Rheumatoid Arthritis: Kremer J

Kremer J. · No affiliation provided · Arthritis Rheum. · Pubmed #16208649 links to  free full text

This publication has no abstract.

Kremer J. · Center for Rheumatology, Albany Medical College, 1367 Washington Avenue, Albany, NY 12203, USA. · Ann Rheum Dis. · Pubmed #16239384 links to  free full text

This publication has no abstract.

Wolfe F, Rehman Q, Lane NE, Kremer J. · National Data Bank for Rheumatic Diseases--Arthritis Research Center Foundation, Inc., Wichita, Kansas 67214, USA. · J Rheumatol. · Pubmed #11469485 No free full text.

Abstract: Our aim was to investigate the practices and standards by which disease modifying antirheumatic drugs (DMARD) and biologics are and have been prescribed. We reviewed the literature and examined data from patients with rheumatoid arthritis (RA) participating in a national cohort: the National Data Bank for Rheumatic Diseases (NDB). Four pathways for DMARD prescription were identified: (1) A time-based pyramidal approach (the RA pyramid); (2) a severity-based pyramid in which the most effective treatment is given to those with more active disease; (3) a cost-based pathway in which the primary goal is cost containment--this pathway intertwines with the severity-based pathway; and (4) a patient preference pathway where treatment is geared to patient needs and wishes regardless of severity. Data show that the time-based and severity-based pathways are not generally used in contemporary expert practice, and that patients with all degrees of severity and disease duration are receiving DMARD and biologic treatment. With the abandonment of the pyramid and the development of effective therapy, rheumatic disease care has swung away from the imperative of time and severity-based treatment to the imperative of care based on patient preference. It is the standard of practice to treat patients with mild and early disease with aggressive therapy, with the goal of limiting subsequent damage and retarding progression, and with the realistic purpose of relieving symptoms. The standard may at times be in conflict with the goals of insurers, but there is no legitimate medical reason for such limitations.

Weinblatt M, Schiff M, Goldman A, Kremer J, Luggen M, Li T, Chen D, Becker JC. · Rheumatology and Immunology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. · Ann Rheum Dis. · Pubmed #16935912 No free full text.

Abstract: OBJECTIVE: To investigate the efficacy and safety of abatacept in combination with etanercept in patients with active rheumatoid arthritis during a 1-year, randomised, placebo-controlled, double-blind phase, followed by an open-label, long-term extension (LTE). METHODS: Patients continued etanercept (25 mg twice weekly) and were randomised to receive abatacept 2 mg/kg (n = 85) or placebo (n = 36). As the effective dose of abatacept was established as 10 mg/kg in a separate trial, all patients received abatacept 10 mg/kg and etanercept during the LTE. RESULTS: A total of 121 patients were randomised; 80 completed double-blind treatment and entered the LTE. During double-blind treatment, the difference in the percentage of patients achieving the primary end point (modified American College of Rheumatology (ACR) 20 response at 6 months) was not significant between groups (48.2% v 30.6%; p = 0.072). At 1 year, no notable changes in modified ACR responses were observed. Subsequent to the dosing change, similar modified ACR responses were seen during the LTE. Significant improvements in quality of life were observed with abatacept and etanercept versus placebo and etanercept in five of the eight short-form 36 subscales at 1 year. More abatacept and etanercept-treated patients experienced serious adverse events (SAEs) at 1 year than patients receiving placebo and etanercept (16.5% v 2.8%), with 3.5% v 0% experiencing serious infections. CONCLUSION: The combination of abatacept (at a dose of 2 mg/kg during the double-blind phase and 10 mg/kg during the LTE) and etanercept was associated with an increase in SAEs, including serious infections, with limited clinical effect. On the basis of the limited efficacy findings and safety concerns, abatacept in combination with etanercept should not be used for rheumatoid arthritis treatment.

