1164 articles - 08.09.10
1: Arthritis Rheum. 2010 Aug 18; [Epub ahead of print]
Boers M, Kostense PJ.
Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, Netherlands.
OBJECTIVE: Current trials in rheumatoid arthritis often report the American College of Rheumatology response rate (ACR20) as primary outcome, but almost universally analyze ACR50 and ACR70 rates as well. Such analyses are not statistically independent due to overlap: patients experiencing an ACR70 are also ACR50 and ACR20 responders, and ACR50 responders are also ACR20 responders. This paper introduces a better way to analyze response. METHODS & RESULTS: We suggest 4 non-overlapping categories of response: 'nonresponse' (i.e. less than ACR20); 'ACR20 not 50'; 'ACR50 not 70'; and ACR70. Differences between treatment groups in these categories of response can be tested in one global test: the chisquare test for linear trend. We also suggest a new cumulative step graph to display the results. The method is explained in a hypothetical trial with response rates drawn from a recent meta-analysis. CONCLUSION: Trials measuring ACR response should report and test non-overlapping response rates.
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20722016&dopt=ExternalLink
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PMID: 20722016 [PubMed - as supplied by publisher]2: Arthritis Rheum. 2010 Jul 28; [Epub ahead of print]
Lofgren SE, Delgado-Vega AM, Gallant CJ, Sanchez E, Frostegard J, Truedsson L, Garrido ED, Sabio JM, Gonzalez-Escribano MF, Pons-Estel BA, D'Alfonso S, Witte T, Lauwerys BR, Endreffy E, Kovacs L, Vasconcelos C, da Silva BM, Martin J, Alarcon-Riquelme ME, Kozyrev SV.
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 751 85, Uppsala, Sweden.
OBJECTIVE.: Co-stimulatory receptor CD226 plays an important role in T cell activation, differentiation and cytotoxicity. We studied the genetic association of CD226 with systemic lupus erythematosus (SLE) and investigated its functional implications. METHODS.: Twelve tag SNPs in CD226 were typed in 1163 patients and 1481 healthy controls from Europe or of European ancestry. Association analysis was performed by single marker Cochran-Mantel-Haenzsel meta-analysis followed by haplotype analysis. Gene expression was analyzed by quantitative real-time PCR using RNA from peripheral blood mononuclear cells, and by FACS analysis. To study the functional impact of the associated variants, luciferase reporter constructs containing different portions of the 3'UTR region of the gene were prepared and used in transfection experiments. RESULTS.: A three variant haplotype rs763361-rs34794968-rs727088 (ATC) in the last exon of the gene was associated with SLE (P=1.3x10(-4), OR 1.24 (1.11-1.38)). The risk haplotype correlated with low CD226 transcript expression and protein levels on the surface of CD4(+), CD8(+) T cells and NK T cells. NK cells expressed high levels of CD226, but this expression was independent of the haplotype. Reporter assays with deletion constructs indicated that only rs727088 may accounts for the difference in the levels of luciferase transcripts. CONCLUSION.: We have identified an association of CD226 with SLE in individuals of European ancestry. Our data support the importance of the 3'UTR SNP rs727088 for the regulation of CD226 transcription in T and NK T cells.
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20669283&dopt=ExternalLink
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PMID: 20669283 [PubMed - as supplied by publisher]3: Arthritis Rheum. 2010 Jun 17; [Epub ahead of print]
Graudal N, Jurgens G.
Department of Rheumatology TA, Copenhagen University Hospital, Rigshospitalet, Copenhagen Denmark.
OBJECTIVE:: The purpose of this treatment review of rheumatoid arthritis (RA) was to define the differences in effects on joint destruction between disease modifying anti rheumatic drug (DMARD) single- and combination therapy, glucocorticoid therapy and biologic therapy. METHODS:: Randomised controlled trials of RA patients investigating the effect of drug treatment on the percentage of the annual radiographic progression rate (PARPR) were included in a meta-analysis performed with review manager 5.0 according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). RESULTS:: Data from 70 trials (112 comparisons, 16 interventions) were summarized in 21 meta-analyses. Compared with placebo, PARPR was 0.90% smaller in the single DMARD group (p<0.00001) and 0.54% smaller in the glucocorticoid group (p<0.00001). Compared with single-DMARD treatment, PARPR was 0.80% smaller in the DMARD combination group (p<0.001) and 0.63% smaller in the biologic + methotrexate group (p<0.00001). The effect of a combination of two DMARDs + step-down glucocorticoids did not differ from the effect of a biologic + methotrexate (-0.07% [-0.25,0.11]) (p=0.44). CONCLUSION:: DMARDs, glucocorticoids, biologics and combination treatments significantly reduced radiographic progression at one year with a relative effect of 50-80%. A direct comparison between a combination of biologic + MTX and a double DMARD combination + initial glucocorticoid revealed no difference. Consequently, biologics should still be reserved for DMARD resistant patients. In the future, trials of the effect of biologics on RA should be compared with combination treatments involving DMARDs and glucocorticoids.
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20560138&dopt=ExternalLink
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PMID: 20560138 [PubMed - as supplied by publisher]4: Arthritis Rheum. 2010 Jul;62(7):2093-100.
Sacre K, Brihaye B, Hyafil F, Serfaty JM, Escoubet B, Zennaro MC, Lidove O, Laissy JP, Papo T.
Bichat-Claude Bernard Hospital, Assistance Publique-Hopitaux de Paris, and Paris 7 University, Paris, France.
