Stable Dose Of Methotrexate Research Articles

Concomitant iguratimod therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate: a randomized, double-blind, placebo-controlled trial

Objectives To investigate the efficacy and safety of iguratimod (T-614) in Japanese patients with active rheumatoid arthritis who had inadequate response to stable background methotrexate (MTX) alone.Methods In this multicenter, double-blind, controlled trial, a total of 253 patients were randomized at 2:1 ratio to either the iguratimod group or the placebo group. Iguratimod was orally administered at dosages of 25 mg/day for the first 4 weeks (25 mg once daily) and 50 mg/day for the subsequent 20 weeks (25 mg twice daily). MTX at dosage of 6 or 8 mg/week was administered to patients in both groups.Results The rate of 20 % improvement in American College of Rheumatology criteria (ACR20) at week 24 was 69.5 % in the iguratimod group compared with 30.7 % in the placebo group (P < 0.001). Significant improvements in the ACR50, ACR70, Health Assessment Questionnaire Disability Index, Disease Activity Score 28 <3.2, and rheumatoid factor were also observed. The most commonly reported adverse events (AEs) were blood iron decrease, nasopharyngitis, and lymphocyte decrease. These AEs were mild or moderate in severity. No deaths occurred.Conclusion The study results suggest that iguratimod in combination with MTX was efficacious and had a manageable safety profile.

Rheumatology meeting: Efficacy, safety of biologics central focus

Comparing two biologics Based on 1-year results from the AMPLE (Abatacept Versus Adalimumab Comparison in Biologic-Naive RA Subjects with Background Methotrexate) trial, Roy Fleischmann, MD, and colleagues reported that use of subcutaneous abatacept (Orencia—Bristol-Myers Squibb) or adalimumab (Humira—Abbott) resulted in comparable rates of remission in biologic-naive patients who had an inadequate response to methotrexate (abstract 1340). AMPLE is the fi rst head-to-head trial to compare the effi cacy of two different biologics for the management of RA. In this ongoing, randomized, investigator-blinded, 24-month Phase IIIb study, researchers randomized biologic-naive patients with RA who had an inadequate response to methotrexate to abatacept 125 mg weekly (n = 318) or adalimumab 40 mg biweekly (n = 328). All patients remained on a stable dose of methotrexate throughout the trial. Researchers assessed various remission criteria, including DAS28CRP (Disease Activity Score 28 Based on C-Reactive Protein), RAPID3 (Routine Assessment of Patient Index Data 3), CDAI (Clinical Disease Activity Index), and SDAI (Simple Disease Activity Index). After 12 months, clinical, functional, and radiographic effi cacy, and safety were similar between the two groups. The proportion of patients meeting the various remission criteria for abatacept and adalimumab were 43.3% versus 41.9% for DAS28-CRP ≤ 2.6, 27.2% versus 25.1% for RAPID3 < 1.0, 23.5% versus 24.0% for CDAI ≤ 2.8, and 23.3% versus 24.8% for SDAI ≤ 3.3. Across all assessed remission criteria, 76% to 85% of patients in both treatment arms achieved Health Assessment Questionnaire response at year 1. In addition, 63% to 100% of patients had no radiographic progression, depending on the remission criteria employed.

The role of bromocriptine in the treatment of patients with active rheumatoid arthritis

We decided to determine the effectiveness of oral bromocriptine in patients with active rheumatoid arthritis (RA) who are in methotrexate (MTX) therapy. Patients receiving stable doses of MTX were randomized to one of two groups and received 3 months of double-blind bromocriptine (5 mg/day) or matching placebo. The moderate and major outcome measures were the proportion of patients with > 0.6 and > 1.2 improvement in RA based on the Disease Activity Score 28 (DAS28) at 3 months. Safety measures included adverse events and laboratory assessments. On a background treatment of MTX, the percentage of patients with moderate and major DAS28 responses at 3 months in the bromocriptine group (73.8%/59.5%) was not significantly different from placebo (63.1%/31.6%). Side effects were typically mild and included mild nausea and sleep disturbance; we did not have any adverse events resulting in discontinuation of the study drug. In patients with active RA receiving stable doses of MTX, bromocriptine showed non-significant improvement in efficiency outcomes compared to placebo.

