR 1) and CLEAR 2. Radiographic data and CRP measurements were available for 294 individuals from CLEAR 1 (median (interquartile range (IQR) 25-75) disease duration of 1 (0.6-1.6) year) and in 407 persons from CLEAR 2 (median (IQR 25-75) disease duration of 8.9 (3.5-17.7) years). In CLEAR 1, in adjusted models, the minor allele of rs2808630 was associated with total radiographic score (incident rate ratio 0.37 (95% confidence interval (CI) 0.19-0.74), P-value=0.0051). In CLEAR 2, the minor allele of rs3093062 was associated with increased plasma CRP levels (P-value=0.002). For each rs3093062 minor allele, the plasma CRP increased by 1.51 (95% CI 1.15-1.95) mg dl(-1) when all the other covariates remained constant. These findings have important implications for assessment of the risk of joint damage in African Americans with RA.
Subject(s)
Arthritis, Rheumatoid/ethnology , Arthritis, Rheumatoid/genetics , Black or African American/genetics , C-Reactive Protein/genetics , Adult , Aged , Alleles , Arthritis, Rheumatoid/diagnostic imaging , Cross-Sectional Studies , Female , Genetic Association Studies , Genetic Predisposition to Disease/etiology , Genetic Variation , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , RadiographyABSTRACT
OBJECTIVES: To analyse the differences between patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) entered into randomised clinical trials (RCTs) and those followed in large observational cohorts. METHODS: The main characteristics and outcomes of patients with generalised and/or severe GPA or MPA with a five-factor score ≥ 1 enrolled in the French Vasculitis Study Group (FVSG) or the US-Canadian-based Vasculitis Clinical Research Consortium cohorts were compared to those enrolled in one of 2 FVSG clinical RCTs (WEG91, WEGENT) or 3 European Vasculitis Society clinical trials (CYCLOPS, CYCAZAREM, IMPROVE). RESULTS: 657 patients (65.3% with GPA) in RCTs were compared to 437 in cohorts (90.6% with GPA). RCT patients were older at diagnosis than the cohort patients (56.6 ± 13.9 vs. 46.8 ± 17.3 years), had higher Birmingham vasculitis activity score (19.5 ± 9.1 vs. 16.9 ± 7.4), and more frequent kidney disease (84.0% vs. 54.9%) but fewer ear, nose, and throat symptoms (56.8% vs. 72.2%). At 56 months post-diagnosis, mortality and relapse rates, adjusted for age and renal function, were higher for patients with GPA in RCTs vs. cohorts (10.7% vs. 2.5% [p=0.001] and 22.5% vs. 15.6% [p=0.03], respectively) but similar for patients with MPA (6.2% vs. 6.6% [p=0.92] and 16.6% vs. 10.1% [p=0.39], respectively). CONCLUSIONS: Patients with GPA or MPA in RCTs and those in observational cohorts show important differences that should be remembered when interpreting results based on these study populations.
Subject(s)
Granulomatosis with Polyangiitis/epidemiology , Microscopic Polyangiitis/epidemiology , Observational Studies as Topic , Randomized Controlled Trials as Topic , Adult , Age Distribution , Aged , Antibodies, Antineutrophil Cytoplasmic/immunology , Cohort Studies , Female , Granulomatosis with Polyangiitis/complications , Granulomatosis with Polyangiitis/immunology , Humans , Kidney Diseases/etiology , Male , Microscopic Polyangiitis/complications , Microscopic Polyangiitis/immunology , Middle Aged , Myeloblastin/immunology , Otorhinolaryngologic Diseases/etiology , Patient Selection , Peroxidase/immunology , Severity of Illness IndexABSTRACT
Methotrexate (MTX) has emerged as first-line therapy for early moderate-to-severe rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. We tested the associations between 863 known pharmacogenetic variants and MTX response in 471 Treatment of Early Aggressive Rheumatoid Arthritis Trial participants with early RA. Efficacy and toxicity were modeled using multiple regression, adjusted for demographic and clinical covariates. Penalized regression models were used to test joint associations of markers and/or covariates with the outcomes. The strongest genetic associations with efficacy were in CHST11 (five markers with P<0.003), encoding carbohydrate (chondroitin 4) sulfotransferase 11. Top markers associated with MTX toxicity were in the cytochrome p450 genes CYP20A1 and CYP39A1, solute carrier genes SLC22A2 and SLC7A7, and the mitochondrial aldehyde dehydrogenase gene ALDH2. The selected markers explained a consistently higher proportion of variation in toxicity than efficacy. These findings could inform future development of personalized therapeutic approaches.