OBJECTIVE: Antiphospholipid syndrome (APS) may cause coronary thrombosis. This study was undertaken to determine the prevalence of silent myocardial disease in patients with APS, using late gadolinium enhancement (LGE) of cardiac magnetic resonance imaging (CMRI). METHODS: Twenty-seven consecutive patients with APS and 81 control subjects without known cardiovascular disease underwent CMRI. The prevalence of occult myocardial ischemic disease, as revealed by LGE, was compared between patients with APS and controls, and factors associated with myocardial disease were identified in patients with APS. RESULTS: Myocardial ischemic disease, as characterized by LGE on CMRI, was present in 8 (29.6%) of 27 patients with APS, and imaging with LGE showed a typical pattern of myocardial infarction (MI) in 3 patients (11.1%). The myocardial scarring revealed on CMRI was not detected by electrocardiography or echocardiography. Although both patients with APS and control subjects shared a low risk of cardiovascular events, as calculated with the Framingham risk equation (mean +/- SD 5.1 +/- 8.2% and 6.5 +/- 7.6%, respectively, for the absolute risk within the next 10 years; P = 0.932), the prevalence of myocardial ischemia was more than 7 times higher in patients with APS (P = 0.0006 versus controls). No association was found between myocardial disease in patients with APS and classic coronary risk factors. The presence of myocardial scarring tended to be more closely associated with specific features of APS, such as duration of the disease, presence of livedo, and positivity for anti-beta(2)-glycoprotein I antibodies. CONCLUSION: The finding of a significant and unexpectedly high prevalence of occult myocardial scarring in patients with APS indicates the usefulness of CMRI with LGE for the identification of silent myocardial disease in such patients.
Publication Types: Clinical Trial
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20506512&dopt=ExternalLink
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PMID: 20506512 [PubMed - indexed for MEDLINE]5: Arthritis Rheum. 2010 Aug;62(8):2227-38.
Ostergaard M, Baslund B, Rigby W, Rojkovich B, Jorgensen C, Dawes PT, Wiell C, Wallace DJ, Tamer SC, Kastberg H, Petersen J, Sierakowski S.
Department of Rheumatology, Copenhagen University Hospitals at Hvidovre and Glostrup, Kettegaard Alle 30, DK-2650 Hvidovre, Denmark. mo@dadlnet.dk
OBJECTIVE: To investigate the safety and efficacy of ofatumumab, a novel human anti-CD20 monoclonal antibody (mAb), in patients with active rheumatoid arthritis (RA) whose disease did not respond to > or = 1 disease-modifying antirheumatic drug. METHODS: This combined phase I/II study investigated the safety and efficacy of 3 doses of ofatumumab. In part A (phase I), 39 patients received 2 intravenous (i.v.) infusions of ofatumumab (300 mg, 700 mg, or 1,000 mg) or placebo in a 4:1 ratio 2 weeks apart, using a specified premedication and infusion regimen. In part B (phase II), 225 patients received study treatment as per phase I in a 1:1:1:1 ratio. Safety was assessed by adverse events (AEs) and laboratory parameters. Efficacy was assessed by the American College of Rheumatology 20% criteria for improvement (ACR20), the Disease Activity Score in 28 joints, and the European League Against Rheumatism (EULAR) response criteria. B cell pharmacodynamics were also investigated. RESULTS: AEs were predominantly reported at the first infusion and were mostly mild to moderate in intensity. Rapid and sustained peripheral B cell depletion was observed in all dose groups. In phase II, patients in all ofatumumab dose groups had significantly higher ACR20 response rates (40%, 49%, and 44% for the 300 mg, 700 mg, and 1,000 mg doses, respectively) than did patients receiving placebo (11%) at week 24 (P < 0.001). Overall, 70% of patients receiving ofatumumab had a moderate or good response according to the EULAR criteria at week 24. CONCLUSION: Our findings indicate that ofatumumab, administered as 2 i.v. infusions of doses up to 1,000 mg, is clinically effective in patients with active RA.
Publication Types: Clinical Trial, Phase I Clinical Trial, Phase II Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20506254&dopt=ExternalLink
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PMID: 20506254 [PubMed - indexed for MEDLINE]6: Arthritis Rheum. 2010 Aug;62(8):2347-52.
Valdes AM, Spector TD, Tamm A, Kisand K, Doherty SA, Dennison EM, Mangino M, Tamm A, Kerna I, Hart DJ, Wheeler M, Cooper C, Lories RJ, Arden NK, Doherty M.
Department of Twin Research and Genetic Epidemiology, St. Thomas' Hospital Campus, King's College London, London SE1 7EH, UK. ana.valdes@kcl.ac.uk
OBJECTIVE: Smad3 (or, MADH3) is a key intracellular messenger in the transforming growth factor beta signaling pathway. In mice, Smad3 deficiency accelerates growth plate chondrocyte maturation and leads to an osteoarthritis (OA)-like disease. We undertook this study to investigate the role of genetic variation in SMAD3 in the risk of large-joint OA in humans. METHODS: Ten tag single-nucleotide polymorphisms (SNPs) in the SMAD3 gene region were tested in a discovery set: 313 patients who had undergone total knee replacement, 214 patients who had undergone total hip replacement, and 520 controls from the UK. The SNP associated with both hip and knee OA was subsequently genotyped in 1,221 controls and 1,074 cases from 2 cohorts of patients with hip OA and 2,537 controls and 1,575 cases from 4 cohorts of patients with knee OA. RESULTS: A SNP (rs12901499) mapping to intron 1 of SMAD3 was associated with both knee and hip OA (P < 0.0022 and P < 0.021, respectively) in the discovery set. In all study cohorts, the major allele (G) was increased among OA patients relative to controls. A meta-analysis for knee OA yielded an odds ratio (OR) of 1.22 (95% confidence interval [95% CI] 1.12-1.34), P < 7.5 x 10(-6). For hip OA, the OR was 1.22 (95% CI 1.09-1.36), P < 4.0 x 10(-4). No evidence for heterogeneity was found (I(2) = 0%). CONCLUSION: Our data indicate that genetic variation in the SMAD3 gene is involved in the risk of both hip OA and knee OA in European populations, confirming the results from animal models on the potential importance of this molecule in the pathogenesis of OA.