Serological identification of fast progressors of structural damage with rheumatoid arthritis

IntroductionRheumatoid arthritis (RA) patients with structural progression are in most need of immediate treatment to maintain tissue integrity. The serum protein fingerprint, type I collagen degradation mediated by matrix metalloproteinases (MMP)-cleavage (C1M), is a biomarker of tissue destruction. We investigated whether baseline serum C1M levels could identify structural progressors and if the biomarker levels changed during anti-inflammatory treatment with tocilizumab (TCZ).MethodsThe LITHE-biomarker study (NCT00106535, n = 585) was a one-year phase III, double-blind, placebo (PBO)-controlled, parallel group study of TCZ 4 or 8 mg/kg every four weeks, in RA patients on stable doses of methotrexate (MTX). Spearman's ranked correlation was used to assess the correlation between baseline C1M levels and structural progression at baseline and at weeks 24 and 52. Multivariate regression was performed for delta structural progression. Change in C1M levels were studied as a function of time and treatment.ResultsAt baseline, C1M was significantly correlated to C-reactive protein (P <0.0001), visual analog scale pain (P <0.0001), disease activity score28-erythrocyte sedimentation rate (DAS28-ESR) (P <0.0001), joint space narrowing (JSN) (P = 0.0056) and modified total Sharp score (mTSS) (P = 0.0006). Baseline C1M was significantly correlated with delta-JSN at Week 24 (R2 = 0.09, P = 0.0001) and at Week 52 (R2 = 0.27, P <0.0001), and with delta-mTSS at 24 weeks (R2 = 0.006, P = 0.0015) and strongly at 52 weeks (R2 = 0.013, P <0.0001) in the PBO group. C1M levels were dose-dependently reduced in the TCZ + MTX group.ConclusionsBaseline C1M levels correlated with worsening joint structure over one year. Serum C1M levels may enable identification of those RA patients that are in most need of aggressive treatmentTrial registrationClinicalTrials.gov: NCT00106535

Oral administration of GLPG0259, an inhibitor of MAPKAPK5, a new target for the treatment of rheumatoid arthritis: a phase II, randomised, double-blind, placebo-controlled, multicentre trial

BackgroundMitogen-activated protein (MAP) kinases are key regulators of cytokine production, and are therefore potential targets for treatment of rheumatoid arthritis (RA).ObjectiveThis two-part phase II study investigated the efficacy and safety...

Digital Gangrene in a Patient with Systemic Lupus Erythematosus and Systemic Sclerosis: Figure 1.

Nearly half of patients with systemic sclerosis (SSc) experience a digital ulcer, and many of these ulcers may progress to digital gangrene. Gangrene can stem from inadequate healing of digital ulcers or complications of comorbidities along with elevated C-reactive protein (CRP) levels. A 49-year-old woman diagnosed with systemic lupus erythematosus (SLE) and an overlap with SSc since 2006 presented in December 2010 with a 1-day history of acute pain and discoloration of all her digits (Figure 1). Figure 1. Dorsal and palmar views showing acute gangrene of all 5 digits on the right hand and chronic ulcers affecting the palmar aspect on the left hand (A, B). Panels (C) and (D) show both hands after 6 months of followup. Note the extensive skin desquamation on both hands. Her connective tissue disease course was characterized by sclerodactyly, gastrointestinal reflux, inflammatory arthritis, serositis, oral ulcers, Raynaud’s phenomenon (RP), positive antinuclear antibody with titer 1:640 in a speckled pattern, rheumatoid factor, anti-Sm, and anti-RNP antibodies. She was treated since 2008 with stable doses of methotrexate and leflunomide. She was not known to have any risk factors for atherosclerosis such as diabetes mellitus, hypertension, or dyslipidemia, and she did …