Subject(s)
Antirheumatic Agents/toxicity , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Genetic Variation , Methotrexate/toxicity , Methotrexate/therapeutic use , Antirheumatic Agents/administration & dosage , Arthritis, Rheumatoid/genetics , Biomarkers/analysis , Female , Humans , Male , Methotrexate/administration & dosage , Middle Aged , Multivariate Analysis , Randomized Controlled Trials as Topic , Regression Analysis , Severity of Illness Index , Time Factors , Treatment OutcomeABSTRACT
The field of phenomics has been investigating network structure among large arrays of phenotypes, and genome-wide association studies (GWAS) have been used to investigate the relationship between genetic variation and single diseases/outcomes. A novel approach has emerged combining both the exploration of phenotypic structure and genotypic variation, known as the phenome-wide association study (PheWAS). The Population Architecture using Genomics and Epidemiology (PAGE) network is a National Human Genome Research Institute (NHGRI)-supported collaboration of four groups accessing eight extensively characterized epidemiologic studies. The primary focus of PAGE is deep characterization of well-replicated GWAS variants and their relationships to various phenotypes and traits in diverse epidemiologic studies that include European Americans, African Americans, Mexican Americans/Hispanics, Asians/Pacific Islanders, and Native Americans. The rich phenotypic resources of PAGE studies provide a unique opportunity for PheWAS as each genotyped variant can be tested for an association with the wide array of phenotypic measurements available within the studies of PAGE, including prevalent and incident status for multiple common clinical conditions and risk factors, as well as clinical parameters and intermediate biomarkers. The results of PheWAS can be used to discover novel relationships between SNPs, phenotypes, and networks of interrelated phenotypes; identify pleiotropy; provide novel mechanistic insights; and foster hypothesis generation. The PAGE network has developed infrastructure to support and perform PheWAS in a high-throughput manner. As implementing the PheWAS approach has presented several challenges, the infrastructure and methodology, as well as insights gained in this project, are presented herein to benefit the larger scientific community.
Subject(s)
Genetic Association Studies/statistics & numerical data , Databases, Genetic , Ethnicity/genetics , Genetic Variation , Genome-Wide Association Study/statistics & numerical data , Humans , Models, Genetic , Models, Statistical , Phenotype , Polymorphism, Single Nucleotide , Racial Groups/geneticsABSTRACT
OBJECTIVE: African Americans with rheumatoid arthritis (RA) may be at increased fracture risk. We applied the World Health Organization (WHO) Fracture Risk Assessment Tool (FRAX) and National Osteoporosis Foundation (NOF) guidelines to a cohort of African Americans with early RA to identify which patients were recommended for osteoporosis treatment. METHODS: Risk factors and bone mineral density (BMD) were assessed in a cohort of African Americans with RA. The WHO FRAX tool estimated 10-year fracture risk. Patients were risk stratified using FRAX without BMD to identify which individuals might be most efficiently targeted for BMD testing. RESULTS: Participants (n = 324) had a mean age of 51 years and included 81% women. There were no associations of RA disease characteristics with BMD. The proportion of patients recommended for osteoporosis treatment varied from 3-86%, depending on age and body mass index (BMI). Ten-year fracture risk calculated with BMI only was generally the same or higher than fracture risk calculated with BMD; adding BMD data provided the most incremental value to risk assessment in patients 55-69 years of age with low/normal BMI, and in those > or =70 years of age with BMI > or =30 kg/m2. CONCLUSION: A high proportion of African Americans with RA were recommended for treatment under the 2008 NOF guidelines. FRAX without BMD identified low-risk patients accurately. Systematic application of FRAX to screen high-risk groups such as patients with RA may be used to target individuals for BMD testing and reduce the use of unnecessary tests and treatments.