Genovese MC, Becker JC, Schiff M, Luggen M, Sherrer Y, Kremer J, Birbara C, Box J, Natarajan K, Nuamah I, Li T, Aranda R, Hagerty DT, Dougados M. · Stanford University Medical Center, Stanford, Calif, USA. · N Engl J Med. · Pubmed #16162882 links to  free full text

Abstract: BACKGROUND: A substantial number of patients with rheumatoid arthritis have an inadequate or unsustained response to tumor necrosis factor alpha (TNF-alpha) inhibitors. We conducted a randomized, double-blind, phase 3 trial to evaluate the efficacy and safety of abatacept, a selective costimulation modulator, in patients with active rheumatoid arthritis and an inadequate response to at least three months of anti-TNF-alpha therapy. METHODS: Patients with active rheumatoid arthritis and an inadequate response to anti-TNF-alpha therapy were randomly assigned in a 2:1 ratio to receive abatacept or placebo on days 1, 15, and 29 and every 28 days thereafter for 6 months, in addition to at least one disease-modifying antirheumatic drug. Patients discontinued anti-TNF-alpha therapy before randomization. The rates of American College of Rheumatology (ACR) 20 responses (indicating a clinical improvement of 20 percent or greater) and improvement in functional disability, as reflected by scores for the Health Assessment Questionnaire (HAQ) disability index, were assessed. RESULTS: After six months, the rates of ACR 20 responses were 50.4 percent in the abatacept group and 19.5 percent in the placebo group (P<0.001); the respective rates of ACR 50 and ACR 70 responses were also significantly higher in the abatacept group than in the placebo group (20.3 percent vs. 3.8 percent, P<0.001; and 10.2 percent vs. 1.5 percent, P=0.003). At six months, significantly more patients in the abatacept group than in the placebo group had a clinically meaningful improvement in physical function, as reflected by an improvement from baseline of at least 0.3 in the HAQ disability index (47.3 percent vs. 23.3 percent, P<0.001). The incidence of adverse events and peri-infusional adverse events was 79.5 percent and 5.0 percent, respectively, in the abatacept group and 71.4 percent and 3.0 percent, respectively, in the placebo group. The incidence of serious infections was 2.3 percent in each group. CONCLUSIONS: Abatacept produced significant clinical and functional benefits in patients who had had an inadequate response to anti-TNF-alpha therapy.

Kremer J, Genovese M, Cannon GW, Caldwell J, Cush J, Furst DE, Luggen M, Keystone E, Bathon J, Kavanaugh A, Ruderman E, Coleman P, Curtis D, Kopp E, Kantor S, Weisman M, Waltuck J, Lindsley HB, Markenson J, Crawford B, Fernando I, Simpson K, Strand V. · Center for Rheumatology, Albany, New York 12206, USA. · J Rheumatol. · Pubmed #15290730 No free full text.

Abstract: OBJECTIVE: To obtain additional safety and efficacy data on leflunomide (LEF) treatment in combination with methotrexate (MTX) therapy in an open-label extension study in patients with rheumatoid arthritis (RA). METHODS: Following a 24 week, randomized, double-blind trial of adding placebo (PLA) or LEF to stable MTX therapy, patients could enter a 24 week extension. Subjects randomized to LEF and MTX continued treatment [(LEF/LEF) + MTX]. Subjects randomized to PLA and MTX switched to LEF (10 mg/day, no loading dose) and MTX [(PLA/LEF) + MTX]. The double-blind regarding initial randomization was maintained. RESULTS: For subjects in the extension phase, American College of Rheumatology 20% (ACR20) responder rates for the (LEF/LEF) + MTX group were maintained from Week 24 (57/96, 59.4%) to Week 48 (53/96, 55.2%). ACR20 responder rates improved in patients switched to LEF from PLA at Week 24 [(PLA/LEF) + MTX] from 25.0% (24/96) at Week 24 to 57.3% (55/96) at Week 48. Patients in the extension who switched from PLA to LEF without a loading dose exhibited a lower incidence of elevated transaminases compared to patients initially randomized to LEF. Diarrhea and nausea were less frequent during the open-label extension in patients who did not receive a LEF loading dose. CONCLUSION: Response to therapy was maintained to 48 weeks of treatment in patients who continued to receive LEF and MTX during the extension. Importantly, ACR20 response rates after 24 weeks of LEF therapy were similar between patients switched from PLA to LEF without loading dose, and those who received a loading does of LEF (100 mg/day x 2 days) at randomization. Fewer adverse events were reported in patients switched to LEF without a loading dose.