Tofacitinib or Adalimumab versus Placebo in Rheumatoid Arthritis

BackgroundTofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated for the treatment of rheumatoid arthritis.MethodsIn this 12-month, phase 3 trial, 717 patients who were receiving stable doses of methotrexate were randomly assigned to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, 40 mg of adalimumab once every 2 weeks, or placebo. At month 3, patients in the placebo group who did not have a 20% reduction from baseline in the number of swollen and tender joints were switched in a blinded fashion to either 5 mg or 10 mg of tofacitinib twice daily; at month 6, all patients still receiving placebo were switched to tofacitinib in a blinded fashion. The three primary outcome measures were a 20% improvement at month 6 in the American College of Rheumatology scale (ACR 20); the change from baseline to month 3 in the score on the Health Assessment Questionnaire–Disability Index (HAQ-DI) (which ranges from 0 to 3, with higher scores indicating greater disability); and the percentage of patients at month 6 who had a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating greater disease activity).ResultsAt month 6, ACR 20 response rates were higher among patients receiving 5 mg or 10 mg of tofacitinib (51.5% and 52.6%, respectively) and among those receiving adalimumab (47.2%) than among those receiving placebo (28.3%) (P<0.001 for all comparisons). There were also greater reductions in the HAQ-DI score at month 3 and higher percentages of patients with a DAS28-4(ESR) below 2.6 at month 6 in the active-treatment groups than in the placebo group. Adverse events occurred more frequently with tofacitinib than with placebo, and pulmonary tuberculosis developed in two patients in the 10-mg tofacitinib group. Tofacitinib was associated with an increase in both low-density and high-density lipoprotein cholesterol levels and with reductions in neutrophil counts.ConclusionsIn patients with rheumatoid arthritis receiving background methotrexate, tofacitinib was significantly superior to placebo and was numerically similar to adalimumab in efficacy. (Funded by Pfizer; ORAL Standard ClinicalTrials.gov number, NCT00853385.)

Concomitant iguratimod therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate: a randomized, double-blind, placebo-controlled trial

To investigate the efficacy and safety of iguratimod (T-614) in Japanese patients with active rheumatoid arthritis who had inadequate response to stable background methotrexate (MTX) alone. In this multicenter, double-blind, controlled trial, a total of 253 patients were randomized at 2:1 ratio to either the iguratimod group or the placebo group. Iguratimod was orally administered at dosages of 25 mg/day for the first 4 weeks (25 mg once daily) and 50 mg/day for the subsequent 20 weeks (25 mg twice daily). MTX at dosage of 6 or 8 mg/week was administered to patients in both groups. The rate of 20 % improvement in American College of Rheumatology criteria (ACR20) at week 24 was 69.5 % in the iguratimod group compared with 30.7 % in the placebo group (P < 0.001). Significant improvements in the ACR50, ACR70, Health Assessment Questionnaire Disability Index, Disease Activity Score 28 <3.2, and rheumatoid factor were also observed. The most commonly reported adverse events (AEs) were blood iron decrease, nasopharyngitis, and lymphocyte decrease. These AEs were mild or moderate in severity. No deaths occurred. The study results suggest that iguratimod in combination with MTX was efficacious and had a manageable safety profile.

A phase II, randomized, double‐blind, placebo‐controlled study evaluating the efficacy and safety of MDX‐1100, a fully human anti‐CXCL10 monoclonal antibody, in combination with methotrexate in patients with rheumatoid arthritis

CXCL10 (also known as interferon-γ-inducible 10-kd protein [IP-10]) is a chemokine that potentially plays a role in the immunopathogenesis of rheumatoid arthritis (RA). We undertook this phase II study to evaluate the efficacy and safety of MDX-1100, a fully human, anti-CXCL10 (anti-IP-10) monoclonal antibody, in RA patients whose disease responded inadequately to methotrexate (MTX). Patients with active RA receiving stable doses of MTX (10-25 mg weekly) were randomized to receive intravenous doses of 10 mg/kg MDX-1100 (n = 35) or placebo (n = 35) every other week. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) on day 85, and patients were followed up for safety to day 141. The ACR20 response rate was significantly higher among MDX-1100-treated patients than among placebo-treated patients (54% versus 17%; P = 0.0024). Statistically significant differences in the ACR20 response rate between treatments were observed starting on day 43 (P < 0.05). The ACR50 and ACR70 response rates on day 85 did not differ between the groups. Overall, 51.4% of MDX-1100-treated patients and 30.3% of placebo-treated patients experienced at least 1 adverse event (AE). No study drug-related serious AEs were reported. MDX-1100 was well tolerated and demonstrated clinical efficacy in RA patients whose disease responded inadequately to MTX. This is the first study to demonstrate clinical efficacy of a chemokine inhibitor in RA and supports the notion of a potential role of IP-10 in the immunopathogenesis of RA.

Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: Results of a forty‐eight–week randomized, double‐blind, placebo‐controlled, parallel‐group phase III trial

To evaluate the efficacy and safety of treatment with ocrelizumab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and an inadequate response to MTX. STAGE was a phase III randomized, double-blind, parallel-group international study to evaluate the safety and efficacy of ocrelizumab compared with placebo in patients with active RA continuing MTX treatment. Patients receiving stable doses of MTX were randomized to receive 2 infusions of placebo (n = 320), ocrelizumab 200 mg (n = 343), or ocrelizumab 500 mg (n = 343) on days 1 and 15 as well as weeks 24 and 26. Coprimary end points were the proportion of patients with an American College of Rheumatology 20% improvement criteria (ACR20) response at weeks 24 and 48. Secondary end points included the change from baseline in the modified Sharp/van der Heijde score (SHS) and the ACR50/70 responses. The ACR20 response rates were 35.7% in the placebo group, 56.9% in the ocrelizumab 200 mg group, and 54.5% in the ocrelizumab 500 mg group at 24 weeks, and 27.6%, 58.3%, and 62.1%, respectively, at 48 weeks (P < 0.0001 versus placebo for each dose at both time points). At week 48, both of the ocrelizumab doses improved the ACR50 and ACR70 response rates 3-fold as compared with placebo and showed a statistically significant (P < 0.0001) reduction in joint damage progression relative to placebo (mean change in SHS reduced by 85% and 100% for the 200-mg and 500-mg doses, respectively). Rates of serious infection were comparable in the placebo (3.48 per 100 patient-years) and ocrelizumab 200 mg (3.54 per 100 patient-years) groups but were elevated in the ocrelizumab 500 mg group (8.66 per 100 patient-years). With both ocrelizumab doses, the primary end point was met, and the signs and symptoms of RA were significantly improved at weeks 24 and 48. Ocrelizumab also significantly inhibited the progression of joint damage. A higher rate of serious infections was observed with 500 mg of ocrelizumab as compared with ocrelizumab 200 mg or placebo.

Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to at least one tumor necrosis factor inhibitor: Results of a forty‐eight–week randomized, double‐blind, placebo‐controlled, parallel‐group phase III trial

To evaluate the safety and efficacy of ocrelizumab plus methotrexate (MTX) or leflunomide (LEF) in patients with active rheumatoid arthritis (RA) and an inadequate response to tumor necrosis factor α inhibitors. This was a multicenter randomized, double-blind, placebo-controlled, parallel-group study that continued over 48 weeks. Patients receiving stable doses of MTX or LEF were randomized to receive 2 infusions of placebo (n = 277), ocrelizumab 200 mg (n = 278), or ocrelizumab 500 mg (n = 285) on days 1 and 15 as well as at weeks 24 and 26. Coprimary end points were the proportion of patients with response according to the American College of Rheumatology 20% improvement criteria (ACR20) at weeks 24 and 48. Secondary end points included the change from baseline in the modified Sharp/van der Heijde score (SHS) and the ACR50/70 responses. ACR20 responses were 22.0% in the placebo group, 42.2% in the ocrelizumab 200 mg group, and 47.9% in the ocrelizumab 500 mg group at 24 weeks and 19.5%, 48.7%, and 50.7%, respectively, at 48 weeks (P < 0.0001 versus placebo for each comparison at each time point). At 48 weeks, patients receiving both doses of ocrelizumab showed significantly improved ACR50 and ACR70 responses of ~3-fold versus placebo. Only those in the ocrelizumab 500 mg group showed statistically significant (P = 0.0017) inhibition of joint damage progression (mean change in the SHS) relative to placebo (61% inhibition) at 48 weeks. Overall adverse events and infections during the 48 weeks of study were comparable in all treatment groups. Serious infections were observed more frequently in patients taking ocrelizumab (5.1% and 4.3%) than in those taking placebo (2.5%). Patients in both of the ocrelizumab groups met the clinical primary efficacy end points. Inhibition of change in the SHS was statistically significant at 48 weeks for those in the ocrelizumab 500 mg group. The rate of serious infections in this trial was higher for both ocrelizumab doses as compared with placebo.

