James R O'Dell

University of Nebraska at Omaha, Omaha, Nebraska, United States

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Publications (107)796.42 Total impact

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    ABSTRACT: Objective: To develop a new evidence-based, pharmacologic treatment guideline for rheumatoid arthritis (RA). Methods: We conducted systematic reviews to synthesize the evidence for the benefits and harms of various treatment options. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence. We employed a group consensus process to grade the strength of recommendations (either strong or conditional). A strong recommendation indicates that clinicians are certain that the benefits of an intervention far outweigh the harms (or vice versa). A conditional recommendation denotes uncertainty over the balance of benefits and harms and/or more significant variability in patient values and preferences. Results: The guideline covers the use of traditional disease-modifying antirheumatic drugs (DMARDs), biologic agents, tofacitinib, and glucocorticoids in early (<6 months) and established (≥6 months) RA. In addition, it provides recommendations on using a treat-to-target approach, tapering and discontinuing medications, and the use of biologic agents and DMARDs in patients with hepatitis, congestive heart failure, malignancy, and serious infections. The guideline addresses the use of vaccines in patients starting/receiving DMARDs or biologic agents, screening for tuberculosis in patients starting/receiving biologic agents or tofacitinib, and laboratory monitoring for traditional DMARDs. The guideline includes 74 recommendations: 23% are strong and 77% are conditional. Conclusion: This RA guideline should serve as a tool for clinicians and patients (our two target audiences) for pharmacologic treatment decisions in commonly encountered clinical situations. These recommendations are not prescriptive, and the treatment decisions should be made by physicians and patients through a shared decision-making process taking into account patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.
    11/2015; DOI:10.1002/acr.22783
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    ABSTRACT: Objective: Studies suggest that circulating type I interferon (IFN) may predict response to biological agents in rheumatoid arthritis (RA). Prediction of response prior to initiating therapy would represent a major advancement. Methods: We studied sera from a test set of 32 patients with RA from the Auto-immune Biomarkers Collaborative Network Consortium and a validation set of 92 patients with RA from the Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository registry. The test set included those with good response or no response to tumour necrosis factor (TNF) inhibitors at 14 weeks by European League Against Rheumatism criteria. The validation set included subjects with good, moderate or no response at 12 weeks. Total serum type I IFN activity, IFN-α and IFN-β activity were measured using a functional reporter cell assay. Results: In the test set, an increased ratio of IFN-β to IFN-α (IFN-β/α activity ratio) in pretreatment serum associated with lack of response to TNF inhibition (p=0.013). Anti-cyclic citrullinated peptide antibody titre and class of TNF inhibitor did not influence this relationship. A receiver-operator curve supported a ratio of 1.3 as the optimal cut-off. In the validation set, subjects with an IFN-β/α activity ratio >1.3 were significantly more likely to have non-response than good response (OR=6.67, p=0.018). The test had 77% specificity and 45% sensitivity for prediction of non-response compared with moderate or good response. Meta-analysis of test and validation sets confirmed strong predictive capacity of IFN-β/α activity ratio (p=0.005). Conclusions: Increased pretreatment serum IFN-β/α ratio strongly associated with non-response to TNF inhibition. This study supports further investigation of serum type I IFN in predicting outcome of TNF inhibition in RA.
    Annals of the rheumatic diseases 11/2015; DOI:10.1136/annrheumdis-2015-208001 · 10.38 Impact Factor
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    ABSTRACT: Objective: Anti-citrullinated protein antibodies (ACPAs) are highly specific for rheumatoid arthritis (RA). However, the molecular basis for ACPA production is still unclear. The purpose of this study was to determine if circulating plasmablasts from RA patients produce ACPAs and if Porphyromonas gingivalis (P. gingivalis) facilitates the generation of ACPAs. Methods: Using a single cell antibody cloning approach, we generated 217 and 110 monoclonal recombinant antibodies from circulating plasmablasts of 7 RA patients and 4 healthy controls, respectively. Antibody reactivity to citrullinated antigens was tested by the 2(nd) generation of anti-cyclic citrullinated peptide (CCP) kit and ELISAs against citrullinated human antigens. Antibody reactivity to P. gingivalis was tested by ELISAs against outer membrane antigens (OMAs) and citrullinated enolase from P. gingivalis. Results: 19.5% of plasmablast-derived antibodies from CCP-positive RA patients, but none from the CCP-negative RA patient or healthy controls, specifically recognized citrullinated antigens. The immunoglobulin genes encoding these ACPAs were highly mutated with increased replacement/silent mutation ratios, suggesting the involvement of active antigen selection in ACPA generation. Interestingly, 63% of the ACPAs cross-reacted with OMAs and/or citrullinated enolase from P. gingivalis. The reactivity of ACPAs against citrullinated proteins from P. gingivalis was confirmed by immuno blot and mass spectrometry. Furthermore, germ-line reversions of some ACPAs completely eliminated their reactivity to citrullinated human antigens but retained their reactivity to P. gingivalis. Conclusion: These results suggest that circulating plasmablasts in RA patients produce ACPAs and this process may be facilitated by the anti-P. gingivalis immune responses. This article is protected by copyright. All rights reserved.