Cohen S, Hurd E, Cush J, Schiff M, Weinblatt ME, Moreland LW, Kremer J, Bear MB, Rich WJ, McCabe D. · Department of Rheumatology, St. Paul Medical Center, Dallas, Texas 75235, USA. · Arthritis Rheum. · Pubmed #11920396 links to  free full text

Abstract: OBJECTIVE: To evaluate the efficacy and safety of anakinra in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA). METHODS: Patients with moderate-to-severe active RA who were receiving MTX for 6 consecutive months, with stable doses for > or = 3 months (those with disease duration of >6 months but <12 years) were randomized into 6 groups: placebo or 0.04, 0.1, 0.4, 1.0, or 2.0 mg/kg of anakinra administered in a single, daily, subcutaneous injection. The primary efficacy end point was the proportion of subjects who met the American College of Rheumatology 20% improvement criteria (attained an ACR20 response) at week 12. RESULTS: A total of 419 patients were randomized in the study. Patient demographics and disease status were similar in the 6 treatment groups. The ACR20 responses at week 12 in the 5 active treatment plus MTX groups demonstrated a statistically significant (P = 0.001) dose-response relationship compared with the ACR20 response in the placebo plus MTX group. The ACR20 response rate in the anakinra 1.0-mg/kg (46%; P = 0.001) and 2.0-mg/kg (38%; P = 0.007) dose groups was significantly greater than that in the placebo group (19%). The ACR20 responses at 24 weeks were consistent with those at 12 weeks. Similar improvements in anakinra-treated subjects were noted in individual ACR components, erythrocyte sedimentation rate, onset of ACR20 response, sustainability of ACR20 response, and magnitude of ACR response. Anakinra was safe and well tolerated. Injection site reaction was the most frequently noted adverse event, and this led to premature study withdrawal in 7% (1.0-mg/kg group) to 10% (2.0-mg/kg group) of patients receiving higher doses. CONCLUSION: In patients with persistently active RA, the combination of anakinra and MTX was safe and well tolerated and provided significantly greater clinical benefit than MTX alone.

Greenberg JD, Fisher MC, Kremer J, Chang H, Rosenstein ED, Kishimoto M, Lee S, Yazici Y, Kavanaugh A, Abramson SB. · New York University Hospital for Joint Diseases, New York, NY. · Clin Exp Rheumatol. · Pubmed #19604430 No free full text.

Abstract: OBJECTIVE:To examine effects of the COX-2 inhibitor market withdrawals on NSAID utilization among patients at increased risk of gastrointestinal (GI) and cardiovascular (CV) toxicities. METHODS:A prospective cohort study was conducted using patients enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) Registry. The study population included rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients prescribed NSAIDs by rheumatologists from 1/1/2003 to 12/31/2005. Three cohorts were defined based on calendar year. The primary outcome assessed whether or not an NSAID gastroprotective strategy was prescribed. Secondary outcomes included rates of COX-2 inhibitor utilization and gastroprotective co-therapy utilization, stratified by the presence of cardiac and GI risk factors. RESULTS:NSAID gastroprotection utilization decreased from 65.1% in 2003 to 47.7% (p<0.001) in 2005. COX-2 inhibitor use decreased from 55.1% to 29.2% (p<0.001), whereas nonselective NSAIDs (nsNSAIDs) use increased from 50.2% to 73.9% (p=<0.01). Among patients with two or more risk factors for NSAID related GI bleeding, gastroprotection decreased from 74.4% in 2003 to 60.9% (p<0.01). For patients with two or more CV risk factors from 2003 to 2005, COX-2 inhibitor utilization decreased significantly, whereas nsNSAID utilization increased significantly.CONCLUSIONS:The COX-2 inhibitor withdrawals resulted in a rapid decline in NSAID gastroprotection prescribed by participating U.S. rheumatologists despite the availability of other gastroprotective options. Channeling toward nsNSAID use was widespread, including among patients at increased CV risk. Longer term follow-up is required to determine the clinical significance of these changes in NSAID prescribing, particularly for NSAID-related GI and CV-related toxicities.