Publication Types: Meta-Analysis Research Support, Non-U.S. Gov't Twin Study
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20506137&dopt=ExternalLink
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PMID: 20506137 [PubMed - indexed for MEDLINE]7: Arthritis Rheum. 2010 May;62(5):1290-7.
Song IH, Heldmann F, Rudwaleit M, Listing J, Appel H, Braun J, Sieper J.
Charite Medical University, Campus Benjamin Franklin, Berlin, Germany.
OBJECTIVE: Histologic studies have shown B cell clusters in the subchondral bone marrow of the spine of patients with ankylosing spondylitis (AS). An immunotherapy targeting B cells in AS is therefore of interest. We undertook this study to examine the efficacy and safety of rituximab in patients with AS refractory to nonsteroidal antiinflammatory drugs in whom previous treatment with tumor necrosis factor alpha (TNFalpha) blockers either had not been tried or had failed. METHODS: In this phase II clinical trial, 1,000 mg rituximab was administered intravenously at baseline and at week 2 in 20 patients with active AS. Ten of these patients had never received TNF blockers, and treatment with TNF blockers had failed in the other 10 patients. The primary end point was a 20% improvement in disease activity at week 24 according to the criteria of the Assessment of SpondyloArthritis international Society (an ASAS20 response). RESULTS: Seventy-five percent of the patients were male, 90% were HLA-B27 positive, their mean age was 39.7 years, and their mean disease duration was 16.8 years. Patients had active disease, defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score >or=4. While there was no clear response at week 24 in the group in whom TNF blockers had failed (30% had achieved an ASAS20 response, 10% had achieved an ASAS40 response, none had achieved partial remission according to the ASAS criteria, and none had achieved 50% improvement on the BASDAI [a BASDAI50 response] beyond an expected placebo response), we observed a good improvement in the TNF blocker-naive group at week 24 (50% had achieved an ASAS20 response, 40% had achieved an ASAS40 response, 30% had achieved partial remission according to the ASAS criteria, and 50% had achieved a BASDAI50 response). CONCLUSION: Although rituximab does not seem to be effective in patients with AS that does not respond to TNF blockers, it had significant efficacy in TNF blocker-naive patients. Therefore, further controlled trials with B cell-directed therapies should be performed in TNF blocker-naive AS patients in the future.
Publication Types: Clinical Trial, Phase II Research Support, Non-U.S. Gov't
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20461780&dopt=ExternalLink
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PMID: 20461780 [PubMed - indexed for MEDLINE]8: Arthritis Rheum. 2010 Apr;62(4):1138-46.
Friedman DM, Llanos C, Izmirly PM, Brock B, Byron J, Copel J, Cummiskey K, Dooley MA, Foley J, Graves C, Hendershott C, Kates R, Komissarova EV, Miller M, Pare E, Phoon CK, Prosen T, Reisner D, Ruderman E, Samuels P, Yu JK, Kim MY, Buyon JP.
New York Medical College, Valhalla, NY, USA.
OBJECTIVE: The recurrence rate of anti-SSA/Ro-associated congenital heart block (CHB) is 17%. Sustained reversal of third-degree block has never been achieved. Based on potential reduction of maternal autoantibody titers as well as fetal inflammatory responses, intravenous immunoglobulin (IVIG) was evaluated as preventive therapy for CHB. METHODS: A multicenter, prospective, open-label study based on Simon's 2-stage optimal design was initiated. Enrollment criteria included the presence of anti-SSA/Ro antibodies in the mother, birth of a previous child with CHB/neonatal lupus rash, current treatment with < or = 20 mg/day of prednisone, and <12 weeks pregnant. IVIG (400 mg/kg) was given every 3 weeks from week 12 to week 24 of gestation. The primary outcome was the development of second-degree or third-degree CHB. RESULTS: Twenty mothers completed the IVIG protocol before the predetermined stopping rule of 3 cases of advanced CHB in the study was reached. CHB was detected at 19, 20, and 25 weeks; none of the cases occurred following the finding of an abnormal PR interval on fetal Doppler monitoring. One of these mothers had 2 previous children with CHB. One child without CHB developed a transient rash consistent with neonatal lupus. Sixteen children had no manifestations of neonatal lupus at birth. No significant changes in maternal titers of antibody to SSA/Ro, SSB/La, or Ro 52 kd were detected over the course of therapy or at delivery. There were no safety issues. CONCLUSION: This study establishes the safety of IVIG and the feasibility of recruiting pregnant women who have previously had a child with CHB. However, IVIG at low doses consistent with replacement does not prevent the recurrence of CHB or reduce maternal antibody titers.
Publication Types: Clinical Trial Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20391423&dopt=ExternalLink
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PMID: 20391423 [PubMed - indexed for MEDLINE]9: Arthritis Rheum. 2010 May;62(5):1412-20.
Chu CR, Williams A, Tolliver D, Kwoh CK, Bruno S 3rd, Irrgang JJ.
