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1.  Concepts of pathogenesis in psoriatic arthritis: genotype determines clinical phenotype 
This review focuses on the genetic features of psoriatic arthritis (PsA) and their relationship to phenotypic heterogeneity in the disease, and addresses three questions: what do the recent studies on human leukocyte antigen (HLA) tell us about the genetic relationship between cutaneous psoriasis (PsO) and PsA – that is, is PsO a unitary phenotype; is PsA a genetically heterogeneous or homogeneous entity; and do the genetic factors implicated in determining susceptibility to PsA predict clinical phenotype? We first discuss the results from comparing the HLA typing of two PsO cohorts: one cohort providing the dermatologic perspective, consisting of patients with PsO without evidence of arthritic disease; and the second cohort providing the rheumatologic perspective, consisting of patients with PsA. We show that these two cohorts differ considerably in their predominant HLA alleles, indicating the heterogeneity of the overall PsO phenotype. Moreover, the genotype of patients in the PsA cohort was shown to be heterogeneous with significant elevations in the frequency of haplotypes containing HLA-B*08, HLA-C*06:02, HLA-B*27, HLA-B*38 and HLA-B*39. Because different genetic susceptibility genes imply different disease mechanisms, and possibly different clinical courses and therapeutic responses, we then review the evidence for a phenotypic difference among patients with PsA who have inherited different HLA alleles. We provide evidence that different alleles and, more importantly, different haplotypes implicated in determining PsA susceptibility are associated with different phenotypic characteristics that appear to be subphenotypes. The implication of these findings for the overall pathophysiologic mechanisms involved in PsA is discussed with specific reference to their bearing on the discussion of whether PsA is conceptualised as an autoimmune process or one that is based on entheseal responses.
PMCID: PMC4422545  PMID: 25948071
2.  Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study 
Annals of the Rheumatic Diseases  2013;74(4):694-702.
The interleukin-6 receptor (IL-6R) blocker tocilizumab (TCZ) reduces inflammatory disease activity in rheumatoid arthritis (RA) but elevates lipid concentrations in some patients. We aimed to characterise the impact of IL-6R inhibition on established and novel risk factors in active RA.
Randomised, multicentre, two-part, phase III trial (24-week double-blind, 80-week open-label), MEASURE, evaluated lipid and lipoprotein levels, high-density lipoprotein (HDL) particle composition, markers of coagulation, thrombosis and vascular function by pulse wave velocity (PWV) in 132 patients with RA who received TCZ or placebo.
Median total-cholesterol, low-density lipoprotein-cholesterol (LDL-C) and triglyceride levels increased in TCZ versus placebo recipients by week 12 (12.6% vs 1.7%, 28.1% vs 2.2%, 10.6% vs −1.9%, respectively; all p<0.01). There were no significant differences in mean small LDL, mean oxidised LDL or total HDL-C concentrations. However, HDL-associated serum amyloid A content decreased in TCZ recipients. TCZ also induced reductions (>30%) in secretory phospholipase A2-IIA, lipoprotein(a), fibrinogen and D-dimers and elevation of paraoxonase (all p<0.0001 vs placebo). The ApoB/ApoA1 ratio remained stable over time in both groups. PWV decreases were greater with placebo than TCZ at 12 weeks (adjusted mean difference 0.79 m/s (95% CI 0.22 to 1.35; p=0.0067)).
These data provide the first detailed evidence for the modulation of lipoprotein particles and other surrogates of vascular risk with IL-6R inhibition. When compared with placebo, TCZ induced elevations in LDL-C but altered HDL particles towards an anti-inflammatory composition and favourably modified most, but not all, measured vascular risk surrogates. The net effect of such changes for cardiovascular risk requires determination.
PMCID: PMC4392313  PMID: 24368514
Cardiovascular Disease; Lipids; Inflammation; Rheumatoid Arthritis; DMARDs (biologic)
3.  Preliminary test of the LFA rapid evaluation of activity in lupus (LFA-REAL): an efficient outcome measure correlates with validated instruments 
Lupus Science & Medicine  2015;2(1):e000075.
Current disease activity measures for systemic lupus erythematosus (SLE) are difficult to score or interpret and problematic for use in clinical practice. Lupus Foundation of America (LFA)-Rapid Evaluation of Activity in Lupus (REAL) is a pilot application composed of anchored visual analogue scores (0–100 mm each) for each organ affected by lupus. This study evaluated the use of LFA-REAL in capturing SLE disease activity.
In a preliminary test of LFA-REAL, this simplified, organ-based system was compared with the most widely used outcome measures in clinical trials, the British Isles Lupus Assessment Group 2004 Index (BILAG), the SLE Disease Activity Index (SLEDAI) and the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Physician's Global Assessment (SS-PGA). The level of agreement was analysed using Spearman rank correlations.