Greenberg JD, Harrold LR, Bentley MJ, Kremer J, Reed G, Strand V. · Department of Rheumatology, New York University Hospital for Joint Diseases, New York, NY 10003, USA. · Rheumatology (Oxford). · Pubmed #19395544 No free full text.

Abstract: OBJECTIVES: To evaluate composite measures of response without acute-phase reactants in RA patients. Specifically, Clinical Disease Activity Index (CDAI)-derived response criteria were compared with the European League Against Rheumatism (EULAR) response criteria, and the modified ACR (mACR) response criteria were compared to the ACR response criteria. METHODS: Data from 10 108 RA patients enrolled in the Consortium of Rheumatology Researchers of North America registry were examined, including 649 patients initiating DMARD therapy. CDAI cut-off points for disease activity levels and responses were derived using receiver operating characteristic curves with the DAS28 and EULAR response criteria as gold standards. The kappa-statistics were applied to assess agreement between CDAI-derived and EULAR-defined responses, as well as ACR20 and ACR50 with mACR20- and mACR50-defined responses, respectively. RESULTS: For the components of the EULAR response, the derived CDAI cut-off points for DAS28 levels of 3.2 and 5.1 were 7.6 and 19.6, respectively. The derived CDAI cut-off points were 4.3 and 10.0 for DAS28 changes of 0.6 and 1.2, respectively. There were moderate to substantial agreements between CDAI-derived and EULAR responses (kappa = 0.57-0.71). Agreement of ACR20 and ACR50 with mACR20 and mACR50 responses, respectively, was excellent (kappa = 0.88-0.95). CONCLUSIONS: Agreement between composite measures of response without acute-phase reactants and standard measures ranged from moderate to excellent. The mACR20 and mACR50 criteria as well as CDAI-derived response criteria, can serve as composite measures of response in clinical practice and research settings without access to acute-phase reactants.

Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, Alecock E, Lee J, Kremer J. · Leeds Teaching Hospitals Trust, University of Leeds, Leeds, UK. · Ann Rheum Dis. · Pubmed #18625622 No free full text.

Abstract: OBJECTIVES: The phase III RADIATE study examined the efficacy and safety of tocilizumab, an anti-IL-6 receptor monoclonal antibody in patients with rheumatoid arthritis (RA) refractory to tumour necrosis factor (TNF) antagonist therapy. METHODS: 499 patients with inadequate response to one or more TNF antagonists were randomly assigned to receive 8 mg/kg or 4 mg/kg tocilizumab or placebo (control) intravenously every 4 weeks with stable methotrexate for 24 weeks. ACR20 responses, secondary efficacy and safety endpoints were assessed. RESULTS: ACR20 was achieved at 24 weeks by 50.0%, 30.4% and 10.1% of patients in the 8 mg/kg, 4 mg/kg and control groups, respectively (less than p<0.001 both tocilizumab groups versus control). At week 4 more patients achieved ACR20 in 8 mg/kg tocilizumab versus controls (less than p = 0.001). Patients responded regardless of most recently failed anti-TNF or the number of failed treatments. DAS28 remission (DAS28 <2.6) rates at week 24 were clearly dose related, being achieved by 30.1%, 7.6% and 1.6% of 8 mg/kg, 4 mg/kg and control groups (less than p = 0.001 for 8 mg/kg and p = 0.053 for 4 mg/kg versus control). Most adverse events were mild or moderate with overall incidences of 84.0%, 87.1% and 80.6%, respectively. The most common adverse events with higher incidence in tocilizumab groups were infections, gastrointestinal symptoms, rash and headache. The incidence of serious adverse events was higher in controls (11.3%) than in the 8 mg/kg (6.3%) and 4 mg/kg (7.4%) groups. CONCLUSION: Tocilizumab plus methotrexate is effective in achieving rapid and sustained improvements in signs and symptoms of RA in patients with inadequate response to TNF antagonists and has a manageable safety profile. TRIAL REGISTRATION NUMBER: NCT00106522.