Cartilage Restoration Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. chucr@upmc.edu
OBJECTIVE: Quantitative and nondestructive methods for clinical diagnosis and staging of articular cartilage degeneration are important to the evaluation of potential disease-modifying treatments in osteoarthritis (OA). Optical coherence tomography (OCT) is a novel imaging technology that can generate microscopic-resolution cross-sectional images of articular cartilage in near real-time. This study tested the hypotheses that OCT can be used clinically to identify early cartilage degeneration and that OCT findings correlate with magnetic resonance imaging (MRI) T2 values and arthroscopy results. METHODS: Patients undergoing arthroscopy for degenerative meniscal tears were recruited under Institutional Review Board-approved protocols. Thirty consecutive subjects completing preoperative 3.0T MRI, arthroscopy, and intraoperative OCT comprised the study group. Qualitative and quantitative OCT results and MRI T2 values were compared with modified Outerbridge cartilage degeneration scores (0-4 scale) assigned at arthroscopy. RESULTS: Arthroscopic grades showed cartilage abnormality in 23 of the 30 patients. OCT grades were abnormal in 28 of the 30 patients. Both qualitative and quantitative OCT strongly correlated with the arthroscopy results (P = 0.004 and P = 0.0002, respectively, by Kruskal-Wallis test). Neither the superficial nor the deep cartilage T2 values correlated with the arthroscopy results. The quantitative OCT results correlated with the T2 values in the superficial cartilage (Pearson's r = 0.39, P = 0.03). CONCLUSION: These data show that OCT can be used clinically to provide qualitative and quantitative assessments of early articular cartilage degeneration that strongly correlate with arthroscopy results. The correlation between the quantitative OCT values and T2 values for the superficial cartilage further supports the utility of OCT as a clinical research tool, providing quantifiable microscopic resolution data on the articular cartilage structure. New technologies for nondestructive quantitative assessment of human articular cartilage degeneration may facilitate the development of strategies to delay or prevent the onset of OA.
Publication Types: Clinical Trial Comparative Study Research Support, N.I.H., Extramural
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20213801&dopt=ExternalLink
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PMID: 20213801 [PubMed - indexed for MEDLINE]10: Arthritis Rheum. 2010 Jun;62(6):1792-802.
Ruperto N, Lovell DJ, Quartier P, Paz E, Rubio-Perez N, Silva CA, Abud-Mendoza C, Burgos-Vargas R, Gerloni V, Melo-Gomes JA, Saad-Magalhaes C, Chavez-Corrales J, Huemer C, Kivitz A, Blanco FJ, Foeldvari I, Hofer M, Horneff G, Huppertz HI, Job-Deslandre C, Loy A, Minden K, Punaro M, Nunez AF, Sigal LH, Block AJ, Nys M, Martini A, Giannini EH; Paediatric Rheumatology International Trials Organization and the Pediatric Rheumatology Collaborative Study Group.
Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini, Genoa, Italy. nicolaruperto@ospedale-gaslini.ge.it
OBJECTIVE: We previously documented that abatacept was effective and safe in patients with juvenile idiopathic arthritis (JIA) who had not previously achieved a satisfactory clinical response with disease-modifying antirheumatic drugs or tumor necrosis factor blockade. Here, we report results from the long-term extension (LTE) phase of that study. METHODS: This report describes the long-term, open-label extension phase of a double-blind, randomized, controlled withdrawal trial in 190 patients with JIA ages 6-17 years. Children were treated with 10 mg/kg abatacept administered intravenously every 4 weeks, with or without methotrexate. Efficacy results were based on data derived from the 153 patients who entered the open-label LTE phase and reflect >or=21 months (589 days) of treatment. Safety results include all available open-label data as of May 7, 2008. RESULTS: Of the 190 enrolled patients, 153 entered the LTE. By day 589, 90%, 88%, 75%, 57%, and 39% of patients treated with abatacept during the double-blind and LTE phases achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), Pedi 50, Pedi 70, Pedi 90, and Pedi 100 criteria for improvement, respectively. Similar response rates were observed by day 589 among patients previously treated with placebo. Among patients who had not achieved an ACR Pedi 30 response at the end of the open-label lead-in phase and who proceeded directly into the LTE, 73%, 64%, 46%, 18%, and 5% achieved ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses, respectively, by day 589 of the LTE. No cases of tuberculosis and no malignancies were reported during the LTE. Pneumonia developed in 3 patients, and multiple sclerosis developed in 1 patient. CONCLUSION: Abatacept provided clinically significant and durable efficacy in patients with JIA, including those who did not initially achieve an ACR Pedi 30 response during the initial 4-month open-label lead-in phase.
Publication Types: Clinical Trial, Phase III Randomized Controlled Trial Research Support, Non-U.S. Gov't
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20191582&dopt=ExternalLink
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PMID: 20191582 [PubMed - indexed for MEDLINE]11: Arthritis Rheum. 2010 Jun;62(6):1592-601.
Masso Gonzalez EL, Patrignani P, Tacconelli S, Garcia Rodriguez LA.
Spanish Centre for Pharmacoepidemiological Research, Madrid, Spain.