91 patients with SLE with mild to severe disease activity were evaluated, their median SLEDAI score was 4.0 (range 0–28) and BILAG score 8.0 (0–32). The median SS-PGA was 38 mm (4–92) versus the total REAL 50 mm (0–268), which expands in range by additive organ scores. Thirty-three patients had moderate to severe disease activity (≥1.5 on SS-PGA landmarks). The median SS-PGA score of this group was 66 mm (50–92) versus median REAL score of 100 mm (59–268), confirming ability to detect a wider distribution of scores at higher disease activity. Total REAL correlated with SLEDAI, BILAG and SS-PGA (correlation coefficient=0.816, 0.933 and 0.903, respectively; p<0.001 for all). Individual LFA-REAL organ scores for musculoskeletal and mucocutaneous also correlated with corresponding BILAG domain scores (correlation coefficient=0.925 and 0.934, p<0.001).
In this preliminary exercise, there were strong correlations between LFA-REAL and validated lupus disease activity indices. Further development may be valuable for consistent scoring in clinical trials, grading optimal assessment of change in disease activity and reliable monitoring of patients in practice.
PMCID: PMC4378376  PMID: 25861457
Autoimmune Diseases; Systemic Lupus Erythematosus; Autoantibodies
4.  Association of Cross-Reactive Antibodies Targeting Peptidyl-Arginine Deiminase 3 and 4 with Rheumatoid Arthritis-Associated Interstitial Lung Disease 
PLoS ONE  2014;9(6):e98794.
A subset of rheumatoid arthritis (RA) patients have detectable antibodies directed against the peptidyl-arginine deiminase (PAD) enzyme isoforms 3 and 4. Anti-PAD3/4 cross-reactive antibodies (anti-PAD3/4XR) have been shown to lower the calcium threshold required for PAD4 activation, an effect potentially relevant to the pathogenesis of RA-associated interstitial lung disease (ILD).
RA patients underwent multi-detector computed tomography (MDCT) of the chest with interpretation by a pulmonary radiologist for ILD features. A semi-quantitative ILD Score (range 0–32) was calculated. Concurrent serum samples were assessed for antibodies against PAD by immunoprecipitation with radiolabeled PAD3 and PAD4.
Among the 176 RA patients studied, any ILD was observed in 58 (33%) and anti-PAD3/4XR was detected in 19 (11%). The frequency of any ILD among those with anti-PAD3/4XR was 68% vs. 29% among those with no anti-PAD (crude OR = 5.39; p = 0.002) and vs. 27% among those with anti-PAD4 that was not cross-reactive with PAD3 (crude OR = 5.74; p = 0.001). Both associations were stronger after adjustment for relevant confounders (adjusted ORs = 7.22 and 6.61, respectively; both p-values<0.01). Among ever smokers with anti-PAD3/4XR, the adjusted frequency of any ILD was 93% vs. 17% for never smokers without the antibody (adjusted OR = 61.4; p = 0.001, p-value for the interaction of smoking with anti-PAD3/4XR<0.05).
The prevalence and extent of ILD was markedly higher among RA patients with anti-PAD3/4 cross-reactive antibodies, even after accounting for relevant confounders, particularly among ever smokers. These findings may suggest etiopathologic mechanisms of RA-ILD, and their clinical utility for predicting ILD warrants additional study.
PMCID: PMC4047055  PMID: 24901704
5.  A Dual-Center Randomized Controlled Double Blind Trial Assessing the Effect of Acupuncture in Reducing Musculoskeletal Symptoms in Breast Cancer Patients Taking Aromatase Inhibitors 
Up to 50% of women receiving aromatase inhibitor (AI) complain of AI-associated musculoskeletal symptoms (AIMSS) and 15% discontinue treatment. We conducted a randomized, sham-controlled trial to evaluate whether acupuncture improves AIMSS and to explore potential mechanisms.
Patients and Methods
Postmenopausal women with early stage breast cancer, experiencing AIMSS were randomized to 8 weekly real or sham acupuncture sessions. We evaluated changes in the Health Assessment Questionnaire Disability Index (HAQ-DI) and pain visual analog scale (VAS) following the intervention compared to baseline. Serum estradiol, β-endorphin and proinflammatory cytokine concentrations were measured pre and post-intervention.
We enrolled 51 women, of whom 47 were evaluable, including 23 randomized to real and 24 to sham acupuncture. Baseline characteristics were balanced between groups with the exception of a higher HAQ-DI score in the real acupuncture group (p=0.047). We did not observe a statistically significant difference in reduction of HAQ-DI (p=0.30) or VAS (p=0.31) between the two groups. Following 8 weekly treatments, we observed a statistically significant reduction of IL-17 (p≤0.009) in both groups. No significant modulation was seen in estradiol, β-endorphin, or other proinflammatory cytokine concentrations in either group.
We did not observe a significant difference in AIMSS changes between real and sham acupuncture. As sham acupuncture used in this study may not be equivalent to placebo, further studies with a non-acupuncture arm may be required to establish whether acupuncture is beneficial for the treatment of AIMSS.
PMCID: PMC3594526  PMID: 23393007
6.  Erosive rheumatoid arthritis is associated with antibodies that activate PAD4 by increasing calcium sensitivity 
Science translational medicine  2013;5(186):186ra65.