    Arthritis and Rheumatology 10/2015; DOI:10.1002/art.39455
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    ABSTRACT: Objective: The aim of this study was to investigate omega-3 fatty acid (FA) supplement use and omega-3 FAs in erythrocyte membranes [omega-3 FA % in erythrocyte membranes (RBC)] and their association with anti-CCP autoantibodies in a population without RA, but who are at genetic risk for RA. Methods: The multicentre Studies of the Etiology of RA (SERA) cohort includes RA-free subjects who are first-degree relatives of RA probands or are enriched with the HLA-DR4 allele. In a nested case-control study, 30 SERA cases were identified who were anti-CCP2 antibody positive. We further identified 47 autoantibody negative controls, frequency matched to cases on age at study visit, sex, race and study site. Anti-CCP2 status, self-reported omega-3 FA supplement use and omega-3 FA % in RBCs were obtained from a single visit. Results: Anti-CCP2 positive cases were less likely than controls to report omega-3 FA supplement use (odds ratio: 0.14; 95% CI 0.03, 0.68). In addition, the likelihood of anti-CCP2 positivity was inversely associated with total omega-3 FA % in RBCs (odds ratio: 0.47; 95% CI 0.24, 0.92, for a s.d. increase). Conclusion: The inverse association between anti-CCP2 positivity and self-reported omega-3 FA supplement use and omega-3 FA % in RBCs suggests that omega-3 FAs may protect against the development of RA-related autoimmunity in pre-clinical RA.
    Rheumatology (Oxford, England) 09/2015; DOI:10.1093/rheumatology/kev266 · 4.48 Impact Factor
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    ABSTRACT: To assess and compare the impact of total knee arthroplasty (TKA) in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Rheumatologist-diagnosed arthritis patients undergoing primary TKA during 1999-2012 were identified. Indices of pain (overall, index and contralateral knee) and HRQoL were obtained in three consecutive 6-month intervals: pre-operative (baseline), peri-operative and post-operative (recovery). Descriptive statistics and one-way ANOVA were used to compare TKA outcomes by diagnosis, whereas effect sizes and standardized response means (SRM) were calculated between baseline and recovery. Of the participating 18,897 patients, 834 RA (5.3%) and 315 OA (10.2%) patients had undergone index TKA at similar mean ages (65 and 68 years). Post TKA, significant improvements were observed for most domains of pain, function and HRQoL within both disease groups, with greater impact in OA. By SRM, maximum improvement was shown in index knee pain (SRM: RA -1.33 OA -1.34; Effect sizes: RA -1.75 vs. OA -1.94). HAQ II and SF-36 PCS were the most responsive HRQoL indices in detecting post-TKA improvement in RA. A diagnosis of RA, lower income, and pre-operative anxiety were independently associated with lower improvements in index knee pain following TKA. TKA is highly effective in reducing clinically relevant knee pain to a greater extent than other subjective HRQoL indices in patients with RA, although this improvement is less marked as compared to OA patients. TKA serves as a "time machine" via which patients can return to a less disabled lifestyle, before the arthritic process catches up. This article is protected by copyright. All rights reserved. © 2015, American College of Rheumatology.
    Arthritis and Rheumatology 07/2015; 67(9). DOI:10.1002/art.39221
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    ABSTRACT: Objective: Malondialdehyde-acetaldehyde (MAA) adducts are a product of oxidative stress associated with tolerance loss in several disease states. This study was undertaken to investigate the presence of MAA adducts and circulating anti-MAA antibodies in patients with rheumatoid arthritis (RA). Methods: Synovial tissue from patients with RA and patients with osteoarthritis (OA) were examined for the presence of MAA-modified and citrullinated proteins. Anti-MAA antibody isotypes were measured in RA patients (n = 1,720) and healthy controls (n = 80) by enzyme-linked immunosorbent assay. Antigen-specific anti-citrullinated protein antibodies (ACPAs) were measured in RA patients using a multiplex antigen array. Anti-MAA isotype concentrations were compared in a subset of RA patients (n = 80) and matched healthy controls (n = 80). Associations of anti-MAA antibody isotypes with disease characteristics, including ACPA positivity, were examined in all RA patients. Results: Expression of MAA adducts was increased in RA synovial tissue compared to OA synovial tissue, and colocalization with citrullinated proteins was found. Increased levels of anti-MAA antibody isotypes were observed in RA patients compared to controls (P < 0.001). Among RA patients, anti-MAA antibody isotypes were associated with seropositivity for ACPAs and rheumatoid factor (P < 0.001) in addition to select measures of disease activity. Higher anti-MAA antibody concentrations were associated with a greater number of positive antigen-specific ACPA analytes (expressed at high titer) (P < 0.001) and a higher ACPA score (P < 0.001), independent of other covariates. Conclusion: MAA adduct formation is increased in RA and appears to result in robust antibody responses that are strongly associated with ACPAs. These results support speculation that MAA formation may be a cofactor that drives tolerance loss, resulting in the autoimmune responses characteristic of RA.
