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1.  Talbot phase-contrast X-ray imaging for the small joints of the hand 
Physics in medicine and biology  2011;56(17):5697-5720.
A high resolution radiographic method for soft tissues in the small joints of the hand would aid in the study and treatment of Rheumatoid Arthritis (RA) and Osteoarthritis (OA), which often attacks these joints. Of particular interest would be imaging with <100 μm resolution the joint cartilage, whose integrity is a main indicator of disease. Differential phase-contrast or refraction based X-ray imaging (DPC) with Talbot grating interferometers could provide such a method, since it enhances soft tissue contrast and it can be implemented with conventional X-ray tubes. A numerical joint phantom was first developed to assess the angular sensitivity and spectrum needed for a hand DPC system. The model predicts that due to quite similar refraction indexes for joint soft tissues, the refraction effects are very small, requiring high angular resolution. To compare our model to experiment we built a high resolution bench-top interferometer using 10 μm period gratings, a W anode tube and a CCD based detector. Imaging experiments on animal cartilage and on a human finger support the model predictions. For instance, the estimated difference between the index of refraction of cartilage and water is of only several percent at ~25 keV mean energy, comparable to that between the linear attenuation coefficients. The potential advantage of DPC imaging comes thus mainly from the edge enhancement at the soft tissue interfaces. Experiments using a cadaveric human finger are also qualitatively consistent with the joint model, showing that refraction contrast is dominated by tendon embedded in muscle, with the cartilage layer difficult to observe in our conditions. Nevertheless, the model predicts that a DPC radiographic system for the small hand joints of the hand could be feasible using a low energy quasi-monochromatic source, such as a K-edge filtered Rh or Mo tube, in conjunction with a ~2 m long ‘symmetric’ interferometer operated in a high Talbot order.
PMCID: PMC3166798  PMID: 21841214
2.  OARSI/OMERACT Initiative to Define States of Severity and Indication for Joint Replacement in Hip and Knee Osteoarthritis. An OMERACT 10 Special Interest Group 
The Journal of Rheumatology  2011;38(8):1765-1769.
To define pain and physical function cutpoints that would, coupled with structural severity, define a surrogate measure of “need for joint replacement surgery,” for use as an outcome measure for potential structure-modifying interventions for osteoarthritis (OA).
New scores were developed for pain and physical function in knee and hip OA. A cross-sectional international study in 1909 patients was conducted to define data-driven cutpoints corresponding to the orthopedic surgeons’ indication for joint replacement. A post hoc analysis of 8 randomized clinical trials (1379 patients) evaluated the prevalence and validity of cutpoints, among patients with symptomatic hip/knee OA.
In the international cross-sectional study, there was substantial overlap in symptom levels between patients with and patients without indication for joint replacement; indeed, it was not possible to determine cutpoints for pain and function defining this indication. The post hoc analysis of trial data showed that the prevalence of cases that combined radiological progression, high level of pain, and high degree of function impairment was low (2%–12%). The most discriminatory cutpoint to define an indication for joint replacement was found to be [pain (0–100) + physical function (0–100) > 80].
These results do not support a specific level of pain or function that defines an indication for joint replacement. However, a tentative cutpoint for pain and physical function levels is proposed for further evaluation. Potentially, this symptom level, coupled with radiographic progression, could be used to define “nonresponders” to disease-modifying drugs in OA clinical trials.
PMCID: PMC3260473  PMID: 21807799
3.  Myocardial citrullination in rheumatoid arthritis: a correlative histopathologic study 
The aim of this study was to explore the presence and localization of myocardial citrullination in samples from rheumatoid arthritis (RA) patients compared to rheumatic and non-rheumatic disease control groups.
Archived myocardial samples obtained during autopsy from 1995 to 2009 were assembled into four groups: RA; scleroderma; fatal myocarditis; and non-rheumatic disease controls. Samples were examined by immunohistochemistry (IHC) for the presence and localization of citrullination and peptidyl arginine deiminase enzymes (PADs) by a single cardiovascular pathologist blinded to disease group and clinical characteristics.