Peptidylarginine deiminases (PADs) play a critical role in generating autoantigens in rheumatoid arthritis (RA), but the mechanisms underlying their dysregulation in this disease remain unknown. Although PADs require supraphysiologic concentrations of calcium for activity in vitro, the enzymes are clearly active in vivo (e.g. in RA synovial fluid) where calcium concentrations are much lower. In this study, we have discovered a novel subset of anti-PAD4 autoantibodies (identified by their cross-reactivity with PAD3) which strikingly increase the catalytic efficiency of PAD4 by decreasing the enzyme’s requirement for calcium into the physiologic range. Patients with these novel PAD3/PAD4 cross-reactive autoantibodies had higher baseline radiographic damage scores and a higher likelihood of radiographic progression compared to individuals negative for these antibodies. The ability of autoantibodies to activate an enzyme that itself generates citrullinated autoantigens identifies an important feed-forward loop which may drive the erosive outcome observed in RA patients with these autoantibodies. PAD3 autoantibodies may therefore identify RA patients who would benefit from early aggressive treatment or addition of PAD-inhibitor therapy.
PMCID: PMC3740946  PMID: 23698378
7.  Association of Vitamin D with Cardiometabolic Risk Factors in Rheumatoid Arthritis 
Arthritis care & research  2012;64(10):1497-1504.
Individuals with rheumatoid arthritis (RA) are at a greater risk for cardiovascular disease (CVD). Vitamin D deficiency is a potential risk factor for CVD and metabolic syndrome. Since patients with RA have a high prevalence of vitamin D deficiency, we investigated the association of vitamin D levels with cardiometabolic risk factors in a cohort of RA patients with no prior history of CVD.
Serum 25(OH)D levels were measured among RA patients enrolled in a cohort study of subclinical CVD. The cross-sectional associations of 25(OH)D level with traditional CVD risk factors, such as insulin resistance [estimated using the Homeostatic Model Assessment (HOMA)], adiopokines, markers of systemic inflammation and endothelial activation were explored, adjusting for pertinent sociodemographic, lifestyle, and RA characteristics.
Among 179 RA patients, 73 (41%) had a 25(OH)D level <30ng/mL. Only 23 patients (13%) had a 25(OH)D level ≥45ng/mL. After adjusting for demographics and BMI, 25(OH)D remained significantly associated with HDL and inversely associated with HOMA-IR, fibrinogen, E-selectin, and s-ICAM. Significant associations with HDL, E-selectin, and s-ICAM were maintained after adjusting for DAS28 and autoantibody status. These associations were similar between groups subdivided by gender, ethnicity, body mass index, DAS28 level and autoantibody status.
These data suggest that vitamin D deficiency is common in RA and may be independently associated with several cardiometabolic intermediates in this population.
PMCID: PMC3462271  PMID: 22555877
8.  Progression of coronary artery atherosclerosis in rheumatoid arthritis: comparison with participants from the Multi-Ethnic Study of Atherosclerosis 
Arthritis Research & Therapy  2013;15(5):R134.
In cross-sectional studies, patients with rheumatoid arthritis (RA) have higher coronary artery calcium (CAC) than controls. However, their rate of progression of CAC and the predictors of CAC progression have heretofore remained unknown.
Incidence and progression of CAC were compared in 155 patients with RA and 835 control participants. The association of demographic characteristics, traditional cardiovascular risk factors, RA disease characteristics and selected inflammatory markers with incidence and progression of CAC were evaluated.
The incidence rate of newly detected CAC was 8.2/100 person-years in RA and 7.3/100 person-years in non-RA control subjects [IRR 1.1 (0.7-1.8)]. RA patients who developed newly detectable CAC were older (59±7 vs. 55±6 years old, p=0.03), had higher triglyceride levels (137±86 vs. 97±60 mg/dL, p=0.03), and higher systolic blood pressure (129±17 vs. 117±15 mm Hg, p=0.01) compared to those who did not develop incident CAC. Differences in blood pressure and triglyceride levels remained significant after adjustment for age (p<=0.05). RA patients with any CAC at baseline had a median rate of yearly progression of 21 (7–62) compared to 21 (5–70) Agatston units in controls. No statistical differences between RA progressors and RA non-progressors were observed for inflammatory markers or for RA disease characteristics.
The incidence and progression of CAC did not differ between RA and non-RA participants. In patients with RA, incident CAC was associated with older age, higher triglyceride levels, and higher blood pressure, but not with inflammatory markers or RA disease characteristics.
PMCID: PMC3978773  PMID: 24286380
9.  Muscle Density in Rheumatoid Arthritis: Associations with Disease Features and Functional Outcomes 
Arthritis and rheumatism  2012;64(8):2438-2450.
To explore the associations of thigh computed tomography (CT)-derived measures of body composition with functional outcomes in patients with rheumatoid arthritis (RA).
Patients with RA underwent bilateral mid-femoral quantitative CT for measurement of thigh fat area (TFA), muscle area (TMA), and muscle density (TMD). The associations of thigh composition measures with disability and physical performance, measured with the Health Assessment Questionnaire (HAQ), Valued Life Activities (VLA) scale, and Short Physical Performance Battery (SPPB), were explored for the total cohort and by gender, controlling for pertinent demographic, lifestyle, and RA disease and treatment covariates.