    Arthritis and Rheumatology 03/2015; 67(3):645-655. DOI:10.1002/art.38969
  • Manpreet K Sethi · James R O'Dell ·
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    ABSTRACT: Dramatic improvement seen in the prognosis of rheumatoid arthritis has been driven by higher expectations, led by newer drugs and more intensive use of the older drugs. Although methotrexate has retained its place as the first-line agent, there has been great interest in comparing biologicals to conventional Disease Modifying Anti Rheumatic Drugs (DMARDs) over the past few years with the updated guidelines from both the American College of Rheumatology and European League Against Rheumatism. We have tried to critically summarize the findings of some landmark trials that compare these two approaches. Treatment of Early Rheumatoid Arthritis, The Swedish Pharmacotherapy study and Rheumatoid Arthritis Comparison of Active Therapies are landmark trials that were designed to compare strategies using biologicals vs. conventional DMARDs. We will review the safety and efficacy data from these three trials here and also briefly the important cost differential. Methotrexate should be the first-line therapy for most rheumatoid arthritis patients and will produce the desired results in greater than one-third of the patients. When methotrexate is not adequate, triple DMARD therapy should be added which will result in control of approximately another one-third of the patients. Ultimately, and usually before 1 year of disease, the remainder of patients will require biological therapies usually added to conventional DMARDs. There is no evidence that this step-up approach results in any long-term disadvantage and good evidence that it results in substantial cost savings.
    Current Opinion in Rheumatology 01/2015; 27(2). DOI:10.1097/BOR.0000000000000153 · 4.89 Impact Factor
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    ABSTRACT: Objective: To evaluate the effect of sustained ACR/EULAR Boolean remission on residual joint inflammation assessed by magnetic resonance imaging (MRI) and to secondarily evaluate other clinical definitions of remission, within an early seropositive rheumatoid arthritis (RA) cohort.Methods: A subcohort of 118 RA patients were enrolled from patients who completed the two-year double-blind randomized Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial. Patients received a single contrast enhanced 1.5 Tesla MRI of their most involved wrist. Two readers scored MRI for synovitis, osteitis, tenosynovitis, and erosions. Clinical assessments were performed every three months during the trial and at time of MRI.Results: The subcohort was 92% seropositive with mean age 51 years, duration 4.1 months, and DAS28-ESR 5.8 at TEAR entry. Total MRI Inflammatory Scores (tenosynovitis+synovitis+osteitis) were lower among patients in clinical remission. Lower MRI scores were correlated with longer duration of CDAI remission (rho=0.22, p=0.03). At the time of MRI, 89 patients had no wrist pain/tenderness/swelling; however, all 118 patients had MRI evidence of residual joint inflammation after two years. No statistically significant differences in damage or MRI inflammatory scores were observed across treatment groups.Conclusion: This is the first detailed appraisal describing the relationship between clinical remission cut-points and MRI inflammatory scores within a RA RCT. The most stringent remission criteria (2011 ACR/EULAR and CDAI) best differentiate the total MRI inflammatory scores. These results document that 2-years of triple therapy or TNF+methotrexate treatment in early RA does not eliminate MRI evidence of joint inflammation. This article is protected by copyright. All rights reserved.
    12/2014; 67(7). DOI:10.1002/acr.22541
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    ABSTRACT: Background Trial reports are much more detailed on benefit than on harm. The Outcome in Rheumatology (OMERACT) Initiative has suggested a simultaneous analysis of the occurrence of benefit and harm at the individual patient level rather than at the group level [1]. Objectives To apply the OMERACT analysis strategy to the TEAR trial comparing combination to step-up strategies in early rheumatoid arthritis (RA) [2]. Methods The OMERACT method creates 3 levels for benefit (good, moderate or no response) and for harm (no adverse events [AEs], non-serious adverse events and serious adverse events [SAEs]). The outcome of each patient is expressed as a pair of values expressing the level of both benefit and harm, summarized in a contingency table. Patients achieving a good response without serious adverse events are labeled as “unqualified success” [3], and patients experiencing no response but at least one adverse event as “unmitigated failure”. TEAR randomized 755 early RA patients to 1 of 4 treatments in addition to methotrexate: immediate etanercept; immediate hydroxychloroquine plus sulfasalazine; and the same treatments delayed, and only applied in case of inadequate response at 24 weeks. In the primary study report, analysis at 6 months showed a better response in the immediate treatment groups compared to the delayed groups, but no differences in safety between the 4 treatment groups. For this post-hoc analysis, initially 3 benefit/harm categories were made by applying the EULAR response criteria and the adverse event reports. Patients dropping out prematurely for “side effects or any other medical issue” were coded as adverse events. Subsequently the data were further collapsed into 2×2 tables by combining the AE and SAE categories for harm, and the “good” and “moderate” categories for benefit; and similarly, by combining the “moderate” and “non” categories. Results Response data at 6 months was available for 693/755 patients. Only 4% of patients experienced a serious adverse event. Overall, 15% patients experienced an unqualified success and 15% an unmitigated failure (Table). The occurrence of benefit and harm were not correlated. Proportions were similar across the four treatment arms. Combining the counts of good and moderate responders increased the numbers of patients with unqualified success, as expected (32%), and combining those of moderate and non-response increased the numbers with unmitigated failure (38%). Results were similar at one and two years' follow up (data not shown). Conclusions Reporting the occurrence and benefit and harm together enhances the understanding of the patient experience. However, in this trial the occurrence of benefit and harm showed no correlation, and no differences between treatment groups were identified. The possible correlation between benefit and harm needs to be studied in more trials. References Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1954