OBJECTIVE: Traditional nonsteroidal antiinflammatory drugs (NSAIDs) increase the risk of upper gastrointestinal (GI) bleeding/perforation, but the magnitude of this effect for coxibs in the general population and the degree of variability between individual NSAIDs is still under debate. This study was undertaken to assess the risk of upper GI bleeding/perforation among users of individual NSAIDs and to analyze the correlation between this risk and the degree of inhibition of whole blood cyclooxygenase 1 (COX-1) and COX-2 in vitro. METHODS: We conducted a systematic review of observational studies on NSAIDs and upper GI bleeding/perforation published between 2000 and 2008. We calculated pooled relative risk (RR) estimates of upper GI bleeding/perforation for individual NSAIDs. Additionally, we verified whether the degree of inhibition of whole blood COX-1 and COX-2 in vitro by average circulating concentrations predicted the RR of upper GI bleeding/perforation. RESULTS: The RR of upper GI bleeding/perforation was 4.50 (95% confidence interval [95% CI] 3.82-5.31) for traditional NSAIDs and 1.88 (95% CI 0.96-3.71) for coxibs. RRs lower than that for NSAIDs overall were observed for ibuprofen (2.69 [95% CI 2.17-3.33]), rofecoxib (2.12 [95% CI 1.59-2.84]), aceclofenac (1.44 [95% CI 0.65-3.2]), and celecoxib (1.42 [95% CI 0.85-2.37]), while higher RRs were observed for ketorolac (14.54 [95% CI 5.87-36.04]) and piroxicam (9.94 [95% CI 5.99-16.50). Estimated RRs were 5.63 (95% CI 3.83-8.28) for naproxen, 5.57 (95% CI 3.94-7.87) for ketoprofen, 5.40 (95% CI 4.16-7.00) for indomethacin, 4.15 (95% CI 2.59-6.64) for meloxicam, and 3.98 (95% CI 3.36-4.72) for diclofenac. The degree of inhibition of whole blood COX-1 did not significantly correlate with RR of upper GI bleeding/perforation associated with individual NSAIDs (r(2) = 0.34, P = 0.058), but a profound and coincident inhibition (>80%) of both COX isozymes was associated with higher risk. NSAIDs with a long plasma half-life and with a slow-release formulation were associated with a greater risk than NSAIDs with a short half-life. CONCLUSION: The results of our analysis demonstrate that risk of upper GI bleeding/perforation varies between individual NSAIDs at the doses commonly used in the general population. Drugs that have a long half-life or slow-release formulation and/or are associated with profound and coincident inhibition of both COX isozymes are associated with a greater risk of upper GI bleeding/perforation.
Publication Types: Meta-Analysis Research Support, Non-U.S. Gov't
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20178131&dopt=ExternalLink
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PMID: 20178131 [PubMed - indexed for MEDLINE]12: Arthritis Rheum. 2010 May;62(5):1478-86.
Hanly JG, Omisade A, Su L, Farewell V, Fisk JD.
Dalhousie University, Halifax, Nova Scotia, Canada. john.hanly@cdha.nshealth.ca
OBJECTIVE: Computerized neuropsychological testing may facilitate screening for cognitive impairment in systemic lupus erythematosus (SLE). This study was undertaken to compare patients with SLE, patients with rheumatoid arthritis (RA), and patients with multiple sclerosis (MS) with healthy controls using the Automated Neuropsychological Assessment Metrics (ANAM). METHODS: Patients with SLE (n = 68), RA (n = 33), and MS (n = 20) were compared with healthy controls (n = 29). Efficiency of cognitive performance on 8 ANAM subtests was examined using throughput (TP), inverse efficiency (IE), and adjusted IE scores. The latter is more sensitive to higher cognitive functions because it adjusts for the impact of simple reaction time on performance. The results were analyzed using O'Brien's generalized least squares test. RESULTS: Control subjects were the most efficient in cognitive performance. MS patients were least efficient overall (as assessed by TP and IE scores) and were less efficient than both SLE patients (P = 0.01) and RA patients (P < 0.01), who did not differ. Adjusted IE scores were similar between SLE patients, RA patients, and controls, reflecting the impact of simple reaction time on cognitive performance. Thus, 50% of SLE patients, 61% of RA patients, and 75% of MS patients had impaired performance on >or=1 ANAM subtest. Only 9% of RA patients and 11% of SLE patients had impaired performance on >or=4 subtests, whereas this was true for 20% of MS patients. CONCLUSION: ANAM is sensitive to cognitive impairment. While such computerized testing may be a valuable screening tool, our results emphasize the lack of specificity of slowed performance as a reliable indicator of impairment of higher cognitive function in SLE patients.
Publication Types: Comparative Study Controlled Clinical Trial Research Support, Non-U.S. Gov't Validation Studies
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20155829&dopt=ExternalLink
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PMID: 20155829 [PubMed - indexed for MEDLINE]13: Arthritis Rheum. 2010 May;62(5):1236-45.
van der Woude D, Lie BA, Lundstrom E, Balsa A, Feitsma AL, Houwing-Duistermaat JJ, Verduijn W, Nordang GB, Alfredsson L, Klareskog L, Pascual-Salcedo D, Gonzalez-Gay MA, Lopez-Nevot MA, Valero F, Roep BO, Huizinga TW, Kvien TK, Martin J, Padyukov L, de Vries RR, Toes RE.
Leiden University Medical Center, Leiden, The Netherlands.
OBJECTIVE: The protective effect of HLA-DRB1 alleles on the development of rheumatoid arthritis (RA) is poorly understood. The aim of this study was to perform a meta-analysis of 4 European populations to investigate which HLA-DRB1 alleles are associated with protection in anti-citrullinated protein antibody (ACPA)-positive RA and ACPA-negative RA. METHODS: Data for >2,800 patients and >3,000 control subjects for whom information on HLA-DRB1 typing and ACPA status was available were collected from 4 European countries: Norway, Sweden, The Netherlands, and Spain. The odds ratios (ORs) and 95% confidence intervals (95% CIs) associated with the different HLA-DRB1 alleles were analyzed in a combined meta-analysis focused on protective alleles and classifications. The analysis of ACPA-positive RA was stratified for the shared epitope (SE) alleles, to correct for skewing due to this association. RESULTS: In ACPA-positive RA, the only alleles that conveyed protection after stratification for SE were HLA-DRB1*13 alleles (OR 0.54 [95% CI 0.38-0.77]). The protective effect of the allele classifications based on the DERAA and D70 sequences was no longer present after exclusion of DRB1*13 (for D70, OR 0.97 [95% CI 0.75-1.25]), indicating that DRB1*13, rather than the DERAA or D70 sequence as such, is associated with protection. Among the DRB1*13 alleles, only DRB1*1301 was associated with protection (OR 0.24 [95% CI 0.09-0.59]). Protection appeared to follow a north-to-south gradient, with the strongest association in northern European countries. In ACPA-negative RA, there were no robust associations with HLA-DRB1 alleles. CONCLUSION: Our data do not support any of the classifications of protective alleles and indicate that protection against ACPA-positive RA is predominantly associated with HLA-DRB1*1301.