Myocardial samples from seventeen RA patients were compared with those from fourteen controls, five fatal myocarditis patients, and ten scleroderma patients. Strong citrullination staining was detected exclusively in the myocardial interstitium in each of the groups. However, average and peak anti-citrulline staining was 59% and 44% higher, respectively, for the RA group compared to the combined non-RA groups (P < 0.05 for both comparisons). Myocardial fibrosis did not differ between the groups. In contrast to citrullination, PADs 1 to 3 and 6 were detected in cardiomyocytes (primarily PADs 1 and 3), resident inflammatory cells (primarily PADs 2 and 4), and, to a smaller extent, in endothelial cells and vascular smooth muscle cells. PAD staining did not co-localize with anti-citrulline staining in the interstitium and did not vary by disease state.
Staining for citrullination was higher in the myocardial interstitium of RA compared to other disease states, a finding that could link autoimmunity to the known increase in myocardial dysfunction and heart failure in RA.
PMCID: PMC3392839  PMID: 22364592
4.  The 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis 
Arthritis and rheumatism  2010;62(9):2582-2591.
The American College of Rheumatology and the European League Against Rheumatism have developed new classification criteria for rheumatoid arthritis (RA). The aim of Phase 2 of the development process was to achieve expert consensus on the clinical and laboratory variables that should contribute to the final criteria set.
Twenty-four expert RA clinicians (12 from Europe and 12 from North America) participated in Phase 2. A consensus-based decision analysis approach was used to identify factors (and their relative weights) that influence the probability of “developing RA,” complemented by data from the Phase 1 study. Patient case scenarios were used to identify and reach consensus on factors important in determining the probability of RA development. Decision analytic software was used to derive the relative weights for each of the factors and their categories, using choice-based conjoint analysis.
The expert panel agreed that the new classification criteria should be applied to individuals with undifferentiated inflammatory arthritis in whom at least 1 joint is deemed by an expert assessor to be swollen, indicating definite synovitis. In this clinical setting, they identified 4 additional criteria as being important: number of joints involved and site of involvement, serologic abnormality, acute-phase response, and duration of symptoms in the involved joints. These criteria were consistent with those identified in the Phase 1 data-driven approach.
The consensus-based, decision analysis approach used in Phase 2 complemented the Phase 1 efforts. The 4 criteria and their relative weights form the basis of the final criteria set.
PMCID: PMC3077961  PMID: 20872596
5.  Moderators of the Negative Effects of Catastrophizing in Arthritis 
Pain medicine (Malden, Mass.)  2010;11(4):591-599.
Pain is among the most frequently-reported, bothersome, and disabling symptoms described by patients with rheumatoid arthritis, and the experience of pain is partially shaped by catastrophizing, a set of cognitive and emotional pain-related processes. However, other variables may moderate catastrophizing’s influence on the experience of pain. In this study, we investigated a variety of factors that might buffer or magnify catastrophizing’s deleterious consequences among patients with RA.
A total of 185 RA patients were surveyed to determine levels of catastrophizing, pain, general psychological distress, and physical functioning.
Catastrophizing was associated with increased pain severity and psychological distress, and with poorer physical functioning. Some of these relationships were significantly moderated by education and social functioning; among RA patients with above-average social functioning and a college education, minimal relationships of catastrophizing with pain and distress symptoms were observed, while these associations were highly significant (p’s< .001) among patients with lower levels of education or social functioning.
Collectively, educational achievement and positive social interactions may protect against some of the deleterious effects of catastrophizing. The design of future interventions to reduce catastrophizing, or ameliorate its impact on pain outcomes, may benefit from further study of these subgroups of patients.
PMCID: PMC2868122  PMID: 20210869
Pain; Coping; Catastrophizing; Rheumatoid Arthritis; Education
6.  Adiponectin is a Mediator of the Association of Adiposity with Radiographic Damage in Rheumatoid Arthritis 
Arthritis and rheumatism  2009;61(9):1248-1256.
Recent reports have suggested that increasing adiposity may protect against radiographic damage in rheumatoid arthritis. We explored the role of serum adipokines (adiponectin, resistin, leptin) in mediating this association.
RA patients underwent total-body dual-energy absorptiometry for measurement of total and regional body fat and lean mass, abdominal computed tomography for measurement of visceral fat area, and radiographs of the hands and feet scored according to the Sharp-van der Heijde method. Serum levels of adipokines were measured and cross-sectional associations with radiographic damage were explored, adjusting for pertinent confounders. The associations of measures of adiposity with radiographic damage were explored with the introduction of adipokines into multivariable modeling as potential mediators.