A total of 152 RA patients were studied. Among potential determinants of TMD, higher age, higher duration of sedentary activity, longer RA duration, higher tender joint count, higher serum IL-6 levels, use of glucocorticoids, and non-use of hydroxychloroquine were all significantly associated with lower TMD in multivariable modeling. RA characteristics accounted for 77% of the explainable variability in TMD. When co-modeled, higher TFA and lower TMD, but not lower TMA, were significantly and independently associated with higher HAQ scores, lower SF-36 total physical scores, lower composite SPPB scores, and a greater proportion of affected obligatory VLAs.
Thigh CT-derived measures of body composition, particularly fat area and muscle density, were strongly associated with disability and physical performance in RA patients, with RA disease features as potential determinants. Efforts to reduce fat and improve muscle quality may reduce disability in this population with impaired physical functioning.
PMCID: PMC3521589  PMID: 22391952
Body Composition; Disability; Muscle; Adipose
10.  Association of circulating adiponectin levels with progression of radiographic joint destruction in rheumatoid arthritis 
Annals of the rheumatic diseases  2011;70(9):1562-1568.
Adipokines have inflammatory and immunomodulatory properties that may contribute to erosive joint damage. The association of serum adipokine levels with progression of radiographic joint damage in patients with rheumatoid arthritis (RA) was prospectively explored.
Patients with RA underwent serum adipokine assessment (adiponectin, resistin, leptin) at three timepoints and hand/feet x-rays, scored using the Sharp-van der Heijde Score (SHS), at baseline and the third study visit, separated by an average of 39 ± 4 months. The associations of baseline and average adipokine levels with change in SHS were explored, adjusting for pertinent confounders.
Of the 152 patients studied, 85 (56%) showed an increase in SHS (defined as >0 SHS units). Among the adipokines studied, only adiponectin was significantly associated with radiographic progression, with average adiponectin levels more strongly associated than baseline levels. After adjusting for average C reactive protein and baseline SHS, patients in the highest quartile of average adiponectin had a SHS progression rate more than double the lowest quartile (1.00 vs 0.48 units/year; p=0.008). Similarly, those in the highest quartile of adiponectin had a more than fivefold greater odds of any radiographic progression compared with the lowest quartile (OR 5.75; p=0.002). The magnitude of the association of average adiponectin levels with radiographic progression was greater in women, those with body mass index <30 kg/m2 and those receiving baseline biological disease-modifying antirheumatic drugs.
These prospective data provide evidence of temporality and dose-response in the relationship between circulating adiponectin and erosive joint destruction in RA, and highlight subgroups of patients at highest risk for adiponectin-associated radiographic progression.
PMCID: PMC3543946  PMID: 21571734
11.  Prevalence of Traditional Modifiable Cardiovascular Risk Factors in Patients with Rheumatoid Arthritis: Comparison with Control Subjects from the Multi-Ethnic Study of Atherosclerosis 
Despite the recognized risk of accelerated atherosclerosis in patients with rheumatoid arthritis (RA), little is known about cardiovascular risk management in contemporary cohorts of these patients. We tested the hypotheses that major modifiable cardiovascular risk factors were more frequent and rates of treatment, detection, and control were lower in patients with RA than in non-RA controls.
The prevalence of hypertension, diabetes, elevated low-density lipoprotein (LDL) cholesterol, elevated body mass index, smoking, moderate-high 10-year cardiovascular risk and the rates of underdiagnosis, therapeutic treatment, and recommended management were compared in 197 RA patients and 274 frequency-matched control subjects, and their associations with clinical characteristics were examined.
Eighty percent of RA patients and 81% of control subjects had at least 1 modifiable traditional cardiovascular risk factor. Hypertension was more prevalent in the RA group (57%) than in controls [42%, P =0.001]. There were no statistically significant differences in the frequency of diabetes, elevated body mass index, smoking, intermediate-high 10-year coronary heart disease risk, or elevated LDL in patients with RA versus controls. Rates of newly identified diabetes, hypertension, and hyperlipidemia were similar in RA patients versus controls. Rates of therapeutic interventions were low in both groups but their use was associated with well-controlled blood pressure (OR = 4.55, 95% CI: 1.70, 12.19) and lipid levels (OR = 9.90, 95% CI: 3.30, 29.67).
Hypertension is more common in RA than in controls. Other traditional cardiovascular risk factors are highly prevalent, underdiagnosed, and poorly controlled in patients with RA, as well as controls.
PMCID: PMC3538033  PMID: 22340996
rheumatoid arthritis; cardiovascular risk; epidemiology
12.  Peptidylarginine deiminase 2, 3 and 4 have distinct specificities against cellular substrates: Novel insights into autoantigen selection in rheumatoid arthritis 
To define the relationship between autoantigen citrullination and different peptidylarginine deiminase (PAD) enzymes in rheumatoid arthritis (RA).