Keystone E, Burmester GR, Furie R, Loveless JE, Emery P, Kremer J, Tak PP, Broder MS, Yu E, Cravets M, Magrini F, Jost F. · University of Toronto, Toronto, Ontario, Canada. · Arthritis Rheum. · Pubmed #18512710 links to  free full text

Abstract: OBJECTIVE: To assess the effects of treatment with rituximab plus methotrexate on patient-reported outcomes in patients with active rheumatoid arthritis (RA) who experienced inadequate response to anti-tumor necrosis factor therapy. METHODS: Patients with active RA were randomly assigned to rituximab (1,000 mg on days 1 and 15) or placebo. The primary end point was the proportion of patients with an American College of Rheumatology 20% response at week 24. Additional goals were to assess treatment effects on pain, fatigue, functional disability, health-related quality of life, and disease activity by comparing mean changes between groups. The analysis was conducted in the intent-to-treat population. The proportion of patients who achieved the minimum clinically important difference on the Health Assessment Questionnaire (HAQ) disability index (DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and Short Form 36 (SF-36) was determined. RESULTS: Rituximab patients had statistically significantly greater pain relief. The FACIT-F showed significantly greater improvement in rituximab patients than placebo patients from weeks 12 through 24. Mean improvement from baseline in functional disability (measured by the HAQ DI) was significantly greater in rituximab patients from weeks 8 to 24. The mean +/- SD change from baseline for the SF-36 Physical Component Score was 6.64 +/- 8.74 for rituximab patients and 1.48 +/- 7.32 for placebo patients (P < 0.0001). The mean change from baseline for the SF-36 Mental Component Score was 5.32 +/- 12.41 for rituximab patients and 2.25 +/- 12.23 for placebo patients (P = 0.0269). CONCLUSION: Rituximab produced rapid, clinically meaningful, and statistically significant improvements in patient-reported pain, fatigue, functional disability, health-related quality of life, and disease activity. These effects were sustained throughout the study.

Dervieux T, Greenstein N, Kremer J. · Prometheus, San Diego, California, USA. · Arthritis Rheum. · Pubmed #17009228 links to  free full text

Abstract: OBJECTIVE: To evaluate the contribution of metabolites (methotrexate [MTX] and folate polyglutamate [PG] levels) and pharmacogenetic biomarkers in the folate pathway to the effects of MTX in patients with rheumatoid arthritis not previously treated with this antifolate. METHODS: Forty-eight MTX-naive adult patients were enrolled in a prospective longitudinal study. MTX therapy was initiated at 7.5 mg/week and was increased every 4-6 weeks until a therapeutic response was achieved. Response was assessed using the Disease Activity Score in 28 joints (DAS28). Red blood cell (RBC) MTX and folate PG levels were measured with 9 common polymorphisms in the folate pathway. Statistical analyses consisted of generalized linear models and multivariate regressions. RESULTS: After 6 months of therapy, the median weekly MTX dosage was 17.5 mg and the median decrease in the DAS28 was 2.0. There was a large interpatient variability in RBC MTXPG levels (median 35 nmoles/liter [interquartile range 28-51] at month 6). Patients with a lesser decrease in the DAS28 (fewer improvements) had lower RBC MTXPG levels (P < 0.05) despite the higher MTX dose administered (P < 0.05). RBC folate PG levels decreased significantly during treatment, and a lesser decrease in RBC folate PGs was associated with a lesser decrease in the DAS28 (P < 0.05). Primary side effects were gastrointestinal and neurologic in nature. Risk genotypes associated with toxicity were in gamma-glutamyl hydrolase (-401CC), 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (347GG), methylenetetrahydrofolate reductase (1298AC/CC), methionine synthase (2756AA), and methionine synthase reductase (66GG). CONCLUSION: RBC MTXPG levels are a useful means by which to monitor therapy. The genetic associations presented generate hypotheses, and confirmation in independent cohorts is warranted.