Among the 197 patients studied, adiponectin demonstrated a strong association with radiographic damage, with the log Sharp score increasing 0.40 units for each log unit increase in adiponectin (p=0.001) after adjusting for pertinent predictors of radiographic damage. Adiponectin independently accounted for 6.1% of the explainable variability in Sharp score, a proportion comparable to rheumatoid factor and greater than HLA-DRB1 shared epitope alleles or C-reactive protein. Resistin and leptin were not associated with radiographic damage in adjusted models. An inverse association between visceral fat area and radiographic damage was attenuated when adiponectin was modeled as a mediator. The association of adiponectin with radiographic damage was stronger in patients with longer disease duration.
Adiponectin may represent a mechanistic link between low adiposity and increased radiographic damage in RA. Adiponectin modulation may represent a novel strategy for attenuating articular damage.
PMCID: PMC2759038  PMID: 19714593
adipose; body composition; erosion; rheumatoid arthritis; comorbidity
7.  The delivery of evidence-based preventive care for older Americans with arthritis 
Arthritis Research & Therapy  2010;12(4):R144.
Previous research suggests patients with rheumatoid arthritis (RA) may receive suboptimal care with respect to preventive tests and services. We evaluated the proportion of older Americans with RA, psoriatic arthritis (PsA), and osteoarthritis (OA) receiving these services and the specialty of the providers delivering this care.
Using data from 1999 to 2006 from the Medicare Chronic Conditions Warehouse, we identified persons age >/= 65 in the national 5% sample. Over the required five-year observation period, we identified tests and services recommended for older adults and the associated healthcare provider. Services of interest included dual energy x-ray absorptiometry (DXA), influenza and pneumococcal vaccination, hyperlipidemia lab testing, mammography and colonoscopy.
After accounting for the sampling fraction, we identified 141,140 RA, 6,300 PsA, and 770,520 OA patients eligible for analysis. Over five years, a majority of RA, PsA, and OA patients were tested for hyperlipidemia (84%, 89% and 87% respectively) and received DXA (69%, 75%, and 52%). Only approximately one-third of arthritis patients received pneumococcal vaccination; 19% to 22% received influenza vaccination each year. Approximately 20% to 35% of arthritis patients never underwent mammography and colonoscopy over five years. Concomitant care from both a rheumatologist and a primary care physician was significantly associated with a greater likelihood of receiving almost all preventive tests and services.
Among older Americans on Medicare, the absolute proportion of persons with arthritis receiving various recommended preventive services and screening tests was substantially less than 100%. Improved co-management between primary care and arthritis physicians may in part improve the delivery of preventive care for arthritis patients, but novel systematic interventions in this area are needed.
PMCID: PMC2945038  PMID: 20637072
8.  The Effect of Glucosamine and/or Chondroitin Sulfate on the Progression of Knee Osteoarthritis: A GAIT Report 
Arthritis and rheumatism  2008;58(10):3183-3191.
Osteoarthritis of the knee causes significant morbidity and current medical treatment is limited to symptom relief, as therapies able to slow structural damage remain elusive. This study sought to evaluate the effect of glucosamine hydrochloride (glucosamine, G), sodium chondroitin sulfate (chondroitin sulfate, CS) (alone and in combination), celecoxib and placebo on progressive loss of joint space width (JSW).
A double-blind twenty-four month placebo-controlled study conducted at nine sites in the United States enrolled 572 participants from Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) who satisfied radiographic criteria (Kellgren and Lawrence (K&L) Grade 2 or 3 changes and JSW of at least 2mm at baseline). Persons with primarily lateral compartment narrowing at any time point were excluded. Patients continued G 500mg three times daily, CS 400mg three times daily, the combination, celecoxib 200mg daily or placebo as randomized for GAIT. Minimum medial tibiofemoral JSW was measured at baseline, 12 and 24 months. The primary outcome measure was JSW change from baseline.
The average JSW loss at 2 years for placebo, adjusted for design and clinical factors, was 0.16mm. No statistically significant difference for any treatment group compared to the placebo group was observed. Treatment effects for K&L Grade 2 knees, but not K&L Grade 3 knees showed a trend toward improvement relative to placebo. The study’s power was diminished by sample size, variance of JSW measurement and a smaller than expected loss in JSW.