Citrullinated autoantigens were identified by immunoblotting control and ionomycin-activated human primary neutrophil lysate with RA sera. Autoantigen identity and citrullination sites were defined by mass spectrometry. PAD isoenzyme expression in human neutrophils was determined by immunoblotting. PAD substrate specificity was addressed in HL-60 cell lysates co-incubated with human recombinant PAD2, PAD3 and PAD4.
Although prominent protein citrullination is observed in ionomycin activated neutrophils, RA sera only recognized a limited number of these citrullinated molecules. Among these, we identified that beta and gamma actins are citrullinated on at least ten arginine residues, generating a novel 47kDa species that is frequently recognized by RA autoantibodies. Interestingly, we showed that the PAD enzymes expressed in human neutrophils (i.e. PAD2, PAD3 and PAD4) have unique substrate specificities, independent of their subcellular distribution. Thus, only PAD2 was able to citrullinate native beta/gamma-actin, while histone H3 was only citrullinated by PAD4.
These studies identified beta and gamma actins as novel citrullinated autoantigens in RA, allowing enzyme specificity against intracellular substrates to be addressed. The studies provide evidence that PAD enzymes have the intrinsic capacity to select unique protein targets. We propose that unique PAD specificity may play a role in autoantigen selection in RA.
PMCID: PMC3302156  PMID: 21859690
Citrullination; rheumatoid arthritis; anti-CCP; actin; peptidylarginine deiminase
13.  Longitudinal Predictors of Progression of Carotid Atherosclerosis in Rheumatoid Arthritis 
Arthritis and rheumatism  2011;63(11):3216-3225.
To explore predictors of change in measures of carotid atherosclerosis among rheumatoid arthritis (RA) patients without known cardiovascular disease (CVD) at baseline
RA patients underwent carotid ultrasonography at two timepoints, separated by an average of 3.2 ± 0.3 years. The associations of baseline and average patient characteristics with the average yearly change in mean maximal intima-medial thickness (IMT) of the common (CCA) and internal carotid arteries (ICA), and with incident or progressive plaque in the ICA/carotid bulb, were explored.
Among the 158 RA patients, maxCCA-IMT increased in 82% (median=16 μm/year; p<0.001) and maxICA-IMT increased in 70% (median=25 μm/year; p<0.001). Incident plaque was observed in 14% without baseline plaque [incidence rate=4.2/100 person-years (95% CI 1.61–6.82)]. Plaque progression was observed in 5% with baseline plaque. Among RA predictors, the adjusted average yearly change in maxCCA-IMT was significantly greater in patients with earlier RA vs. longer disease. Those prescribed TNF inhibitors at baseline had a 37% lower adjusted rate of maxCCA-IMT progression vs. non-users (14 vs. 22 μm/year; p=0.026). For maxICA-IMT, cumulative prednisone exposure was associated with progression [1.2 μm/year per gram (95% CI 0.1–2.4)] after adjustment, and was lower in patients prescribed statins concomitant with prednisone. Higher swollen joint count and higher average CRP were both associated with incident or progressive plaque, primarily in patients with elevated baseline CVD risk based on the Framingham score.
These prospective data provide evidence for inflammation as a contributor to subclinical atherosclerosis progression in RA, potentially modified favorably by TNF inhibitors and detrimentally by glucocorticoids.
PMCID: PMC3205252  PMID: 21965129
Atherosclerosis; Inflammation; prediction; carotid ultrasound
14.  Increased Generation of TRAP Expressing Multinucleated Giant Cells in Patients with Granulomatosis with Polyangiitis 
PLoS ONE  2012;7(8):e42659.
Tissue-infiltrating multinucleated giant cells (MNGs) within geographic necrosis are pathologic hallmarks of granulomatosis with polyangiitis (GPA). However, the origin, phenotype, and function of these cells in GPA remain undefined.
Methodology/Principal Findings
MNG phenotype in GPA lung tissue was examined by immunohistochemistry using antibody directed against cathepsin K and calcitonin-receptor. Tartrate-resistant-acid-phosphatase (TRAP) expression was assessed using enzymatic color reaction. Peripheral blood mononuclear cells (PBMCs) from 13 GPA patients (5 with localized and 8 with systemic disease) and 11 healthy controls were cultured in the presence of RANKL and M-CSF for 9 days, and TRAP+ MNGs containing 3 or more nuclei were identified. GPA lung granulomata contained numerous MNGs that expressed osteoclastic TRAP and cathepsin K but not calcitonin receptors. In the presence of RANKL and M-CSF, PBMCs of GPA patients formed significantly more MNGs than healthy controls (114±29 MNG/well vs. 22±9 MNG/well, P = 0.02). In a subgroup analysis, patients with systemic disease generated significantly more MNGs than patients with localized disease (161±35 MNG/well vs. 39±27 MNG/well, P<0.01) or healthy controls (P<0.01). MNG production did not differ between localized GPA and control subjects (P = 0.96).
MNGs in granulomata in the GPA lung express osteoclastic enzymes TRAP and cathepsin K. GPA patients have a higher propensity to form TRAP+ MNGs from peripheral blood than healthy controls. These data suggest that (i) the tendency to form MNGs is a component of the GPA phenotype itself, and (ii) that lesional MNGs might participate in the destructive process through their proteolytic enzymes.