Subject(s)
Arthritis, Rheumatoid/ethnology , Black or African American , Fractures, Spontaneous/ethnology , Osteoporosis/ethnology , Absorptiometry, Photon , Adult , Aged , Aged, 80 and over , Arthritis, Rheumatoid/metabolism , Bone Density , Comorbidity , Disability Evaluation , Female , Femur Neck/diagnostic imaging , Femur Neck/metabolism , Fractures, Spontaneous/metabolism , Health Status , Humans , Lumbar Vertebrae/diagnostic imaging , Lumbar Vertebrae/metabolism , Male , Middle Aged , Osteoporosis/diagnosis , Osteoporosis/metabolism , Risk Assessment , Severity of Illness Index , Young AdultABSTRACT
OBJECTIVE: To examine the association of smoking with clinical and serological features in African Americans with recent-onset rheumatoid arthritis (RA) and to explore whether this association is dependent on the presence of the HLA-DRB1 shared epitope (SE). METHODS: In African Americans with recent-onset RA (n = 300), we examined the association of cigarette smoking (current versus past versus never and pack-years of exposure) with anti-cyclic citrullinated peptide antibody, rheumatoid factor (RF) (IgM and IgA), rheumatoid nodules and baseline radiographic erosions using logistic and cumulative logistic regression (adjusting for SE status). We also examined for evidence of interaction between smoking status and SE for all outcomes. RESULTS: Although there was no association with RF-IgA seropositivity, current smokers were approximately twice as likely as never smokers to have higher IgA-RF concentrations (based on tertiles; OR = 1.74; 95% CI 1.05 to 2.88) and nodules (OR = 2.43; 95% CI 1.13 to 5.22). These associations were most pronounced in those with more than 20 pack-years of exposure. There was no association of smoking status or cumulative tobacco exposure with anti-cyclic citrullinated peptide antibody, IgM-RF or radiographic erosions. There was also no evidence of a biological or statistical SE-smoking interaction for any of the outcomes examined. CONCLUSIONS: This is the first study to systematically examine the association of cigarette smoking with RA-related features in African Americans. Cigarette smoking is associated with both subcutaneous nodules and higher serum concentrations of IgA-RF in African Americans with RA, associations that may have important implications for long-term outcomes in this population.
Subject(s)
Arthritis, Rheumatoid/etiology , Autoantibodies/blood , Black or African American/genetics , Smoking/adverse effects , Adult , Aged , Arthritis, Rheumatoid/ethnology , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/immunology , Cross-Sectional Studies , Female , Genetic Predisposition to Disease , Genotype , HLA-DR Antigens/genetics , HLA-DRB1 Chains , Humans , Immunoglobulin A/blood , Male , Middle Aged , Peptides, Cyclic/immunology , Rheumatoid Factor/blood , Rheumatoid Nodule/etiology , Rheumatoid Nodule/genetics , Rheumatoid Nodule/immunology , Smoking/ethnology , Smoking/genetics , Smoking/immunology , United States/epidemiologyABSTRACT
OBJECTIVE: To estimate minimally important differences (MIDs) in scores for the modified Rodnan Skin Score (mRSS) and Health Assessment Questionnaire-Disability Index (HAQ-DI) in a clinical trial on diffuse systemic sclerosis (SSc). PARTICIPANTS AND METHODS: 134 people participated in a 2-year, double-blind, randomised clinical trial comparing efficacy of low-dose and high-dose D-penicillamine in diffuse SSc. At 6, 12, 18 and 24 months, the investigator was asked to rate the change in the patient's health since entering the study: markedly worsened, moderately worsened, slightly worsened, unchanged, slightly improved, moderately improved or markedly improved. Patients who were rated as slightly improved were defined as the minimally changed subgroup and compared with patients rated as moderately or markedly improved. RESULTS: The MID estimates for the mRSS improvement ranged from 3.2 to 5.3 (0.40-0.66 effect size) and for the HAQ-DI from 0.10 to 0.14 (0.15-0.21 effect size). Patients who were rated to improve more than slightly were found to improve by 6.9-14.2 (0.86-1.77 effect size) on the mRSS and 0.21-0.55 (0.32-0.83 effect size) on the HAQ-DI score. CONCLUSION: MID estimates are provided for improvement in the mRSS and HAQ-DI scores, which can help in interpreting clinical trials on patients with SSc and be used for sample size calculation for future clinical trials on diffuse SSc.