At two years, no treatment achieved a predefined clinically important difference in JSW loss compared to placebo. However, patients with K&L Grade 2 osteoarthritis appear to have the greatest potential for modification by these treatments ( number, NCT00032890).
PMCID: PMC2836125  PMID: 18821708
9.  Enhanced reactivity to pain in patients with rheumatoid arthritis 
Maladaptive physiological responses to stress appear to play a role in chronic inflammatory diseases such as rheumatoid arthritis (RA). However, relatively little stress research in RA patients has involved the study of pain, the most commonly reported and most impairing stressor in RA. In the present study, we compared psychophysical and physiological responses to standardized noxious stimulation in 19 RA patients and 21 healthy controls.
Participants underwent a single psychophysical testing session in which responses to a variety of painful stimuli were recorded, and blood samples were taken at multiple time points to evaluate the reactivity of cortisol, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) to the experience of acute pain.
The findings suggest that RA patients display a fairly general hyperalgesia to mechanical and thermal stimuli across several body sites. In addition, while serum cortisol levels did not differ at baseline or following pain testing in patients relative to controls, the RA patients tended to show elevations in serum IL-6 and demonstrated enhanced pain-reactivity of serum levels of TNF-α compared with the healthy controls (P < 0.05).
These findings highlight the importance of pain as a stressor in RA patients and add to a small body of literature documenting amplified responses to pain in RA. Future studies of the pathophysiology of RA would benefit from the consideration of acute pain levels when comparing RA patients with other groups, and future trials of analgesic interventions in RA patients may benefit from evaluating the effects of such interventions on inflammatory activity.
PMCID: PMC2714104  PMID: 19413909
10.  Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients 
Annals of the Rheumatic Diseases  2012;72(9):1496-1502.
Evaluation of long-term safety of rituximab in rheumatoid arthritis (RA).
Pooled observed case analysis of data from patients with moderate-to-severe, active RA treated with rituximab in a global clinical trial programme.
As of September 2010, 3194 patients had received up to 17 rituximab courses over 9.5 years (11 962 patient-years). Of these, 627 had >5 years’ follow-up (4418 patient-years). A pooled placebo population (n=818) (placebo+methotrexate (MTX)) was also analysed. Serious adverse event and infection rates generally remained stable over time and multiple courses. The overall serious infection event (SIE) rate was 3.94/100 patient-years (3.26/100 patient-years in patients observed for >5 years) and was comparable with placebo+MTX (3.79/100 patient-years). Serious opportunistic infections were rare. Overall, 22.4% (n=717) of rituximab-treated patients developed low immunoglobulin (Ig)M and 3.5% (n=112) low IgG levels for ≥4 months after ≥1 course. SIE rates were similar before and during/after development of low Ig levels; however, in patients with low IgG, rates were higher than in patients who never developed low IgG. Rates of myocardial infarction and stroke were consistent with rates in the general RA population. No increased risk of malignancy over time was observed.
This analysis demonstrates that rituximab remains generally well tolerated over time and multiple courses, with a safety profile consistent with published data and clinical trial experience. Overall, the findings indicate that there was no evidence of an increased safety risk or increased reporting rates of any types of adverse events with prolonged exposure to rituximab during the 9.5 years of observation.
PMCID: PMC3756452  PMID: 23136242
Rheumatoid Arthritis; Treatment; B cells
11.  MTRX1011A, a humanized anti-CD4 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a Phase I randomized, double-blind, placebo-controlled study incorporating pharmacodynamic biomarker assessments 
Arthritis Research & Therapy  2011;13(5):R177.
The purpose of this study was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the humanized anti-CD4 monoclonal antibody MTRX1011A in a randomized, double-blind placebo-controlled Phase 1 study in patients with rheumatoid arthritis (RA).
In the single ascending dose (SAD) portion of the study, patients received single doses of a placebo or MTRX1011A at 0.3, 1.0, 3.5 and 7.0 mg/kg intravenously (IV) or 1.0 and 3.5 mg/kg subcutaneously (SC), followed by five weeks of evaluation. In the multi-dose (MD) portion of the study, placebo or MTRX1011A was administered weekly for eight doses at 1.5 or 3.5 mg/kg SC, or 5 mg/kg IV, followed by eight weeks of evaluation.