PMCID: PMC3414441  PMID: 22905158
15.  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
16.  Abdominal Adiposity in Rheumatoid Arthritis: Association with Cardiometabolic Risk Factors and Disease Characteristics 
Arthritis and rheumatism  2010;62(11):3173-3182.
Abdominal adiposity, especially visceral adiposity, is an emerging cardiometabolic risk factor. How abdominal fat is distributed in rheumatoid arthritis (RA) and its RA-related determinants have not been explored.
Men and women with RA were compared to non-RA controls from the Multi-Ethnic Study of Atherosclerosis. Participants underwent anthropometric measures and quantification of visceral and subcutaneous fat areas (VFA, SFA) using abdominal computed tomography.
A total of 131 RA patients were compared with 121 controls. Despite similar body mass index and waist circumference between the RA and control groups, the adjusted mean VFA was 45cm2 higher (+51%) for RA vs. control men (p=0.005) but not significantly different by RA status in women. The adjusted mean SFA was 119cm2 higher (+68%) for RA vs. control women (p<0.001) but not significantly different by RA status in men. Elevated VFA (>75th percentile) was associated with a significantly higher adjusted probability of having an elevated fasting glucose, hypertension, or the composite definition of the metabolic syndrome for the RA group compared with controls. Within the RA group, rheumatoid factor seropositivity and higher cumulative prednisone exposure were significantly associated with a higher mean adjusted VFA. Higher C-reactive protein levels and lower Sharp scores were significantly associated with both VFA and SFA.
The distribution of abdominal fat differs significantly by RA status. Higher VFA in men with RA, and the more potent association of VFA with cardiometabolic risk factors in men and women with RA, may contribute to cardiovascular risk in RA populations.
PMCID: PMC2962724  PMID: 20589684
17.  Prospective characterization of musculoskeletal symptoms in early stage breast cancer patients treated with aromatase inhibitors 
Aromatase inhibitors (AIs) are increasingly used as adjuvant treatment of postmenopausal women with hormone receptor-positive breast cancer. AIs are commonly associated with musculoskeletal symptoms. The primary objective of this study was to describe the musculoskeletal symptoms that developed in the first 100 subjects enrolled who had at least 6 months follow-up.
Women with early stage hormone receptor-positive breast cancer were recruited into a multicenter randomized clinical trial to study the pharmacogenomics of two AIs, exemestane, and letrozole. Patients completed the Health Assessment Questionnaire (HAQ) and Visual Analog Scale (VAS) at baseline, 1, 3, 6, and 12 months to assess changes in function and pain, respectively. Patients were referred for evaluation by a rheumatologist if their HAQ and/or VAS scores exceeded a predefined threshold.
Forty-four of 97 eligible patients (45.4%) met criteria for rheumatologic referral. Three patients were ineligible because of elevated baseline HAQ (2) and failure to initiate AI therapy (1). No baseline characteristics were significantly associated with referral. Median time to onset of symptoms was 1.6 months (range 0.4–10 months). Clinical and laboratory evaluation of patients evaluated by rheumatology suggested that the majority developed either non-inflammatory musculoskeletal symptoms or inflammation localized to tenosynovial structures. Thirteen patients discontinued AI therapy because of musculoskeletal toxicity after a median 6.1 months (range 2.2–13 months).
Musculoskeletal side effects were common in AI-treated patients, resulting in therapy discontinuation in more than 10% of patients. There are no identifiable pre-therapy indicators of risk, and the etiology remains elusive.
PMCID: PMC3081690  PMID: 17922185
Aromatase inhibitor; Arthralgia; Breast cancer; Musculoskeletal symptoms; Rheumatology
18.  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
19.  Left Ventricular Structure and Function by Cardiac Magnetic Resonance Imaging in Rheumatoid Arthritis 
Arthritis and rheumatism  2010;62(4):940-951.
Heart failure is a major contributor to cardiovascular morbidity and mortality in rheumatoid arthritis. However, little is known about myocardial structure and function in this population.
Using cardiac magnetic resonance imaging, measures of myocardial structure and function were assessed in men and women with rheumatoid arthritis enrolled in ESCAPE RA, a cohort study of subclinical cardiovascular disease in rheumatoid arthritis, and compared with controls without rheumatoid arthritis enrolled in the Baltimore cohort of the Multi-Ethnic Study of Atherosclerosis.
Myocardial measures were compared between 75 rheumatoid arthritis patients and 225 matched controls. After adjustment, mean left-ventricular mass was 26 grams lower for the RA group compared to controls (p<0.001), an 18% difference. After similar adjustment, mean left-ventricular ejection fraction, cardiac output, and stroke volume were modestly lower in the rheumatoid arthritis group vs. controls. Mean left-ventricular end-systolic and end-diastolic volumes did not differ by rheumatoid arthritis status. Within the rheumatoid arthritis group, higher levels of anti-CCP antibodies and current use of biologics, but not other disease activity or severity measures, were associated with significantly lower adjusted mean left-ventricular mass, end-diastolic volume, and stroke volume, but not ejection fraction. The combined associations of anti-CCP antibody level and biologic use on myocardial measures were additive, without evidence of interaction.