Efficacy of Vitamin D in patients with active rheumatoid arthritis receiving methotrexate therapy

To determine the efficacy of oral vitamin D [25(OH)D] in patients with active rheumatoid arthritis (RA) who are in methotrexate (MTX) therapy, patients receiving stable doses of MTX were randomized to one of two dose groups and received 12 weeks of double-blind vitamin D[25(OH)D] (50,000 IU per week) or matching placebo. The moderate and major efficacy measure was the proportion of patients with >0.6 and >1.2 improvement in RA based on the Disease Activity Score 28(DAS 28) at 12 weeks. Safety measures included adverse events and laboratory assessments. On a background of MTX, the percentage of patients with a moderate/major DAS 28 response at week 12 in the vitamin D groups (76/44%) was not significantly different from placebo (64.6/33.4%). Adverse events were typically mild and included small hepatic enzyme elevation; we did not have any undesirable events resulting in discontinuation of study drug. In patients with active RA receiving stable doses of MTX, vitamin D showed non-significant improvement in efficacy outcomes compared to placebo.

Evaluation of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis: Results from a randomized controlled trial

To assess the safety of rituximab in combination with a tumor necrosis factor (TNF) inhibitor and methotrexate (MTX) in patients with rheumatoid arthritis (RA). Adult patients with active RA (≥ 5 swollen and ≥ 5 tender joints) receiving a stable dose of MTX (10-25 mg/week) and stable dose of TNF inhibitor (etanercept or adalimumab) for ≥ 12 weeks were randomized 2:1 to receive one course of rituximab or placebo, given intravenously at a dose of 2 × 500 mg. The primary end point was the proportion of patients developing ≥ 1 serious infection through week 24. Fifty-one patients were treated with either rituximab or placebo in combination with background MTX and a TNF inhibitor. Baseline characteristics were generally balanced between groups, except for corticosteroid usage (36% in the rituximab arm versus 17% in the placebo arm). A serious infection (pneumonia) was observed in 1 patient (3%) in the rituximab group after 14.4 patient-years of exposure (6.95 events per 100 patient-years, 95% confidence interval 0.98-49.35), compared with none in the placebo group at week 24. Infections were reported in 18 patients (55%) and 11 patients (61%) in the rituximab and placebo groups, respectively. Grade 3 infections were reported in 3 patients (9%) receiving rituximab and in none of the patients receiving placebo. No grade 4 infections were observed, nor were there any opportunistic, fungal, or tuberculosis infections. Serious adverse events (SAEs) were reported in 2 rituximab-treated patients (pneumonia and coronary artery occlusion), whereas there were no SAEs reported in placebo-treated patients. At week 24, the percentage of patients achieving an American College of Rheumatology 20% (ACR20) improvement response was 30% in the rituximab group compared with 17% in the placebo group, and ACR50 responses were achieved by 12% and 6% of patients, respectively. The preliminary safety profile of rituximab in combination with a TNF inhibitor and MTX was consistent with the safety profile of rituximab in combination with MTX in other RA trials without a TNF inhibitor, with no new safety signals observed. SAEs were numerically more frequent in the rituximab group, and there was no clear evidence of an efficacy advantage in patients receiving rituximab in combination with a TNF inhibitor and MTX.