Subject(s)
Antirheumatic Agents/administration & dosage , Health Status Indicators , Penicillamine/administration & dosage , Scleroderma, Diffuse/drug therapy , Adult , Antirheumatic Agents/therapeutic use , Disability Evaluation , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Humans , Male , Middle Aged , Penicillamine/therapeutic use , Scleroderma, Diffuse/rehabilitation , Severity of Illness Index , Treatment OutcomeABSTRACT
BACKGROUND: The anti-folate drug methotrexate (MTX) is commonly used to treat rheumatoid arthritis. OBJECTIVE: To determine the allele frequencies of five common coding single-nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene in African-Americans and Caucasians with rheumatoid arthritis and controls to assess whether there are differences in allele frequencies among these ethnic or racial groups and whether these SNPs differentially affect the efficacy or toxicity of MTX. METHODS: Allele frequencies in the 677, 1298 and 3 additional SNPs in the MTHFR coding region in 223 (193 Caucasians and 30 African-Americans) patients with rheumatoid arthritis who previously participated in one of two prospective clinical trials were characterised, and genotypes were correlated with the efficacy and toxicity of MTX. Another 308 subjects with rheumatoid arthritis who participated in observational studies, one group predominantly Caucasian and the other African-American, as well as 103 normal controls (53 African-Americans and 50 Caucasians) were used to characterise allele frequencies of these SNPs and their associated haplotypes. RESULTS: Significantly different allele frequencies were seen in three of the five SNPs and haplotype frequencies between Caucasians and African-Americans. Allele frequencies were similar between patients with rheumatoid arthritis and controls of the same racial or ethnic group. Frequencies of the rs4846051C, 677T and 1298C alleles were 0.33, 0.11 and 0.13, respectively, among African-Americans with rheumatoid arthritis. Among Caucasians with rheumatoid arthritis, these allele frequencies were 0.08 (p<0.001 compared with African-Americans with rheumatoid arthritis), 0.30 (p = 0.002) and 0.34 (p<0.001), respectively. There was no association between SNP alleles or haplotypes and response to MTX as measured by the mean change in the 28-joint Disease Activity Score from baseline values. In Caucasians, the 1298 A (major) allele was associated with a significant increase in MTX-related adverse events characteristic of a recessive genetic effect (odds ratio 15.86, 95% confidence interval 1.51 to 167.01; p = 0.021), confirming previous reports. There was an association between scores of MTX toxicity and the rs4846051 C allele, and haplotypes containing this allele, in African-Americans, but not in Caucasians. CONCLUSIONS: : These results, although preliminary, highlight racial or ethnic differences in frequencies of common MTHFR SNPs. The MTHFR 1298 A and the rs4846051 C alleles were associated with MTX-related adverse events in Caucasians and African-Americans, respectively, but these findings should be replicated in larger studies. The rs4846051 SNP, which is far more common in African-Americans than in Caucasians, can also be proved to be a useful ancestry informative marker in future studies on genetic admixture.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/genetics , Methotrexate/therapeutic use , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Polymorphism, Single Nucleotide , Black or African American/genetics , Antirheumatic Agents/adverse effects , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/ethnology , Gene Frequency , Haplotypes , Humans , Methotrexate/adverse effects , Prospective Studies , Treatment Outcome , White People/geneticsABSTRACT
OBJECTIVE: Infliximab plus methotrexate (MTX) is approved for the treatment of rheumatoid arthritis (RA). Based on the benefit/risk profile of this combination therapy, lower doses of MTX would be preferable when infliximab efficacy can be maintained. We evaluated the ability of patients receiving infliximab plus MTX to achieve and maintain a clinical response while the dose of MTX was tapered. METHODS: Infliximab infusions were administered at a minimum dosage of 3 mg/kg at 8-week intervals (following three loading doses at weeks 0, 2, and 6) to patients who had an inadequate response to MTX. MTX tapering was initiated at week 22 or later when at least a 40% improvement in the combined tender and swollen joint count was achieved; dosages were reduced by 