Publication Types: Meta-Analysis Research Support, Non-U.S. Gov't
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20131291&dopt=ExternalLink
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PMID: 20131291 [PubMed - indexed for MEDLINE]14: Arthritis Rheum. 2010 May;62(5):1273-9.
Vital EM, Dass S, Rawstron AC, Buch MH, Goeb V, Henshaw K, Ponchel F, Emery P.
University of Leeds, Chapel Allerton Hospital and Leeds Teaching Hospitals National Health Service Trust, Leeds, UK.
OBJECTIVE: A proportion of patients with rheumatoid arthritis (RA) have disease that fails to respond to an initial cycle of rituximab. Using highly sensitive flow cytometry (HSFC), it has been shown that most patients who do not exhibit a response, as measured using the European League Against Rheumatism (EULAR) criteria, have persistent circulating B cell levels at week 2 after initial treatment with rituximab. This study was undertaken to examine whether an additional cycle of rituximab would improve B cell depletion and clinical response in patients whose disease did not respond to the initial cycle. METHODS: Patients with RA (n = 158) were treated with a first cycle of rituximab (2 infusions of 1 gm each). Clinical responses were assessed using EULAR criteria, and patients were categorized as either first-cycle responders or first-cycle nonresponders. Baseline characteristics of first-cycle nonresponders (n = 38) and first-cycle responders (n = 65) with complete data were compared. First-cycle nonresponders (n = 25) were treated with a second cycle of rituximab at least 6 months after the first cycle. HSFC was performed at baseline, immediately prior to the second infusion (week 2), 1 month after the second infusion (week 6), and then every 3 months for each cycle of rituximab. Complete B cell depletion was defined as being <0.0001 x 10(9) cells/liter. RESULTS: At baseline, the number of preplasma cells was significantly higher in first-cycle nonresponders than in first-cycle responders (P = 0.003). Following the first infusion of the first cycle of rituximab, only 9% of first-cycle nonresponders (3 of 34) exhibited complete depletion of B-lineage cells, compared with 37% of first-cycle responders (22 of 59) (P = 0.007). Following the first infusion of the second cycle of rituximab, 38% of first-cycle nonresponders exhibited complete depletion. Twenty-six weeks after the second cycle, there was a significant improvement in the Disease Activity Score in 28 joints, with 72% of patients exhibiting a EULAR response. CONCLUSION: RA patients whose disease did not respond to an initial cycle of rituximab have higher circulating preplasma cell numbers at baseline and incomplete depletion. Our findings indicate that an additional cycle of rituximab administered prior to total B cell repopulation enhances B cell depletion and clinical responses.
Publication Types: Clinical Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20131284&dopt=ExternalLink
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PMID: 20131284 [PubMed - indexed for MEDLINE]15: Arthritis Rheum. 2010 Apr;62(4):917-28.
Kremer J, Ritchlin C, Mendelsohn A, Baker D, Kim L, Xu Z, Han J, Taylor P.
Albany Medical College and The Center for Rheumatology, Albany, New York 12206, USA. jkremer@joint-docs.com
OBJECTIVE: To assess the efficacy and safety of intravenous administration of golimumab in patients with rheumatoid arthritis (RA). METHODS: Adult patients with RA in whom disease activity was persistent despite treatment with methotrexate (MTX) at a dosage of 15-25 mg/week for > or = 4 weeks were randomized to receive intravenous infusions of placebo plus MTX or intravenous infusions of golimumab at a dose of 2 mg/kg or 4 mg/kg, with or without MTX, every 12 weeks through week 48. Patients with <20% improvement in the swollen and tender joint counts could enter early escape and receive additional active treatment (week 16) or could have their dose regimen adjusted (week 24). The primary end point was the proportion of patients achieving a 50% response according to the American College of Rheumatology improvement criteria (ACR50) at week 14. RESULTS: The primary study end point was not met (at week 14, an ACR50 response was observed in 21% of the patients treated with golimumab plus MTX compared with 13% of the patients treated with placebo plus MTX [P = 0.051]). By week 24, significantly more patients treated with golimumab plus MTX had achieved an ACR50 response. Differences in the proportion of patients achieving an ACR50 response between the group receiving golimumab monotherapy and the group receiving placebo plus MTX were not significant at either week 14 (16% versus 13%) or week 24 (10% versus 9%). At week 48, the proportions of patients achieving ACR20 and ACR50 responses were highest among those who had received golimumab 4 mg/kg plus MTX (70% and 48%, respectively). Concomitant treatment with MTX was associated with a lower incidence of antibodies to golimumab. The most commonly reported adverse events through week 48 were infections (48% of patients treated with golimumab with or without MTX and 41% of patients receiving placebo plus MTX). CONCLUSION: The primary end point was not met. However, intravenously administered golimumab plus MTX appears to have benefit in the longer-term reduction of RA signs/symptoms in MTX-resistant patients, with no unexpected safety concerns.
Publication Types: Clinical Trial, Phase III Randomized Controlled Trial Research Support, Non-U.S. Gov't
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20131276&dopt=ExternalLink
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PMID: 20131276 [PubMed - indexed for MEDLINE]16: Arthritis Rheum. 2010 Apr;62(4):929-39.