    Annals of the Rheumatic Diseases 06/2014; 73(Suppl 2):139-139. DOI:10.1136/annrheumdis-2014-eular.1954 · 10.38 Impact Factor
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    ABSTRACT: Background Biomarkers predictive of drug efficacy are lacking in rheumatoid arthritis (RA) and would be useful in clinical practice and clinical trials. Single cell network profiling (SCNP) is a multiparametric flow cytometry-based assay that measures induced changes (phosphorylation) in intracellular signaling proteins, providing a functional measure of pathway activity and immune networking in multiple cell subsets without physical separation. Objectives Induced signaling was measured in specific subsets of monocytes, B and T cells from RA patients (pts) initiating new treatment, and analyzed to build models to predict treatment response. Methods PBMCs from RA pts (n=87) starting TNF inhibitors (TNFi) were examined by SCNP of 42 nodes (combinations of modulator and intracellular readout) within 21 immune cell subsets. A subset of ∼200 RA pts from the Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository (TETRAD) were studied. Blood samples were collected before treatment with TNFi (adalimumab, etanercept, infliximab, golimumab). Clinical data included DAS28 and EULAR response criteria at baseline, 3, 6, and 12 months. For the 53 evaluable patients, ordinal logistic regression and multivariate modeling were performed to identify signaling profiles associated with response to TNFi. Results Immune cell subsets from RA pts before TNFi treatment exhibited heterogeneity in induced intracellular signaling. Of note, T cell receptor (TCR) and IFNα modulation produced cell subset-specific signaling profiles that were associated with response at 3 months. Specifically, in CD4−CD45RA+ (naive and effector) T cells, phosphorylation of CD3ζ after stimulation through the TCR (TCR→p-CD3ζ) was weakest in pts that had a good EULAR response to TNFi (p=0.04). In contrast, phosphorylation of STAT3 after stimulation with IL-6 (IL-6→p-STAT3) in naive CD4+ T cells was weakest in autoantibody-positive pts with no response (p=0.01). Signaling nodes modulated by IFNα, TNFα, and IL-6 were combined to construct models to predict response and compared to models generated with standard clinical variables, including age, sex, and DAS28. Models utilizing cell signaling capacity of samples had greater performance with an internal cross-validated AUROC of 0.75 compared to 0.45 for clinical models. Conclusions This is the first evidence that measurement of peripheral blood immune cell function can: 1) identify patients likely to respond to TNFi, and 2) reveal the biology associated with TNFi response or lack thereof. SCNP has revealed predictive biomarkers that, once replicated in future studies, may enable patient stratification in clinical practice and clinical trials. Disclosure of Interest J. Ptacek Shareholder of: Nodality, Inc., Employee of: Nodality, Inc., R. Hawtin Shareholder of: Nodality, Inc., Employee of: Nodality, Inc., B. Louie Shareholder of: Nodality, Inc., Employee of: Nodality, Inc., E. Evensen Shareholder of: Nodality, Inc., Employee of: Nodality, Inc., J. Cordeiro Shareholder of: Nodality, Inc., Employee of: Nodality, Inc., B. Mittleman Shareholder of: Nodality, Inc., Employee of: Nodality, Inc., M. Atallah Shareholder of: Nodality, Inc., Employee of: Nodality, Inc., A. Cesano Shareholder of: Nodality, Inc., Employee of: Nodality, Inc., G. Cavet Shareholder of: Nodality, Inc., Employee of: Nodality, Inc., C. Bingham III: None declared, S. Cofield: None declared, J. Curtis: None declared, M. Danila: None declared, R. Furie: None declared, M. Genovese: None declared, M. Levesque: None declared, L. Moreland: None declared, P. Nigrovic: None declared, J. O'Dell: None declared, W. Robinson: None declared, N. Shadick: None declared, E. W. St. Clair: None declared, C. Striebich: None declared, G. Thiele: None declared, P. Gregersen: None declared, S. L. Bridges, Jr.: None declared DOI 10.1136/annrheumdis-2014-eular.2057
    Annals of the Rheumatic Diseases 06/2014; 73(Suppl 2):393-394. DOI:10.1136/annrheumdis-2014-eular.2057 · 10.38 Impact Factor
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    ABSTRACT: To examine the degree to which shared risk factors explain the relationship of periodontitis (PD) to rheumatoid arthritis (RA) and to determine the associations of PD and Porphyromonas gingivalis with pathologic and clinical features of RA. Patients with RA (n = 287) and patients with osteoarthritis as disease controls (n = 330) underwent a standardized periodontal examination. The HLA-DRB1 status of all participants was imputed using single-nucleotide polymorphisms from the extended major histocompatibility complex. Circulating anti-P gingivalis antibodies were measured using an enzyme-linked immunosorbent assay, and subgingival plaque was assessed for the presence of P gingivalis using polymerase chain reaction (PCR). Associations of PD with RA were examined using multivariable regression. Presence of PD was more common in patients with RA and patients with anti-citrullinated protein antibody (ACPA)-positive RA (n = 240; determined using the anti-cyclic citrullinated peptide 2 [anti-CCP-2] test) than in controls (35% and 37%, respectively, versus 26%; P = 0.022 and P = 0.006, respectively). There were no differences between RA patients and controls in the levels of anti-P gingivalis or the frequency of P gingivalis positivity by PCR. The anti-P gingivalis findings showed a weak, but statistically significant, association with the findings for both anti-CCP-2 (r = 0.14, P = 0.022) and rheumatoid factor (RF) (r = 0.19, P = 0.001). Presence of PD was associated with increased swollen joint counts (P = 0.004), greater disease activity according to the 28-joint Disease Activity Score using C-reactive protein level (P = 0.045), and higher total Sharp scores of radiographic damage (P = 0.015), as well as with the presence and levels of anti-CCP-2 (P = 0.011) and RF (P < 0.001). The expression levels of select ACPAs (including antibodies to citrullinated filaggrin) were higher in patients with subgingival P gingivalis and in those with higher levels of anti-P gingivalis antibodies, irrespective of smoking status. Associations of PD with established seropositive RA were independent of all covariates examined, including evidence of P gingivalis infection. Both PD and P gingivalis appear to shape the autoreactivity of RA. In addition, these results demonstrate an independent relationship between PD and established seropositive RA.