5 mg every 8 weeks to a protocol-specified minimum dosage of 5 mg per week. If the required dosage of MTX after a flare was greater than the baseline dosage, the patient was considered a treatment failure. RESULTS: Of the 210 patients enrolled, 159 (76%) achieved a 40% or better improvement in the combined tender and swollen joint count and had their MTX doses tapered. In these 159 responders, the median (mean) dose of MTX was reduced from 15 (16.5) mg per week at baseline to 5 (7.1) mg per week at week 54. From the time of initial response, 79% of these patients had a zero- or a one-vial increase in infliximab, corresponding to an approximate dose increase of 1 mg/kg, through week 54. CONCLUSION: Approximately 75% of the patients participating in this trial achieved at least a 40% reduction in the combined swollen and tender joint count (correlating with an American College of Rheumatology 20% [ACR20] response in 83% of patients) while reducing the mean MTX dose by 57%.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antirheumatic Agents/administration & dosage , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Methotrexate/administration & dosage , Methotrexate/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Arthritis, Rheumatoid/physiopathology , Drug Therapy, Combination , Female , Humans , Infliximab , Male , Middle Aged , Pain MeasurementABSTRACT
We analyzed clinical and genetic factors contributing to infections in 457 subjects with early rheumatoid arthritis (RA) enrolled in a prospective, 1-year clinical trial of methotrexate and the TNF inhibitor etanercept. Subjects were genotyped for the following single nucleotide polymorphisms (SNPs): (TNF -308, -238, and + 488); lymphotoxin-alpha (LTA) (LTA + 249, + 365, and + 720); and Fc gamma receptors FCGR2A 131 H/R; FCGR3A 176 F/V; and FCGR3B NA 1/2 and genotypes were correlated with infections. At least one URI was noted in 52% of subjects (99/191) with the NA2/NA2 genotype of the neutrophil-specific FCGR3B gene, compared to 42% (77/181) of those with the NA1/NA2 genotype and 39% (23/59) of those with the NA1/NA1 genotype (P = 0.038). Urinary tract infection (UTI) was associated with the TNF -238 A (odds ratio(OR) 2.56, 95% confidence interval (CI) 1.05-6.25) and LTA +365 C (OR 1.73, 95% CI 1.07-2.79) alleles, and marginally with the FCGR3A F allele (OR 1.72, 95% CI 0.99-3.00). There was a striking linear correlation between UTI and the number of risk alleles defined by these three SNPs (P < 0.001), suggesting an additive effect on susceptibility. These findings have important implications for the role of genetics in susceptibility to bacterial and viral infections.
Subject(s)
Arthritis, Rheumatoid/complications , Genetic Predisposition to Disease , Urinary Tract Infections/genetics , Age Factors , Aged , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/genetics , Etanercept , Female , Genotype , Humans , Immunoglobulin G/therapeutic use , Lymphotoxin-alpha/genetics , Male , Methotrexate/therapeutic use , Middle Aged , Polymorphism, Single Nucleotide , Prospective Studies , Receptors, IgG/genetics , Receptors, Tumor Necrosis Factor/therapeutic use , Risk Factors , Tumor Necrosis Factor-alpha/genetics , Urinary Tract Infections/complicationsABSTRACT
OBJECTIVE: To assess the efficacy and safety of 100 mg daily anakinra (Kineret), a recombinant form of the naturally occurring interleukin 1 receptor antagonist, plus methotrexate (MTX) in reducing the signs and symptoms of rheumatoid arthritis (RA). METHODS: Patients with active RA (n = 506) despite current treatment with MTX were enrolled in this multicentre, double blind, randomised, placebo controlled study. Patients received subcutaneous injections of anakinra 100 mg/day or placebo. They were assessed monthly for 6 months for improvement in signs and symptoms of RA and for adverse events. The primary efficacy measure was the percentage of patients attaining ACR20 response at week 24. RESULTS: Significantly greater proportions of patients treated with anakinra compared with placebo achieved ACR20 (38% v 22%; p<0.001), ACR50 (17% v 8%; p<0.01), and ACR70 (6% v 2%; p<0.05) responses. The response to anakinra was rapid; the proportion of patients with an ACR20 response at the first study assessment (4 weeks) was twice as high with anakinra as with placebo (p<0.005). Clinically meaningful and statistically significant responses were also seen in individual components of the ACR response (for example, Health Assessment Questionnaire, pain, C reactive protein levels, and erythrocyte sedimentation rate). Anakinra was well tolerated, with a safety profile, similar to that of placebo with one exception: mild to moderate injection site reactions were more common with anakinra than with placebo (65% v 24%). CONCLUSIONS: This study confirms previous observations from a dose-ranging study showing that anakinra, in combination with MTX, is an effective and safe treatment for patients with RA who have inadequate responses to MTX alone.