The effect of genotype on methotrexate polyglutamate variability in juvenile idiopathic arthritis and association with drug response

The response to and toxicity of methotrexate (MTX) are unpredictable in patients with juvenile idiopathic arthritis (JIA). Intracellular polyglutamation of MTX, assessed by measuring concentrations of MTX polyglutamates (MTXGlu), has been demonstrated to be a promising predictor of drug response. Therefore, this study was aimed at investigating the genetic predictors of MTXGlu variability and associations between MTXGlu and drug response in JIA. The study was designed as a single-center cross-sectional analysis of patients with JIA who were receiving stable doses of MTX at a tertiary care children's hospital. After informed consent was obtained from the 104 patients with JIA, blood was withdrawn during routine MTX-screening laboratory testing. Clinical data were collected by chart review. Genotyping for 34 single-nucleotide polymorphisms (SNPs) in 18 genes within the MTX metabolic pathway was performed. An ion-pair chromatographic procedure with mass spectrometric detection was used to measure MTXGlu1-7. Analysis and genotyping of MTXGlu was completed in the 104 patients. K-means clustering resulted in 3 distinct patterns of MTX polyglutamation. Cluster 1 had low red blood cell (RBC) MTXGlu concentrations, cluster 2 had moderately high RBC MTXGlu1+2 concentrations, and cluster 3 had high concentrations of MTXGlu, specifically MTXGlu3-5. SNPs in the purine and pyrimidine synthesis pathways, as well as the adenosine pathway, were significantly associated with cluster subtype. The cluster with high concentrations of MTXGlu3-5 was associated with elevated liver enzyme levels on liver function tests (LFTs), and there were higher concentrations of MTXGlu3-5 in children who reported gastrointestinal side effects and had abnormal findings on LFTs. No association was noted between MTXGlu and active arthritis. MTXGlu remains a potentially useful tool for determining outcomes in patients with JIA being treated with MTX. The genetic predictors of MTXGlu variability may also contribute to a better understanding of the intracellular biotransformation of MTX in these patients.

Efficacy and safety of a selective estrogen receptor β agonist, ERB‐041, in patients with rheumatoid arthritis: A 12‐week, randomized, placebo‐controlled, phase II study

Selective estrogen receptor β (ERβ) agonists have demonstrated relevant antiinflammatory effects in different animal models. This study aimed to compare the efficacy and safety of one of these agonists, ERB-041, in subjects with rheumatoid arthritis (RA). A total of 291 patients with active RA receiving stable doses of methotrexate were randomized to receive 5, 25, or 75 mg of ERB-041 or placebo for 12 weeks. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) at 12 weeks. Secondary end points included the ACR 50% improvement criteria (ACR50) and the ACR 70% improvement criteria (ACR70) responses, health outcomes measures, C-reactive protein (CRP) levels, and potential exposure-response relationships. Medical history, physical examination, and laboratory values were obtained at screening, baseline, and weeks 2, 4, 8, and 12. No statistically significant difference for the ACR20 was found between the ERB-041 treatment and placebo groups (P = 0.518). Nor was a significant difference observed for ACR50 and ACR70 responses, health outcomes measures, CRP levels, and overall incidence of adverse events among all groups. Forty-four subjects (15.1%) discontinued the study and the rate of discontinuation was similar among the treatment groups. The most commonly reported treatment-emergent adverse events were headache (7.6%), nausea (6.2%), infection (4.8%), and bronchitis (4.1%). None of the adverse events was considered treatment related. Although well tolerated and safe, ERB-041 failed to demonstrate antiinflammatory efficacy in RA patients, despite evidence of strong activity in preclinical arthritis models. These results suggest that selective ERβ agonists would not have effects on regulating inflammatory response in RA. Nevertheless, further studies are warranted to establish their efficacy in inflammatory arthritis.