MTRX1011A was well tolerated in the SAD phase up to 7 mg/kg IV and in the MD phase up to 1.5 mg/kg SC. At weekly doses of 3.5 mg/kg SC and 5 mg/kg IV, a moderate pruritic papular rash was observed in some MTRX1011A-treated patients, which was considered a dose-limiting toxicity for this clinical indication. No serious adverse events occurred in any cohort. Reduction in disease activity was modest. PD assessments demonstrated that MTRX1011A induced a dose-dependent down-modulation of CD4 expression on peripheral blood CD4 T cells, CD4 receptor occupancy, increases in serum sCD4-MTRX1011A complexes and up-regulation of CD69 on T cells, but was non-depleting.
The maximum tolerated dose of MTRX1011A was 1.5 mg/kg SC administered weekly. At this dose MTRX1011A did not achieve maximum PD activity expected to be required for reduction in disease activity.
PMCID: PMC3308112  PMID: 22029963
rheumatoid arthritis; pharmacodynamics; phase I; antibody
12.  Clinical efficacy and safety over two years use of glucosamine, chondroitin sulfate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: a GAIT report 
Annals of the rheumatic diseases  2010;69(8):1459-1464.
Osteoarthritis (OA) of the knee is a major cause of pain and limited function in older adults. Longer-term studies of medical therapy of OA are uncommon. This study was undertaken to evaluate the efficacy and safety of glucosamine and chondroitin sulfate (CS), alone or in combination, as well as celecoxib and placebo on painful knee OA over 24 months.
A 24-month, double-blind, placebo controlled study, conducted at 9 sites in the United States ancillary to the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), enrolled 662 patients with knee OA who satisfied radiographic criteria (Kellgren/ Lawrence [K/L] grade 2 or grade 3 changes and JSW of at least 2 mm at baseline). Patients who had been randomized to 1 of the 5 groups in GAIT continued to receive glucosamine 500 mg 3 times daily, CS 400 mg 3 times daily, the combination of glucosamine and CS, celecoxib 200 mg daily, or placebo over 24 months. The primary outcome measure was the number who reached a 20% reduction in WOMAC pain over 24 months. Secondary outcomes included reaching an OMERACT/OARSI response and change from baseline in WOMAC pain and function.
The odds of achieving a 20%WOMAC were 1.21 for celecoxib, 1.16 for glucosamine, 0.83 for glucosamine and chondroitin sulfate and 0.69 for chondroitin sulfate alone with widely overlapping confidence intervals for all treatments.
Over 2 years, no treatment achieved a clinically important difference in WOMAC Pain or Function as compared with placebo. However, glucosamine and celecoxib showed beneficial trends. Adverse reactions were not meaningfully different among treatment groups and serious adverse events were rare for all therapies.
PMCID: PMC3086604  PMID: 20525840
Osteoarthritis; nutraceutical; coxib; adverse events; efficacy
13.  Consensus statement on blocking the effects of interleukin-6 and in particular by interleukin-6 receptor inhibition in rheumatoid arthritis and other inflammatory conditions 
Annals of the Rheumatic Diseases  2012;72(4):482-492.
Since approval of tocilizumab (TCZ) for treatment of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), interleukin 6 (IL-6) pathway inhibition was evaluated in trials of TCZ and other agents targeting the IL-6 receptor and ligand in various RA populations and other inflammatory diseases. This consensus document informs on interference with the IL-6 pathway based on evidence and expert opinion.
Preparation of this document involved international experts in RA treatment and RA patients. A systematic literature search was performed that focused on TCZ and other IL6-pathway inhibitors in RA and other diseases. Subsequently, incorporating available published evidence and expert opinion, the steering committee and a broader expert committee (both including RA patients) formulated the current consensus statement.
The consensus statement covers use of TCZ as combination- or monotherapy in various RA populations and includes clinical, functional and structural aspects. The statement also addresses the second approved indication in Europe JIA and non-approved indications. Also early phase trials involving additional agents that target the IL-6 receptor or IL-6 were evaluated. Safety concerns, including haematological, hepatic and metabolic issues as well as infections, are addressed likewise.
The consensus statement identifies points to consider when using TCZ, regarding indications, contraindications, screening, dose, comedication, response evaluation and safety. The document is aimed at supporting clinicians and informing patients, administrators and payers on opportunities and limitations of IL-6 pathway inhibition.
PMCID: PMC3595138  PMID: 23172750
Rheumatoid Arthritis; DMARDs (biologic); Treatment

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