    Arthritis and Rheumatology 05/2014; 66(5):1090-1100. DOI:10.1002/art.38348
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    ABSTRACT: Background Double-blind placebo controlled trials have demonstrated the efficacy of 16 different therapies in RA patients with active disease despite MTX. However, there have been no blinded trials comparing conventional combination therapy to biologicals in this population. This gap in knowledge is important since biologicals are substantially more expensive than conventional therapy and have different toxicities. We compared two treatment strategies, adding conventional oral DMARDs or adding a biological, etanercept, in patients with active disease despite MTX followed by switch to the other treatment when clinically indicated. Methods This investigator-initiated multinational double-blind non-inferiority trial randomized 353 patients with active RA despite MTX to treatment with triple DMARD therapy (MTX, sulfasalazine and hydroxychloroquine) or etanercept + MTX. Treatment continued for 48 wks, with blinded treatment switch at 24 wks for patients in either group if their disease activity had failed to improve by a clinically significant amount (ΔDAS28 of <1.2). The primary end point was DAS28 improvement at wk 48 based on the initial randomization. Radiographic progression, physical functioning and pain were secondary endpoints. Patients were enrolled from 16 VA centers, 12 other US sites and 8 sites in Canada. Results Study population baseline characteristics: mean age 57 yrs, 54% males, DAS28 = 5.8, disease duration 5.2 yrs and mean initial MTX dose 19.6 mg/wk. There were no significant differences between groups at baseline. Both groups improved significantly over 24 wks (p=0.001). The proportion of patients requiring a switch at 24 wks was nearly identical (27.0% for triple and 26.7% for etanercept). In patients who switched, both groups improved significantly (p <0.0001) and the response was not different between therapies (p=0.08). At 48 wks the change in DAS28 was virtually the same based on initial randomization (-2.1 [triple] and- 2.3 [etanercept]). Importantly, for patients in either group who had responded at wk 24 (73% of the patients) the response was maintained at 48 wks. Radiographic progression was minimal and not different between groups (+ 0.54 for triple vs + 0.29 for etanercept, [p=0.43]). Secondary patient-reported outcomes HAQII, pain, EQ-5D were also not different. Comparing the direct medication costs of the two strategies, the difference of the drug costs alone between triple DMARD and etanercept is $10,200 per patient year. Conclusions The strategy of continuing MTX with the addition of sulfasalazine and hydroxychloroquine is comparable to adding etanercept in RA patients with active disease despite MTX and results in similar benefits in disease measures, function and radiographic progression. At the health system level, the cost-saving potential and the cost-effectiveness of the strategy of starting with conventional DMARD combinations and then switching to biologicals in those who do not respond may be substantial. Acknowledgements Funding Sources: Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development, CIHR and NIAMS by interagency agreements. Placebo etanercept donated by Amgen Disclosure of Interest J. O’Dell: None Declared, T. Mikuls Grant/research support from: Genentech, T. Taylor: None Declared, V. Ahluwalia Grant/research support from: Abbott, Janssen, Roche, UCB, Consultant for: Abbott, Amgen/Wyeth, BMS, Janssen, Roche, Speakers bureau: Abbott, Janssen, Roche, M. Brophy: None Declared, S. Warren: None Declared, R. Lew: None Declared, C. Phibbs: None Declared, A. Anis: None Declared, A. Cannella: None Declared, G. Kunkel: None Declared, E. Keystone Grant/research support from: Abbott Laboratories; Amgen, Inc.; AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb; Centocor, Inc.; F. Hoffmann-LaRoche Inc.; Genzyme, Merck, Novartis Pharmaceuticals, Pfizer Pharmaceuticals, UCB, Consultant for: Abbott Laboratories; AstraZeneca Pharma, Biotest, Bristol-Myers Squibb Company; Centocor, Inc.; F. Hoffmann-LaRoche Inc.; Genentech Inc.; Merck, Nycomed, Pfizer Pharmaceuticals, UCB, Speakers bureau: Abbott Laboratories; Bristol-Myers Squibb Co.; F. Hoffmann-LaRoche Inc.; Merck; Pfizer Pharmaceuticals; UCB; Amgen; Abbott, Janssen Inc.