Analysis of intracellular methotrexate polyglutamates in patients with juvenile idiopathic arthritis: Effect of route of administration on variability in intracellular methotrexate polyglutamate concentrations

Intracellular methotrexate (MTX) polyglutamates (MTXGlu) have been shown to be potentially useful biomarkers of clinical response in adult patients with rheumatoid arthritis. The present study was undertaken to measure intracellular MTXGlu concentrations in a cohort of patients with juvenile idiopathic arthritis (JIA) to determine the predictors of MTXGlu variability in these patients. Blood samples were obtained from patients with JIA who were being treated with a stable dose of MTX for >or=3 months. Clinical data were collected by chart review. Concentrations of MTXGlu(1-7) in red blood cell lysates were quantitated using an innovative ion-pairing chromatography procedure, with detection by mass spectrometry. Patients with JIA from a single center (n = 99; mean +/- SD age 117.8 +/- 56.5 months, 69 female) were included in the analysis. The mean +/- SD dose of MTX was 0.51 +/- 0.25 mg/kg per week, with a median treatment duration of 18 months (interquartile range 3-156 months). MTX was administered subcutaneously in 66 patients (67%). Fifty-six patients (57%) had active arthritis at the time of the clinic visit. Total intracellular MTXGlu (MTXGlu(TOT)) concentrations varied 40-fold, with a mean +/- SD total concentration of 85.8 +/- 48.4 nmoles/liter. Concentrations of each MTXGlu subtype (MTXGlu(1-7)) were measured individually and as a percentage of MTXGlu(TOT) in each patient. MTXGlu(3) was the most prominent subtype identified, comprising 42% of MTXGlu(TOT), and the interindividual variability in the concentration of MTXGlu(3) was the most highly correlated with that of MTXGlu(TOT) (r = 0.96). The route of MTX administration was significantly associated with MTXGlu(1-5) subtypes; higher concentrations of MTXGlu(1 + 2) were observed in patients receiving oral doses of MTX, whereas higher concentrations of MTXGlu(3-5) were observed in patients receiving subcutaneous doses of MTX (P < 0.0001). In this cohort of patients with JIA, the MTXGlu(TOT) concentration varied 40-fold. Individual MTXGlu metabolites (MTXGlu(1-7)), which have, until now, not been previously reported in patients with JIA, were detected. The route of MTX administration contributed to the variability in concentrations of MTXGlu(1-5).

Denosumab prevents metacarpal shaft cortical bone loss in patients with erosive rheumatoid arthritis

Osteoclast-mediated bone loss in the hand predicts future bone erosions in patients with rheumatoid arthritis (RA). Osteoclast activity depends on RANKL, which is inhibited by denosumab, an investigational fully human monoclonal antibody against RANKL. We measured metacarpal shaft cortical bone thickness using a novel computer-based technique, digital x-ray radiogrammetry (DXR), to evaluate the effects of denosumab on cortical bone in RA. Patients (n = 227) with active, erosive RA were randomized to receive subcutaneous denosumab 60 mg or 180 mg or placebo every 6 months. All patients received stable doses of methotrexate and daily calcium and vitamin D. For this blinded post hoc analysis (n = 218), cortical bone loss was determined by DXR using computer-assisted measurement of cortical thickness and shaft width at 21 midshaft levels of the second through fourth metacarpal bones of both hands. At 12 months, patients receiving denosumab had significantly less metacarpal bone loss versus placebo (denosumab 60 mg: -0.0034, denosumab 180 mg: 0.0001 gain, placebo: -0.0108; P < or = 0.01 for both denosumab doses). Twelve-month decreases from baseline greater than the smallest detectable change occurred in 2 patients in the denosumab 180 mg group, 9 patients in the denosumab 60 mg group, and 12 patients in the placebo group. Negative correlation was significant between static cortical thickness ratios and static erosion scores (6 and 12 months), and for placebo, between changes in erosion scores and changes in cortical thickness ratio. Twice-yearly injections of denosumab with ongoing methotrexate treatment significantly reduced cortical bone loss in RA patients for up to 12 months. These results add to the growing evidence supporting the clinical utility of DXR.

Efficacy and safety of pamapimod in patients with active rheumatoid arthritis receiving stable methotrexate therapy

Objective:To determine the efficacy and safety of pamapimod in adult patients with active rheumatoid arthritis (RA) who had an inadequate clinical response to methotrexate (MTX).Methods:Patients receiving stable doses of MTX...