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Methotrexate/therapeutic use , Sialoglycoproteins/therapeutic use , Antirheumatic Agents/adverse effects , Dose-Response Relationship, Drug , Double-Blind Method , Drug Therapy, Combination , Female , Humans , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , Interleukin 1 Receptor Antagonist Protein , Male , Methotrexate/adverse effects , Middle Aged , Receptors, Interleukin-1/antagonists & inhibitors , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic use , Severity of Illness Index , Sialoglycoproteins/adverse effectsABSTRACT
African-Americans have been under-represented in genetic studies of rheumatoid arthritis (RA) susceptibility and severity. Genetic and non-genetic factors influencing the radiographic severity of RA and its response to treatment are poorly understood, particularly in African-Americans. The Consortium for the Longitudinal Evaluation of African-Americans with early RA (CLEAR) Registry, a collaborative effort among four institutions in the southeast USA, will hopefully provide a useful resource to study these issues.
Subject(s)
Arthritis, Rheumatoid/ethnology , Arthritis, Rheumatoid/genetics , Black or African American/genetics , Registries , Adult , Age Distribution , Aged , Arthritis, Rheumatoid/diagnosis , Attitude to Health/ethnology , Female , Humans , Incidence , Male , Middle Aged , Pain Measurement , Prognosis , Range of Motion, Articular , Risk Assessment , Severity of Illness Index , Sex Distribution , United States/epidemiologyABSTRACT
Etanercept, a recombinant human tumor necrosis factor (TNF) inhibitor that binds both soluble and cell-bound TNF, has been shown to reduce disease activity and inhibit joint destruction when administered to patients with rheumatoid arthritis (RA). Because TNF receptors are found on many types of cells that modulate the immune response, we evaluated the general immune function of a subset of RA patients in a blinded clinical study. No significant differences were seen between patients treated with etanercept or placebo in the surface antigen phenotypes of peripheral blood leukocytes, T cell proliferative responses, neutrophil function, delayed-type hypersensitivity (DTH) reactions, serum immunoglobulin levels, or incidence of infections. Although this observational study was relatively small and could detect only major changes in immunological status, the stability of immune function over time in patients receiving etanercept corroborates the findings in clinical studies, which suggest that etanercept does not alter overall global immune function.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Immunoglobulin G/therapeutic use , Receptors, Tumor Necrosis Factor/therapeutic use , Adult , Aged , Arthritis, Rheumatoid/immunology , Double-Blind Method , Etanercept , Humans , Immunoglobulins/blood , Immunophenotyping , Infections/epidemiology , Lymphocyte Activation , Middle Aged , Neutrophils/physiology , T-Lymphocytes/immunologySubject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antirheumatic Agents/administration & dosage , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/diagnostic imaging , Emergencies , Humans , Radiography , Time FactorsABSTRACT
OBJECTIVE: Three 6-12-month, double-blind, randomized, controlled trials have shown leflunomide (LEF; 20 mg/day, loading dose 100 mg x 3 days) to be effective and safe for the treatment of rheumatoid arthritis (RA). This analysis of the North American trial assessed whether the clinical benefit evident at month 12 was sustained over 24 months of treatment with LEF as compared with the efficacy and safety of methotrexate (MTX), an equivalent disease-modifying antirheumatic drug, at 24 months. METHODS: The year-2 cohort, comprising patients continuing into the second year of treatment with > or = 1 dose of study medication and > or = 1 followup visit after week 52, consisted of 235 patients (LEF n = 98; placebo n = 36; MTX n = 101). The mean (+/- SD) maintenance dose of LEF was 19.6 +/- 1.99 mg/day in year 2 