    Annals of the Rheumatic Diseases 01/2014; 72(Suppl 3):A240-A240. DOI:10.1136/annrheumdis-2013-eular.752 · 10.38 Impact Factor
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    ABSTRACT: Joint damage in rheumatoid arthritis (RA) is characterized by cartilage and bone loss resulting in pain, deformity, and loss of joint function. Anti-citrullinated protein antibody (ACPA) has been implicated in RA pathogenesis and predicts radiographical joint damage and clinical severity. Therefore, the purpose of this study was to assess bone loss by micro-CT, histological joint damage, and ACPA levels using a mouse model of RA. Arthritis was induced by immunizing DBA/1 mice with autologous citrullinated type II mouse collagen (CIT-CII) weekly for 4 weeks. Mice immunized with autologous CII served as controls. At week 5, mice were killed, ACPA levels determined, and micro-CT performed to quantitatively analyze bone damage. Micro-CT analysis revealed significant loss of bone density, volume, and surface (p < 0.05) in bone peripheral to the inflamed joints of CIT-CII animals compared to CII controls. Histological staining demonstrated cartilage, proteoglycan, joint collagen, and bone collagen loss in the CIT-CII group compared to CII. Serum ACPA levels were increased (p = 0.03) in the CIT-CII group compared to CII, and these levels were inversely correlated with bone quantity and quality. In this study, we demonstrate that immunization with autologous CIT-CII initiates significant systemic bone and articular cartilage loss in the absence of adjuvant. Significant inverse correlations of circulating ACPA and bone quality/quantity were present. ACPA levels predict the adverse bone morphological changes in this model of early RA.
    Immunologic Research 12/2013; 58(1). DOI:10.1007/s12026-013-8479-7 · 3.10 Impact Factor

  • Annals of the rheumatic diseases 11/2013; 73(4). DOI:10.1136/annrheumdis-2013-204263 · 10.38 Impact Factor
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    ABSTRACT: Objective To compare the diagnostic accuracy and agreement of commonly available assays for anti–citrullinated protein antibodies in patients with established rheumatoid arthritis (RA) and subjects at increased risk of RA. Methods Tests for anti–cyclic citrullinated peptide (anti-CCP) antibodies were performed using CCP2 IgG and CCP3.1 IgA/IgG enzyme-linked immunosorbent assays in the following groups: probands with established RA (n = 340) from the Studies of the Etiology of Rheumatoid Arthritis (SERA) cohort and their first-degree relatives (FDRs) without inflammatory arthritis (n = 681), Department of Defense Serum Repository (DoDSR) RA cases with pre–RA diagnosis samples (n = 83; 47 cases also had post–RA diagnosis samples), and blood donor and DoDSR control subjects (n = 283). ResultsIn patients with established RA, the CCP2 assay was more specific (99.2% versus 93.1%; P < 0.01) but less sensitive (58.7% versus 67.4%; P = 0.01) than the CCP3.1 assay; the specificity of the CCP3.1 assay increased to 97.2% when cutoff levels ≥3-fold the standard level were considered. In all subjects, CCP3.1 assay positivity (using standard cutoff levels) was more prevalent. Among DoDSR cases, the CCP2 assay was more specific than the CCP3.1 for predicting a future diagnosis of RA, and higher CCP levels trended toward increasing specificity for the development of RA within 2 years. At standard cutoff levels, assay agreement was good in patients with established RA (κ = 0.76) but poor in FDRs without inflammatory arthritis (κ = 0.25). Conclusion Anti-CCP assays differ to an extent that may be meaningful for diagnosing RA in patients with inflammatory arthritis and evaluating the natural history of RA development in subjects at risk of RA. The mechanisms underlying these differences in test performance need further investigation.