Genovese MC, Van den Bosch F, Roberson SA, Bojin S, Biagini IM, Ryan P, Sloan-Lancaster J.
Stanford University, Palo Alto, California 94304, USA. genovese@stanford
OBJECTIVE: We undertook this study to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of LY2439821, a humanized anti-interleukin-17 (anti-IL-17) monoclonal antibody, in a first in-human trial in rheumatoid arthritis (RA) patients taking oral disease-modifying antirheumatic drugs (DMARDs). METHODS: This randomized, double-blind, placebo-controlled study consisted of 2 parts. In part A, 20 patients received 1 intravenous (IV) dose of LY2439821 (0.06, 0.2, 0.6, or 2.0 mg/kg, escalating) or placebo followed by 8 weeks of evaluation. End points included safety, tolerability, and pharmacokinetics. In part B, 77 patients received 1 IV dose of LY2439821 (0.2, 0.6, or 2.0 mg/kg) or placebo every 2 weeks for a total of 5 doses, with a total evaluation period of 16 weeks. End points included safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy (Disease Activity Score in 28 joints [DAS28] and percentages of patients meeting American College of Rheumatology 20%, 50%, or 70% improvement criteria [achieving an ACR20, ACR50, or ACR70 response]). The primary efficacy end point was the DAS28 at week 10. RESULTS: Baseline characteristics were similar across all groups. Changes in the DAS28 were significantly greater in the 0.2 mg/kg, 2.0 mg/kg, and all-LY2439821-combined groups (-2.3, -2.4, and -2.3, respectively) than in the placebo group (-1.7) at week 10 (P < or = 0.05), and these differences were significant as early as week 1. Percentages of ACR20, ACR50, and ACR70 responses as well as improvements in the ACR core set of measures were greater in LY2439821-treated patients than in placebo-treated patients at multiple time points. There was no apparent dose-response relationship in treatment-emergent adverse events. CONCLUSION: LY2439821 added to oral DMARDs improved signs and symptoms of RA, with no strong adverse safety signal noted. This first evaluation of LY2439821 supports neutralization of IL-17 as a potential novel goal for the treatment of RA.
Publication Types: Clinical Trial, Phase I Randomized Controlled Trial Research Support, Non-U.S. Gov't
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20131262&dopt=ExternalLink
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PMID: 20131262 [PubMed - indexed for MEDLINE]17: Arthritis Rheum. 2010 Apr;62(4):1153-7.
Izmirly PM, Llanos C, Lee LA, Askanase A, Kim MY, Buyon JP.
New York University School of Medicine, New York, New York 10016, USA. Peter.Izmirly@nyumc.org
OBJECTIVE: Cutaneous disease associated with placental transport of maternal anti-SSA/Ro or anti-SSB/La antibodies is transient, and children often appear to be otherwise healthy. However, the impact of this manifestation of neonatal lupus (NL) on the risk of cardiac disease occurring in a future pregnancy is critical for family counseling and for powering preventive trials. The purpose of this study was to determine the recurrence rates of NL, with specific focus on cardiac NL following cutaneous NL in a child enrolled in the Research Registry for Neonatal Lupus (RRNL). METHODS: Fifty-eight families who were enrolled in the RRNL met the following inclusion criteria for our study: maternal anti-SSA/Ro or anti-SSB/La antibodies, a child with cutaneous NL, and a pregnancy subsequent to the child with cutaneous NL. RESULTS: The majority of the 58 mothers (78%) were Caucasian. Of 77 pregnancies that occurred following the birth of a child with cutaneous NL, the overall recurrence rate for any manifestation of NL was 49% (95% confidence interval [95% CI] 37-62%); 14 pregnancies (18.2%) were complicated by cardiac NL, 23 (29.9%) by cutaneous NL, and 1 (1.3%) by hematologic/hepatic NL. A subset analysis was restricted to the 39 children who were born after the initial child with cutaneous NL had been enrolled in the RRNL. The overall recurrence rate for NL was 36% (95% CI 20-52%); 5 pregnancies (12.8%) were complicated by cardiac NL and 9 (23.1%) by cutaneous NL. There were no significant differences in the following maternal risk factors for having a subsequent child with cardiac or cutaneous NL: age, race/ethnicity, anti-SSB/La status, diagnosis, use of nonfluorinated steroids, or breastfeeding. The sex of the subsequent fetus did not influence the development of cardiac or cutaneous NL. CONCLUSION: Based on data from this large cohort, the identification of cutaneous NL in an anti-SSA/Ro antibody-exposed infant is particularly important, since it predicts a 6-10-fold risk of a subsequent child developing cardiac NL.
Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20131261&dopt=ExternalLink
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PMID: 20131261 [PubMed - indexed for MEDLINE]18: Arthritis Rheum. 2010 Feb;62(2):330-9.
Stach CM, Bauerle M, Englbrecht M, Kronke G, Engelke K, Manger B, Schett G.
University of Erlangen-Nuremberg, Erlangen, Germany.
OBJECTIVE: To define the nature of structural bone changes in patients with rheumatoid arthritis (RA) compared with those in healthy individuals by using the novel technique of high-resolution microfocal computed tomography (micro-CT). METHODS: Fifty-eight RA patients and 30 healthy individuals underwent a micro-CT scan of the proximal wrist and metacarpophalangeal joints. Bone lesions such as cortical breaks, osteophytes, and surface changes were quantified on 2-dimensional (2-D) slices as well as by using 3-D reconstruction images, and exact localization of lesions was recorded. RESULTS: Micro-CT scans could detect bone lesions <0.5 mm in width or depth. Small erosions could be observed in healthy individuals and RA patients, whereas lesions >1.9 mm in diameter were highly specific for RA. Cortical breaks were mostly found along the radial sites of the metacarpal heads. No significant difference in the presence of osteophytes between healthy individuals and RA patients was found. Cortical surface changes, presumably cortical thinning and fenestration, became evident from 3-D reconstructions and were more pronounced in RA patients. CONCLUSION: Micro-CT allows exact detection of morphologic changes of juxtaarticular bone in healthy individuals and RA patients. Even healthy individuals occasionally show bone changes, but the severity of these lesions, with the exception of osteophytes, is greater in RA patients. Thus, micro-CT allows accurate differentiation among physiologic bone changes in joints and among types of pathologic bone damage resulting from RA.