Greenberg JD, Bingham CO, Abramson SB, Reed G, Kishimoto M, Hinkle K, Kremer J. · New York University Hospital for Joint Diseases, New York 10003, USA. · Arthritis Rheum. · Pubmed #16874798 links to  free full text

Abstract: OBJECTIVE: To examine cyclooxygenase 2 inhibitor (coxib) utilization by rheumatologists for patients receiving nonsteroidal antiinflammatory drugs (NSAIDs) prior to the coxib market withdrawals. METHODS: A prospective study of patients with rheumatoid arthritis enrolled in the Consortium of Rheumatology Researchers of North America registry was performed. RESULTS: Of 1,833 patients receiving prescription NSAIDs, 1,380 (75.3%) received gastroprotection, defined as either coxib monotherapy and/or gastroprotective agent (GPA) cotherapy, and 1,207 (65.8%) received coxibs. The distribution of gastroprotective strategies included 860 (46.9%) patients who were prescribed coxib monotherapy, 347 (18.9%) prescribed dual coxib plus GPA cotherapy, 173 (9.4%) prescribed a nonselective NSAID (NS-NSAID) plus GPA cotherapy, and 453 (24.7%) prescribed an NS-NSAID without GPA cotherapy. For patients with 0, 1, and > or =2 identifiable gastrointestinal (GI) risk factors, coxib prescribing rates as a proportion of NSAID agents were 64.1%, 66.4%, and 68.6%, respectively; among dual aspirin/NSAID users, coxib prescribing rates were 66.2%, 78.3%, and 68.5% of NSAID prescriptions, respectively. CONCLUSION: The majority of NSAID users were prescribed a gastroprotective strategy, primarily attributable to coxib utilization. Coxib utilization rates were consistently high across all levels of GI risk, including patients without identifiable risk factors. These data indicate that rheumatologists broadly adopted the coxib class of NSAIDs in a nonselective manner with respect to underlying GI risk and concomitant aspirin use. As novel therapeutic classes are introduced, early evaluation of prescribing patterns using arthritis registries can determine the appropriateness of prescribing patterns and may improve patient outcomes.

Tutuncu Z, Reed G, Kremer J, Kavanaugh A. · Division of Rheumatology, Allergy and Immunology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0943, USA. · Ann Rheum Dis. · Pubmed #16414968 No free full text.

Abstract: Rheumatoid arthritis among elderly people is an increasingly important health concern. Despite several cross-sectional studies, it has not been clearly established whether there are important clinical differences between elderly-onset rheumatoid arthritis (EORA) and younger-onset rheumatoid arthritis (YORA). The aim of this study was to compare disease activity and treatment in EORA and YORA, using the Consortium of Rheumatology Researchers of North America (CORRONA) registry, a database generated by rheumatologist investigators across the USA. From the CORRONA registry database of 9381 patients with rheumatoid arthritis, 2101 patients with disease onset after the age of 60 years (EORA) were matched, on the basis of disease duration, with 2101 patients with disease onset between the ages of 40 and 60 years (YORA). The primary outcome measures were the proportion of patients on methotrexate, multiple disease-modifying antirheumatic drugs (DMARD) and biological agents (etanercept, infliximab, adalimumab and kineret) in each group. Disease activity and severity differed slightly between the EORA and YORA groups: Disability Index of the Health Assessment Questionnaire: 0.30 v 0.35; tender joint count: 3.7 v 4.7; swollen joint count: 5.3 v 5.2; Disease Activity Score 28: 3.8 v 3.6; patient global assessment: 29.1 v 30.9; physician global assessment: 24.9 v 26.3; patient pain assessment: 31.4 v 34.9. Regarding treatment, the use of methotrexate use was slightly more common among patients with EORA (63.9%) than among those with YORA (59.6%), although the mean methotrexate dose among the YORA group was higher than that in the EORA group. The percentage of patients with EORA who were on multiple DMARD treatment (30.9%) or on biological agents (25%) was considerably lower than that of patients with YORA (40.5% and 33.1%, respectively; p<0.0001). Toxicity related to treatment was very minimal in both groups, whereas toxicities related to methotrexate were more common in the YORA group. Patients with EORA receive biological treatment and combination DMARD treatment less frequently than those with YORA, despite identical disease duration and comparable disease severity and activity.