    Arthritis & Rheumatology 09/2013; 65(9). DOI:10.1002/art.38017 · 7.76 Impact Factor
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    ABSTRACT: Objective Methotrexate (MTX) taken as monotherapy is recommended as the initial disease-modifying antirheumatic drug for rheumatoid arthritis (RA). The purpose of this study was to examine outcomes of a blinded trial of initial MTX monotherapy with the option to step-up to combination therapy as compared to immediate combination therapy in patients with early, poor-prognosis RA. Methods In the Treatment of Early Rheumatoid Arthritis (TEAR) trial, 755 participants with early, poor-prognosis RA were randomized to receive MTX monotherapy or combination therapy (MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine). Participants randomized to receive MTX monotherapy stepped-up to combination therapy at 24 weeks if the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) was ≥3.2. ResultsAttrition at 24 weeks was similar in the MTX monotherapy and combination groups. Of the 370 evaluable participants in the initial MTX group, 28% achieved low levels of disease activity and did not step-up to combination therapy (MTX monotherapy group). The mean ± SD DAS28-ESR in participants continuing to take MTX monotherapy at week 102 was 2.7 ± 1.2, which is similar to that in participants who were randomized to immediate combination therapy (2.9 ± 1.2). Participants who received MTX monotherapy had less radiographic progression at week 102 as compared to those who received immediate combination therapy (mean ± SD change in modified Sharp score 0.2 ± 1.1 versus 1.1 ± 6.4). Participants assigned to initial MTX who required step-up to combination therapy at 24 weeks (72%) demonstrated similar DAS28-ESR values (3.5 ± 1.3 versus 3.2 ± 1.3 at week 48) and radiographic progression (change in modified Sharp score 1.2 ± 4.1 versus 1.1 ± 6.4 at week 102) as those assigned to immediate combination therapy. The results for either of the immediate combination approaches, whether triple therapy or MTX plus etanercept, were similar. Conclusion These results in patients with early, poor prognosis RA validate the strategy of starting with MTX monotherapy. This study is the first to demonstrate in a blinded trial that initial MTX monotherapy with the option to step-up to combination therapy results in similar outcomes to immediate combination therapy. Approximately 30% of patients will not need combination therapy, and the 70% who will need it are clinically and radiographically indistinguishable from those who were randomized to receive immediate combination therapy.
    Arthritis & Rheumatology 08/2013; 65(8). DOI:10.1002/art.38012 · 7.76 Impact Factor
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    ABSTRACT: Objective: To examine reactivity to anti-citrullinated protein/peptide antibodies (ACPAs) and determine associations between ACPAs and other rheumatoid arthritis (RA)-related autoantibodies and clinically assessed swollen or tender joints in unaffected first-degree relatives of RA patients. Methods: Serum samples were obtained from first-degree relatives without RA according to the 1987 American College of Rheumatology (ACR) and the 2010 ACR/European League Against Rheumatism classification criteria. A bead-based assay was used to measure 16 separate ACPAs in sera from 111 antibody-positive first-degree relatives who were positive on at least 1 visit for any of 5 RA-related autoantibodies (rheumatoid factor [RF], anti-cyclic citrullinated peptide 2 [anti-CCP-2], and RF isotypes), and sera from 99 antibody-negative first-degree relatives who were never autoantibody positive. Cutoffs for positivity for each ACPA were determined using receiver operating characteristic curves derived from data on 200 RA patients and 98 blood donor controls, in which positivity for ≥9 ACPAs had 92% specificity and 62% sensitivity for RA. In first-degree relatives, ACPA reactivity was assessed, and associations between ACPAs (number positive, and positivity for ≥9 ACPAs) and RA-related characteristics were examined. Results: Fifty-seven percent of anti-CCP-2-positive first-degree relatives and 8% of anti-CCP-2- negative first-degree relatives were positive for ≥9 ACPAs. After adjusting for age, sex, ethnicity, and pack-years of smoking, an increasing number of ACPAs was directly associated with the presence of ≥1 tender joint on examination (odds ratio [OR] 1.18, 95% confidence interval [95% CI] 1.04-1.34), with the greatest risk of having ≥1 tender joint seen in first-degree relatives positive for ≥9 ACPAs (OR 5.00, 95% CI 1.37-18.18). Conclusion: RA-free first-degree relatives (even those negative for RF and anti-CCP-2) demonstrate reactivity to multiple ACPAs, and the presence of an increasing number of ACPAs may be associated with signs of joint inflammation. Prospective evaluation of the relationship between these findings and the progression of classifiable RA is warranted.
    Arthritis & Rheumatology 08/2013; 65(8). DOI:10.1002/art.38022 · 7.76 Impact Factor
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    ABSTRACT: Background: Few blinded trials have compared conventional therapy consisting of a combination of disease-modifying antirheumatic drugs with biologic agents in patients with rheumatoid arthritis who have active disease despite treatment with methotrexate--a common scenario in the management of rheumatoid arthritis. Methods: We conducted a 48-week, double-blind, noninferiority trial in which we randomly assigned 353 participants with rheumatoid arthritis who had active disease despite methotrexate therapy to a triple regimen of disease-modifying antirheumatic drugs (methotrexate, sulfasalazine, and hydroxychloroquine) or etanercept plus methotrexate. Patients who did not have an improvement at 24 weeks according to a prespecified threshold were switched in a blinded fashion to the other therapy. The primary outcome was improvement in the Disease Activity Score for 28-joint counts (DAS28, with scores ranging from 2 to 10 and higher scores indicating more disease activity) at week 48. Results: Both groups had significant improvement over the course of the first 24 weeks (P=0.001 for the comparison with baseline). A total of 27% of participants in each group required a switch in treatment at 24 weeks. Participants in both groups who switched therapies had improvement after switching (P<0.001), and the response after switching did not differ significantly between the two groups (P=0.08). The change between baseline and 48 weeks in the DAS28 was similar in the two groups (-2.1 with triple therapy and -2.3 with etanercept and methotrexate, P=0.26); triple therapy was noninferior to etanercept and methotrexate, since the 95% upper confidence limit of 0.41 for the difference in change in DAS28 was below the margin for noninferiority of 0.6 (P=0.002). There were no significant between-group differences in secondary outcomes, including radiographic progression, pain, and health-related quality of life, or in major adverse events associated with the medications. Conclusions: With respect to clinical benefit, triple therapy, with sulfasalazine and hydroxychloroquine added to methotrexate, was noninferior to etanercept plus methotrexate in patients with rheumatoid arthritis who had active disease despite methotrexate therapy. (Funded by the Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development, and others; CSP 551 RACAT ClinicalTrials.gov number, NCT00405275.)