and that of MTX was 12.6 +/- 4.69 mg/week. Statistical analyses used an intent-to-treat (ITT) approach. Statistical comparisons of the active treatments only were prospectively defined in the protocol. RESULTS: In total, 85% and 79% of LEF and MTX patients, respectively, who entered year 2 completed 24 months of treatment. From month 12 to month 24, the American College of Rheumatology improvement response rates of > or = 20% (LEF 79% versus MTX 67%; P = 0.049), > or = 50% (LEF 56% versus MTX 43%; P = 0.053), and > or = 70% (LEF 26% versus MTX 20%; P = 0.361) were sustained in both of the active treatment groups. The mean change in total Sharp radiologic damage scores at year 2 compared with year 1 and baseline (LEF 1.6 versus MTX 1.2) showed statistically equivalent sustained retardation of radiographic progression in the active treatment groups. Maximal improvements evident at 6 months in the Health Assessment Questionnaire (HAQ) disability index (HAQ DI) and the physical component score of the Medical Outcomes Survey 36-item short form were sustained over 12 months and 24 months; improvement in the HAQ DI with LEF4(-0.60) was statistically significantly superior to that with MTX (-0.37) at 24 months (P = 0.005). Over 24 months in the ITT cohort, serious treatment-related adverse events were reported in 1.6% of the LEF-treated patients and 3.7% of the MTX-treated patients. Frequently reported adverse events included upper respiratory tract infections, diarrhea, nausea and vomiting, rash, reversible alopecia, and transient liver enzyme elevations. CONCLUSION: The safety and efficacy of LEF and MTX were maintained over the second year of this 2-year trial. Both active treatments retarded radiographic progression over 24 months. LEF was statistically significantly superior to MTX in improving physical function as measured by the HAQ DI over 24 months of treatment. Results indicate that LEF is a safe and effective initial treatment for active RA, with clinical benefit sustained over 2 years of treatment without evidence of new or increased toxicity.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Antirheumatic Agents/administration & dosage , Arthritis, Rheumatoid/drug therapy , Isoxazoles/administration & dosage , Methotrexate/administration & dosage , Adult , Aged , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Antirheumatic Agents/adverse effects , Double-Blind Method , Female , Humans , Isoxazoles/adverse effects , Leflunomide , Male , Methotrexate/adverse effects , Middle Aged , Prospective Studies , Treatment OutcomeABSTRACT
Rheumatoid arthritis is one of the most common chronic systemic inflammatory diseases, affecting approximately 1% of the adult population. Disease-modifying antirheumatic drugs (DMARDs) have been the mainstay of treatment for rheumatoid arthritis when combined with physical therapy and aspirin (acetylsalicylic acid) or nonsteroidal anti-inflammatory drugs. Recently, a number of new biological therapies have been introduced for the treatment of this condition and will have a major impact on the future management of this disabling disease. In this review, we summarise data on the efficacy and tolerability of the currently available DMARDs, including gold compounds, antimalarials, penicillamine, cytotoxic drugs (azathioprine and cyclophosphamide), sulfasalazine, methotrexate, leflunomide, cyclosporin, anti-tumour necrosis factor agents, combination therapy and apheresis. A literature review and quality assessment of economic evaluations of DMARDs is presented, illustrating that there has been a paucity of economic evaluations on these agents and showing the variable quality of those studies that are available. The manuscript also addresses the pharmacoeconomic implications of the new agents for rheumatoid arthritis; the need for formal long term economic evaluations in order to determine the cost effectiveness of these costly, but highly effective, new treatments is emphasised.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Antirheumatic Agents/adverse effects , Antirheumatic Agents/economics , Cost-Benefit Analysis , Costs and Cost Analysis , Drug Therapy, Combination , Health Care Costs , HumansABSTRACT