These findings suggest that the progression to heart failure in RA may occur through reduced myocardial mass rather than hypertrophy. Both modifiable and non-modifiable factors may contribute to lower levels of left-ventricular mass and volume.
PMCID: PMC3008503  PMID: 20131277
myocardial dysfunction; heart failure; inflammation; cardiac imaging
20.  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
21.  Assessment of myocardial abnormalities in rheumatoid arthritis using a comprehensive cardiac magnetic resonance approach: a pilot study 
Arthritis Research & Therapy  2010;12(5):R171.
Rheumatoid arthritis (RA) is a multi-organ inflammatory disorder associated with high cardiovascular morbidity and mortality. We sought to assess cardiac involvement using a comprehensive cardiac magnetic resonance imaging (cMRI) approach and to determine its association with disease characteristics in RA patients without symptomatic cardiac disease.
RA patients with no history and/or clinical findings of systemic or pulmonary hypertension, coronary artery disease, severe valvular heart disease, atrial fibrillation, diabetes mellitus, or echocardiographic abnormalities underwent contrast-enhanced cMRI on a 1.5T scanner. Adenosine triphosphate was used to assess perfusion defects due to microvascular impairment or ischemia, and delayed enhanced imaging was obtained for the assessment of myocardial inflammation/fibrosis. We explored the associations of cMRI abnormalities with RA disease activity and severity measures.
Eighteen patients (78% female) with a mean age of 57 ± 10 years were studied. Eight patients (45%) demonstrated a myocardial abnormality. Perfusion defects under pharmacologic stress were seen in two patients (11%), one of whom had a circumferential subendocardial perfusion defect and one had a non-segmental subendocardial perfusion defect. Seven patients (39%) were found to have delayed enhancement, only one of whom also demonstrated a perfusion defect. Mean disease activity score (DAS)28 was significantly higher in the group with delayed enhancement compared to the group without by an average of 1.32 DAS28 units (4.77 vs. 3.44 units, respectively; P = 0.011). Corresponding trends to statistical significance were noted in systemic inflammatory markers, with both C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) quantitatively higher in the group with delayed enhancement. Other RA characteristics, such as disease duration, autoantibody status, and current treatments were not significantly associated with cardiac involvement.
Myocardial abnormalities, as detected by cMRI, were frequent in RA patients without known cardiac disease. Abnormal cMRI findings were associated with higher RA disease activity, suggesting a role for inflammation in the pathogenesis of myocardial involvement in RA.
PMCID: PMC2990998  PMID: 20836862
22.  Respiratory symptoms and disease characteristics as predictors of pulmonary function abnormalities in patients with rheumatoid arthritis: an observational cohort study 
Arthritis Research & Therapy  2010;12(3):R104.
Lung involvement is a common extra-articular manifestation of rheumatoid arthritis (RA) that confers significant morbidity and mortality. The objective of the present study is to assess which respiratory symptoms and patient and disease characteristics are most highly associated with pulmonary function test (PFT) abnormalities in an RA patient cohort without clinical cardiovascular disease.
A total of 159 individuals with RA and without clinically evident cardiovascular disease were evaluated. Respiratory symptoms were assessed with the Lung Tissue Research Consortium questionnaire and all patients underwent evaluation with PFTs. Demographic, lifestyle, RA disease and treatment characteristics were collected. Subclinical coronary artery disease was assessed by cardiac computed tomography. Multivariable regression analysis was used to identify pulmonary symptoms and nonpulmonary parameters associated with PFT abnormalities. Areas under the receiver operating characteristic curves (AUC) were calculated to evaluate the discrimination of these variables for identifying patients with PFT abnormalities.
Respiratory symptoms were reported by 42% of the patient population. Although only 6% carried a prior diagnosis of lung disease, PFT abnormalities were identified in 28% of the subjects. Symptoms combined with other patient and RA characteristics (body mass index, current smoking, anti-cyclic citrullinated peptide antibodies, and current prednisone use) performed satisfactorily in predicting the PFT abnormalities of obstruction (AUC = 0.91, 95% confidence interval = 0.78 to 0.98), restriction (AUC = 0.79, 95% confidence interval = 0.75 to 0.93) and impaired diffusion (AUC = 0.85, 95% confidence interval = 0.59 to 0.92). Co-morbid subclinical coronary artery disease did not modify these relationships.
Assessment of respiratory symptoms along with a limited number of clinical parameters may serve as a useful and inexpensive clinical tool for identifying RA patients in need of further pulmonary investigation.
PMCID: PMC2911894  PMID: 20507627
23.  Association of Autoimmunity to Peptidyl Arginine Deiminase Type 4 With Genotype and Disease Severity in Rheumatoid Arthritis 
Arthritis and rheumatism  2008;58(7):1958-1967.