Greenberg JD, Bingham CO, Abramson SB, Reed G, Sebaldt RJ, Kremer J. · New York University-Hospital for Joint Diseases, New York, New York, USA. · Arthritis Rheum. · Pubmed #15696570 links to  free full text

Abstract: OBJECTIVE: To evaluate the effects of cardiovascular comorbidities and aspirin coprescription on cyclooxygenase (COX)-2 inhibitor (coxib) prescribing patterns among rheumatologists. METHODS: A prospective cohort study was carried out with rheumatoid arthritis and osteoarthritis patients in the Consortium of Rheumatology Researchers of North America registry. Medication and comorbidity data were obtained prospectively from physician and patient questionnaires between March 2002 and September 2003. Multivariate adjusted associations between coxib use and specific cardiovascular variables, including aspirin use, were examined. RESULTS: A total of 3,522 arthritis patients were included. COX inhibitors, including coxibs, nonselective nonsteroidal antiinflammatory drugs (NSAIDs), and meloxicam, were prescribed to a larger proportion of osteoarthritis patients (68.4%) than rheumatoid arthritis patients (47.1%) in our study (P < 0.001). COX inhibitors were prescribed to the majority of aspirin users (51.5%) and a similar proportion of nonusers (49.8%). In multivariate analyses, independent predictors of coxib use versus nonselective NSAID use included diagnoses of osteoarthritis (odds ratio [OR] 2.52, 95% confidence interval [95% CI] 1.81-3.52) and diabetes (OR 1.63, 95% CI 1.06-2.51). Conversely, aspirin use independently predicted selection of a nonselective NSAID rather than a coxib (OR 0.73, 95% CI 0.55-0.98). Neither a history of myocardial infarction nor stroke predicted utilization of a coxib. Similarly, cardiovascular variables did not predict the use of rofecoxib versus celecoxib. CONCLUSION: Our data indicate that COX inhibitor coprescription among aspirin users is frequent. Despite cardiovascular concerns regarding the coxibs, our data suggest that aspirin use, but not cardiovascular comorbidities, predicted the selection of nonselective NSAIDs over coxibs.

Dervieux T, Furst D, Lein DO, Capps R, Smith K, Caldwell J, Kremer J. · Prometheus Laboratories, San Diego, CA, USA. · Ann Rheum Dis. · Pubmed #15677700 links to  free full text

Abstract: OBJECTIVE: To investigate the contribution of red blood cell (RBC) methotrexate polyglutamates (MTX PGs), RBC folate polyglutamates (folate PGs), and a pharmacogenetic index to the clinical status of patients with rheumatoid arthritis treated with MTX. METHODS: 226 adult patients treated with weekly MTX for more than 3 months were enrolled at three sites in a multicentred cross sectional observational study. Clinical status was assessed by the number of joint counts, physician's global assessment of disease activity, and a modified Health Assessment Questionnaire (mHAQ). RBC MTX PG and folate PG metabolite levels were measured by high performance liquid chromatography fluorometry and radioassay, respectively. A composite pharmacogenetic index comprising low penetrance genetic polymorphisms in reduced folate carrier (RFC-1 G80A), AICAR transformylase (ATIC C347G), and thymidylate synthase (TSER*2/*3) was calculated. Statistical analyses were by multivariate linear regression with clinical measures as dependent variables and metabolite levels and the pharmacogenetic index as independent variables after adjustment for other covariates. RESULTS: Multivariate analysis showed that lower RBC MTX PG levels (median 40 nmol/l) and a lower pharmacogenetic index (median 2) were associated with a higher number of joint counts, higher disease activity, and higher mHAQ (p<0.09). Multivariate analysis also established that higher RBC folate PG levels (median 1062 nmol/l) were associated with a higher number of tender and swollen joints after adjustment for RBC MTX PG levels and the pharmacogenetic index (p<0.05). CONCLUSION: Pharmacogenetic and metabolite measurements may be useful in optimising MTX treatment. Prospective studies are warranted to investigate the predictive value of these markers for MTX efficacy.

Dervieux T, Kremer J, Lein DO, Capps R, Barham R, Meyer G, Smith K, Caldwell J, Furst DE. · Prometheus Laboratories, San Diego, California, USA. · Pharmacogenetics. · Pubmed #15564880 No free full text.