There is accumulating evidence that tumor necrosis factor plays a major role in the pathogenesis of rheumatoid arthritis. Recent biotechnological advances have allowed for the development of agents that directly target TNF, a proinflammatory cytokine. In the last 2 years, the U.S. Food and Drug Administration and the European Union's Commission of the European Communities have approved two biological agents for the treatment of refractory RA, etanercept and infliximab. Etanercept is a fusion protein, composed of the Fc portion of immunoglobulin G1 and the extracellular domain of a TNF receptor (p75). Infliximab is a chimeric monoclonal antibody composed of murine variable and human constant regions. In placebo-controlled trials, both agents have proven to be effective and well tolerated in RA patients.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Immunoglobulin G/therapeutic use , Receptors, Tumor Necrosis Factor/therapeutic use , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , Antirheumatic Agents/pharmacokinetics , Biological Availability , Etanercept , Half-Life , Humans , Infliximab , Mice , Randomized Controlled Trials as TopicABSTRACT
Rheumatoid arthritis (RA) is a common disease that affects up to 1% of the population, and causes significant morbidity and early mortality. The aetiology of RA is unknown; however, in the last 10 to 15 years significant advances in molecular technology have provided a greater understanding of the pathogenesis of the disease. This has led to the development of new approaches to the treatment of RA. The disease modifying antirheumatic oral agent leflunomide inhibits the proliferation of activated T cells that are important in the inflammation and degradation of synovial tissues. The 2 biological agents approved for the treatment of RA, infliximab and etanercept, are inhibitors of the pro-inflammatory cytokine, tumour necrosis factor-alpha (TNFalpha). Infliximab is a chimeric human/mouse monoclonal antibody which is administered by intravenous infusion and binds with high affinity to TNFalpha, thereby neutralising its effects. Etanercept is a recombinant, soluble TNF receptor molecule which is administered subcutaneously and binds to TNFalpha in the serum rendering it biologically inactive. The protein A immunoadsorption column is a medical device that in conjunction with plasmapheresis can be used in patients with refractory RA. These agents have provided new and effective therapies for the treatment of patients with RA.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Arthritis, Rheumatoid/etiology , Etanercept , Humans , Immunoglobulin G/adverse effects , Immunoglobulin G/therapeutic use , Infliximab , Isoxazoles/therapeutic use , Leflunomide , Methotrexate/adverse effects , Methotrexate/therapeutic use , Receptors, Tumor Necrosis Factor/therapeutic use , Staphylococcal Protein A/therapeutic use , Tumor Necrosis Factor-alpha/therapeutic useABSTRACT
Interleukin-11 (IL-11) is a pleiotropic cytokine that regulates the growth and development of hematopoietic stem cells and decreases the proinflammatory mediators of cytokine and nitric oxide production. In animal models of arthritis, treatment with recombinant human IL-11 (rhIL-11) reduces both the level of synovitis and the histologic lesion scores in the joints. The goal of this phase-I/II study in adults with rheumatoid arthritis (RA) was to evaluate the safety and clinical activity of different doses and schedules of rhIL-11 in patients with active RA for whom treatment with at least one disease-modifying antirheumatic drug had failed. This was a multicenter, randomized, placebo-controlled trial that evaluated the safety and tolerability of rhIL-11 in 91 patients with active RA. rhIL-11 was administered subcutaneously; patients were randomized into one of five treatment groups (ratio of rhIL-11 to placebo, 4:1). Patients were treated for 12 weeks with either 2.5 or 7.5 microg/kg of rhIL-11 or placebo twice per week or 5 or 15 microg/kg of rhIL-11 or placebo once per week. The status of each subject's disease activity in accordance with the American College of Rheumatology (ACR) criteria was assessed before, during, and after completion of administration of the study drug. Administration of rhIL-11 was well tolerated at all doses and schedules. The most frequent adverse event was a reaction at the injection site. The data suggest a statistically significant reduction in the number of tender joints (P < 0.008) at the 15 microg/kg once-weekly dose schedule but showed no overall significant benefit at the ACR criterion of a 20% response. The trial showed rhIL-11 to be safe and well tolerated at a variety of doses and schedules over a 12-week treatment period in patients with active RA. The only adverse event clearly associated with rhIL-11 administration was reaction at the injection site.