Protein citrullination is an important posttranslational modification recognized by rheumatoid arthritis (RA)–specific autoantibodies. One of the citrullinating enzymes, peptidyl arginine deiminase type 4 (PAD-4), is genetically associated with development of RA in some populations, although the mechanism(s) mediating this effect are not yet clear. There have been descriptions of anti–PAD-4 autoantibodies in different rheumatic diseases. This study was undertaken to investigate whether anti–PAD-4 antibodies are specific to RA, are associated with disease phenotype or severity, and whether PAD-4 polymorphisms influence the anti–PAD-4 autoantibody response.
Sera from patients with established RA, patients with other rheumatic diseases, and healthy adults were assayed for anti–PAD-4 autoantibodies by immunoprecipitation of in vitro–translated PAD-4. The epitope(s) recognized by PAD-4 autoantibodies were mapped using various PAD-4 truncations. PAD-4 genotyping was performed on RA patients with the TaqMan assay. Joint erosions were scored from hand and foot radiographs using the Sharp/van der Heijde method.
PAD-4 autoantibodies were found in 36–42% of RA patients, and were very infrequent in controls. Recognition by anti–PAD-4 autoantibodies required the 119 N-terminal amino acids, which encompass the 3 nonsynonymous polymorphisms associated with disease susceptibility. Strikingly, the anti–PAD-4 immune response was associated with the RA susceptibility haplotype of PADI4. Anti–PAD-4 antibodies were associated with more severe joint destruction in RA.
Our findings indicate that anti–PAD-4 antibodies are specific markers of RA, independently associated with more severe disease, suggesting that an anti–PAD-4 immune response may be involved in pathways of joint damage in this disease. Polymorphisms in the PADI4 gene influence the immune response to the PAD-4 protein, potentially contributing to disease propagation.
PMCID: PMC2692635  PMID: 18576335
24.  Abnormal Body Composition Phenotypes in Older Rheumatoid Arthritis Patients: Association With Disease Characteristics and Pharmacotherapies 
Arthritis and rheumatism  2008;59(6):807-815.
To compare measures of body fat and lean mass and the prevalence of abnormal body composition phenotypes (sarcopenia, overfat, and sarcopenic obesity) in men and women with rheumatoid arthritis (RA) versus matched controls, and to explore the disease-related predictors of abnormal body composition in patients with RA.
A total of 189 men and women with RA and 189 age-, sex-, and race-matched non-RA controls underwent dual-energy x-ray absorptiometry for measurement of total and regional body fat and lean mass. Continuous and categorical measures of body composition were compared between RA and control subjects by sex and according to categories of body mass index (BMI). Within the group of RA patients, demographic, lifestyle, and RA disease and treatment characteristics were compared for RA patients with healthy body composition versus those with abnormal body composition phenotypes.
Compared with non-RA controls, RA status was significantly associated with greater odds of sarcopenia, overfat, and sarcopenic obesity in women, but not in men. Relative differences in body composition phenotypes between RA and control subjects were greatest for patients in the normal weight BMI category (<25 kg/m2). Among RA characteristics, increasing joint deformity, self-reported disability scores, C-reactive protein levels, rheumatoid factor seropositivity, and a lack of current treatment with disease-modifying antirheumatic drugs were significantly associated with abnormal body composition.
Abnormal body composition phenotypes are overrepresented in patients with RA, particularly in those in the normal weight BMI range. RA-associated disease and treatment characteristics contribute to this increase in abnormal body composition.
PMCID: PMC2670994  PMID: 18512711
25.  Association of Body Fat With C-Reactive Protein in Rheumatoid Arthritis 
Arthritis and rheumatism  2008;58(9):2632-2641.
The serum C-reactive protein (CRP) concentration is commonly used in rheumatoid arthritis (RA) as a surrogate marker of systemic inflammation, presumably induced by synovitis. However, other tissues, such as adipose tissue, can induce CRP production. This study was undertaken to explore the associations between measures of adiposity and CRP levels in RA.
One hundred ninety-six men and women with RA underwent anthropometric assessment and total body dual-energy x-ray absorptiometry for measurement of total and regional body fat and lean mass. The associations between measures of fat and lean mass and serum levels of CRP and interleukin-6 (IL-6) were determined in analyses stratified by sex, with adjustment for pertinent demographic, lifestyle, and RA disease and treatment covariates as well as for the potential modifying effects of articular activity and biologic pharmacotherapeutic agents.
All measures of adiposity were significantly associated with the level of CRP in women, but not in men. In women, the measure of adiposity that showed the strongest association with the CRP level was truncal fat, in which, in adjusted analyses, each kilogram increase was associated with a 0.101-unit increase in the logarithmically transformed CRP level (P < 0.001). Neither the level of articular activity nor the use of biologic agents significantly modified this association in women. However, in men, elevated articular involvement was associated with a decreasing CRP level as truncal fat increased. For all analyses, substitution of IL-6 for CRP produced similar findings.
Adiposity is independently associated with CRP levels in women with RA, and thus may confound the estimation of RA disease activity when serum CRP concentration is used as a surrogate for systemic inflammation.
PMCID: PMC2671067  PMID: 18759279

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