Publication Types: Controlled Clinical Trial Research Support, Non-U.S. Gov't Validation Studies
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20112404&dopt=ExternalLink
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PMID: 20112404 [PubMed - indexed for MEDLINE]19: Arthritis Rheum. 2010 Feb;62(2):616-26.
Pagnoux C, Seror R, Henegar C, Mahr A, Cohen P, Le Guern V, Bienvenu B, Mouthon L, Guillevin L; French Vasculitis Study Group.
Universite Paris Descartes, Hopital Cochin, Assistance Publique Hopitaux de Paris, Paris, France. christian.pagnoux@cch.aphp.fr
OBJECTIVE: Previous studies of polyarteritis nodosa (PAN) included patients with microscopic polyangiitis, because these entities were not distinguished prior to the Chapel Hill Consensus Conference (CHCC). This study was undertaken to describe the main characteristics of and long-term outcomes in patients with well-characterized PAN diagnoses. METHODS: We conducted a systematic retrospective study of 348 patients who were diagnosed as having PAN between March 1963 and October 2005, were registered in the French Vasculitis Study Group database, and satisfied the American College of Rheumatology and CHCC criteria. Patient characteristics and outcomes were analyzed and compared according to hepatitis B virus (HBV) status. RESULTS: At diagnosis, the mean +/- SD age was 51.2 +/- 17.3 years. The most frequent findings were general symptoms (93.1%), neurologic manifestations (79%), skin involvement (49.7%), abdominal pain (35.6%), and hypertension (34.8%); 66.2% had renal artery microaneurysms; 70.1% had histologically proven PAN. Patients with HBV-related PAN (n = 123) had more frequent peripheral neuropathy, abdominal pain, cardiomyopathy, orchitis, and hypertension compared with patients with non-HBV-related PAN (n = 225). During a mean +/- SD followup of 68.3 +/- 63.5 months, 76 patients (21.8%) relapsed (63 with non-HBV-related PAN [28%] versus 13 with HBV-related PAN [10.6%]; P < 0.001); 86 patients (24.7%) died (44 with non-HBV-related PAN [19.6%] versus 42 with HBV-related PAN [34.1%]; P = 0.003). Five-year relapse-free survival rates were 59.4% (95% confidence interval [95% CI] 52.6-67.0) versus 67.0% (95% CI 58.5-76.8) for non-HBV-related PAN and HBV-related PAN, respectively. Multivariate analysis retained age >65 years, hypertension, and gastrointestinal manifestations requiring surgery or at least consultation with a surgeon as independent predictors of death, whereas patients with cutaneous manifestations or non-HBV-related PAN had a higher risk of relapse. CONCLUSION: Our findings indicate that the rate of mortality from PAN remains high, especially for the elderly, and relapses do occur, particularly in patients with non-HBV-related PAN with cutaneous manifestations.
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20112401&dopt=ExternalLink
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PMID: 20112401 [PubMed - indexed for MEDLINE]20: Arthritis Rheum. 2010 Feb;62(2):392-401.
Mavragani CP, La DT, Stohl W, Crow MK.
Hospital for Special Surgery, Weill Cornell Medical College, New York, NY, USA.
OBJECTIVE: Despite the substantial clinical efficacy of tumor necrosis factor alpha (TNFalpha) antagonist therapy in patients with rheumatoid arthritis (RA), some patients respond poorly to such agents. Since an interferon (IFN) signature is variably expressed among RA patients, we investigated whether plasma type I IFN activity might predict the response to TNF antagonist therapy. METHODS: RA patients (n = 35), the majority of whom were Hispanic, from a single center were evaluated before and after initiation of TNF antagonist therapy. As controls, 12 RA patients from the same center who were not treated with a TNF antagonist were studied. Plasma type I IFN activity was measured using a reporter cell assay, and disease status was assessed using the Disease Activity Score in 28 joints (DAS28). Levels of interleukin-1 receptor antagonist (IL-1Ra) were determined in baseline plasma samples using a commercial enzyme-linked immunosorbent assay. The clinical response was classified according to the European League Against Rheumatism criteria for improvement in RA. RESULTS: Plasma type I IFN activity at baseline was significantly associated with clinical response (odds ratio 1.36 [95% confidence interval 1.05-1.76], P = 0.020), with high baseline IFN activity associated with a good response. Changes in DAS28 scores were greater among patients with a baseline plasma IFNbeta/alpha ratio >0.8 (indicating elevated plasma IFNbeta levels). Consistent with the capacity of IFNbeta to induce IL-1Ra, elevated baseline IL-1Ra levels were associated with better therapeutic outcomes (odds ratio 1.82 [95% confidence interval 1.1-3.29], P = 0.027). CONCLUSION: The plasma type I IFN activity, the IFNbeta/alpha ratio, and the IL-1Ra level were predictive of the therapeutic response in TNF antagonist-treated RA patients, indicating that these parameters might define clinically meaningful subgroups of RA patients with distinct responses to therapeutic agents.
Publication Types: Clinical Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't
Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20112385&dopt=ExternalLink
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PMID: 20112385 [PubMed - indexed for MEDLINE]