Abstract: We investigated whether polymorphisms in reduced folate carrier (SLC19A1 G80A) and gamma-glutamyl-hydrolase (GGH-401C/T) are predictive of methotrexate polyglutamate (MTXPG) levels in patients with rheumatoid arthritis treated with weekly low-dose methotrexate (MTX). Adult patients treated with MTX were enrolled in a multicentred study. Blood was drawn at the time of the visit, DNA was extracted and red blood cell (RBC) MTXPG levels (up to the penta-order of glutamation) were measured by high-performance liquid chromatography-fluorometry. A G80A polymorphism in SLC19A1 and a -401C/T promoter polymorphism in GGH were measured by polymerase chain reaction-restriction fragment length polymorphism. Multivariate linear and logistic regressions were used to predict long-chain RBC MTXPG3-5. In 226 adult patients receiving MTX (median 15 mg range: 5-25 mg) median RBC long-chain MTXPG3-5 was 56 nmol/l (range < 5-224 nmol/l). A total of 35 patients carried the SLC19A1 80AA genotype whereas 36 patients carried the GGH-401TT genotype. Weekly MTX dose, age, presence of the SLC19A1 80AA and GGH-401TT genotypes predicted independently and significantly MTXPG3-5 levels (global r = 0.38; P < 0.0001). Patients with the GGH-401TT genotype were 4.8-fold [odds ratio (OR) 95% confidence interval (CI) 1.8-13.0; P = 0.002] more likely to have MTXPG3-5 below the group median compared to patient carriers of the GGH-401CC or CT genotype. Conversely, those with the SLC19A1 80AA genotype were 3.4-fold more likely to have MTXPG3-5 levels above the group median compared to those with the SLC19A1 80GG or 80GA genotype (OR CI 95% 1.4-8.4; P = 0.007). These data demonstrate that polymorphisms in SLC19A1 and GGH affect polyglutamation of MTX.

Dervieux T, Furst D, Lein DO, Capps R, Smith K, Walsh M, Kremer J. · Prometheus Laboratories, San Diego, California, USA. · Arthritis Rheum. · Pubmed #15457444 links to  free full text

Abstract: OBJECTIVE: Methotrexate (MTX) enters cells through the reduced folate carrier (RFC-1) and exerts part of its effects through polyglutamation to MTX polyglutamates (MTXPGs) and inhibition of 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC) and thymidylate synthase (TS). We investigated the contribution of common genetic polymorphisms in RFC-1 (G80A), ATIC (C347G), and TS (28-bp tandem repeats located in the TS enhancer region [TSER*2/*3]) and of MTXPGs to the effect of MTX in patients with rheumatoid arthritis. METHODS: The study was cross-sectional. All patients received MTX for at least 3 months. The numbers of tender and swollen joints, the Visual Analog Scale (VAS) scores for the physician's global assessment of disease activity, and the modified Health Assessment Questionnaire scores were collected. Using the VAS score for the physician's assessment of patient's response to MTX, the population of patients was dichotomized into responders to MTX (VAS score < or =2 cm) and nonresponders to MTX (VAS score >2 cm). A pharmacogenetic index was calculated as the sum of homozygous variant genotypes (RFC-1 AA + ATIC 347GG + TSER *2/*2) carried by the patients. MTXPG concentrations were measured in red blood cells (RBCs) by high-performance liquid chromatography. RESULTS: The dose of MTX was not associated with the effects of MTX (P > 0.05). In contrast, increased RBC long-chain MTXPG concentrations (median 40 nmoles/liter; range <5-131 nmoles/liter) and an increased pharmacogenetic index were associated with a lower number of tender and swollen joints (P < 0.05) and a lower score for the physician's global assessment of disease activity (P < or = 0.001). Patients with RBC MTXPG levels of >60 nmoles/liter and carriers of a homozygous variant genotype were 14.0-fold (95% confidence interval [95% CI] 3.6-53.8) and 3.7-fold (95% CI 1.7-9.1), respectively, more likely to have a good response to MTX (P <or = 0.01). CONCLUSION: These data suggest that measuring RBC MTXPG levels and/or the common polymorphisms in the folate-purine-pyrimidine pathway may help in monitoring MTX therapy.

Alarcón GS, Kremer J, Weinblatt M. · No affiliation provided · Arthritis Rheum. · Pubmed #15334490 links to  free full text

This publication has no abstract.