Immunization responses in rheumatoid arthritis patients treated with rituximab: Results from a controlled clinical trial

To examine immunization responses in patients with rheumatoid arthritis (RA) treated with rituximab and to investigate the effects of rituximab-induced CD20+ B cell depletion on immune responses to tetanus toxoid (T cell-dependent antigen), pneumococcal polysaccharide (T cell-independent antigen), and keyhole limpet hemocyanin (KLH) (neoantigen) and on delayed-type hypersensitivity (DTH). In a controlled trial, we enrolled 103 patients with active RA receiving a stable dose of methotrexate (MTX). Tetanus toxoid, pneumococcal polysaccharide, and KLH vaccines as well as a Candida albicans skin test were administered to 1 group of patients receiving rituximab plus MTX (called rituximab-treated patients) for 36 weeks and to 1 group of patients receiving MTX alone for 12 weeks. The primary end point was the proportion of patients with a >or=4-fold rise in antitetanus IgG levels. Antitetanus, antipneumococcal, and anti-KLH serum IgG levels were measured prior to and 4 weeks following vaccine administration. The DTH response to C albicans was measured 2-3 days following placement. Responses to tetanus toxoid vaccine (>or=4-fold rise) were similar in both groups (39.1% of rituximab-treated patients and 42.3% of patients treated with MTX alone). The ability to maintain a positive DTH response to the C albicans skin test was comparable in both groups (77.4% of rituximab-treated patients and 70% of patients treated with MTX alone), showing no effect of rituximab treatment. Rituximab-treated patients had decreased responses to pneumococcal polysaccharide vaccine (57% of patients had a 2-fold rise in titer in response to >or=1 serotype, compared with 82% of patients treated with MTX alone) and to KLH vaccine (47% of patients had detectable anti-KLH IgG, compared with 93% of patients treated with MTX alone). Recall responses to the T cell-dependent protein antigen tetanus toxoid as well as DTH responses were preserved in rituximab-treated RA patients 24 weeks after treatment. Responses to neoantigen (KLH) and T cell-independent responses to pneumococcal vaccine were decreased, but many patients were able to mount responses. These data suggest that polysaccharide and primary immunizations should be administered prior to rituximab infusions to maximize responses.

Examination of the Effect of Increasing Doses of Etoricoxib on Oral Methotrexate Pharmacokinetics in Patients With Rheumatoid Arthritis

The authors designed 2 randomized controlled studies to examine the effects of etoricoxib 60 to 120 mg daily on methotrexate pharmacokinetics in 50 rheumatoid arthritis (RA) patients on stable doses of methotrexate (7.5-20 mg). Patients received oral methotrexate at baseline and on days 7 and 14. In study 1, patients received etoricoxib 60 mg (days 1-7) and then 120 mg (days 8-14); in study 2, patients received etoricoxib 90 mg (days 1-7) and then 120 mg (days 8-14). For study 1, the AUC(0-infinity) geometric mean ratio (GMR) (90% confidence interval [CI]) for day 7 versus baseline was 1.01 (0.91, 1.12) for etoricoxib 60 mg; the area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)) GMR (90% CI) for day 14 was 1.28 (1.15, 1.42) for etoricoxib 120 mg. For study 2, the AUC(0-infinity) GMR (90% CI) for day 7 versus baseline was 1.07 (1.01, 1.13) for etoricoxib 90 mg; the AUC(0-infinity) GMR (90% CI) for day 14 was 1.05 (0.99, 1.11) for etoricoxib 120 mg. In summary, etoricoxib 60 and 90 mg had no effect on methotrexate plasma concentrations. Although no effect on methotrexate pharmacokinetics was observed with etoricoxib 120 mg in study 2, GMR AUC(0-infinity) fell outside the prespecified bounds in study 1. Standard monitoring of methotrexate-related toxicity should be continued when etoricoxib and methotrexate are administered concurrently, especially with doses >90 mg etoricoxib.