    New England Journal of Medicine 06/2013; 369(4). DOI:10.1056/NEJMoa1303006 · 55.87 Impact Factor
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    ABSTRACT: To study changes in lipid profiles at 24 weeks among patients with early rheumatoid arthritis (RA) participating in the Treatment of Early RA (TEAR) trial and randomized to receive methotrexate (MTX) plus etanercept, triple therapy (MTX plus sulfasalazine plus hydroxychloroquine), or aggressively titrated MTX monotherapy. This TEAR substudy included 459 participants with biologic specimens. Serum levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol were measured at 0 and 24 weeks. At 24 weeks, there were statistically significant increases in mean cholesterol levels in the MTX plus etanercept, triple therapy, and MTX monotherapy arms. The observed increases were 31.4 mg/dl, 28.7 mg/dl, and 30 mg/dl in LDL cholesterol, 19.3 mg/dl, 22.3 mg/dl, and 20.6 mg/dl in HDL cholesterol, and 56.8 mg/dl, 53 mg/dl, and 57.3 mg/dl in total cholesterol (P < 0.0001 versus baseline for each comparison). There was a statistically significant decrease in the ratio of total cholesterol to HDL cholesterol at 24 weeks in all 3 treatment groups versus baseline. There was no difference in any lipid changes between the 3 treatment arms. After multivariable adjustment, change in C-reactive protein, but not the Disease Activity Score in 28 joints, was associated with change in LDL cholesterol (P = 0.03) and total cholesterol (P = 0.01). Baseline glucocorticoid use was associated with changes in HDL cholesterol (P = 0.03) and total cholesterol (P = 0.02). Levels of total cholesterol, LDL cholesterol, and HDL cholesterol increased comparably shortly after initiation of MTX plus etanercept, triple therapy, and MTX monotherapy among patients with early RA with active disease participating in a clinical trial. The clinical relevance of short-term changes in traditional lipids on cardiovascular outcomes remains to be determined.
    Arthritis & Rheumatology 06/2013; DOI:10.1002/art.37916 · 7.76 Impact Factor
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    ABSTRACT: Objective: Rapidly predicting future outcomes based on short-term clinical response would be helpful to optimize rheumatoid arthritis (RA) management in early disease. Our aim was to derive and validate a clinical prediction rule to predict low disease activity (LDA) at 1 year among patients participating in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial escalating RA therapy by adding either etanercept or sulfasalazine + hydroxychloroquine [triple therapy (TT)] after 6 months of methotrexate (MTX) therapy. Methods: Eligible subjects included in the derivation cohort (used for model building, n = 186) were participants with moderate or higher disease activity [Disease Activity Score 28-erythrocyte sedimentation rate (DAS-ESR) > 3.2] despite 24 weeks of MTX monotherapy who added either etanercept or sulfasalazine + hydroxychloroquine. Clinical characteristics measured within the next 12 weeks were used to predict LDA 1 year later using multivariable logistic regression. Validation was performed in the cohort of TEAR patients randomized to initially receive either MTX + etanercept or TT. Results: The derivation cohort yielded 3 prediction models of varying complexity that included age, DAS28 at various timepoints, body mass index, and ESR (area under the receiver-operator characteristic curve up to 0.83). Accuracy of the prediction models ranged between 80% and 95% in both derivation and validation cohorts, depending on the complexity of the model and the cutpoints chosen for response and nonresponse. About 80% of patients could be predicted to be responders or nonresponders at Week 12. Conclusion: Clinical data collected early after starting or escalating disease-modifying antirheumatic drug/biologic treatment could accurately predict LDA at 1 year in patients with early RA. For patients predicted to be nonresponders, treatment could be changed at 12 weeks to optimize outcomes.
    The Journal of Rheumatology 04/2013; 40(5). DOI:10.3899/jrheum.120715 · 3.19 Impact Factor

Publication Stats

5k Citations
796.42 Total Impact Points


  • 2007-2015
    • University of Nebraska at Omaha
      • Department of Internal Medicine
      Omaha, Nebraska, United States
  • 1989-2015
    • University of Nebraska Medical Center
      • • Division of Rheumatology and Immunology
      • • Department of Internal Medicine
      • • Department of Anesthesiology
      Omaha, Nebraska, United States
  • 2012
    • University of Alabama at Birmingham
      • Division of Clinical Immunology and Rheumatology
      Birmingham, Alabama, United States
  • 2011-2012
    • The Nebraska Medical Center
      Omaha, Nebraska, United States
  • 2010
    • Albany Medical College
      Albany, New York, United States
  • 2008
    • University of California, Los Angeles
      Los Ángeles, California, United States
  • 2003
    • University of Utah
      • Division of Rheumatology
      Salt Lake City, UT, United States