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1.  [No title available] 
PMCID: PMC3874076  PMID: 23727634
2.  [No title available] 
PMCID: PMC3883892  PMID: 23716070
3.  [No title available] 
PMCID: PMC3902644  PMID: 23345599
4.  [No title available] 
PMCID: PMC3999435  PMID: 24092416
5.  Heart Disease and Rheumatoid Arthritis: Understanding the Risks 
Annals of the rheumatic diseases  2010;69(0 1):i61-i64.
Patients with rheumatoid arthritis (RA) are at increased risk of mortality compared with the general population. Evidence suggests that this increased mortality can largely be attributed to increased cardiovascular (CV) death. In a retrospective study of an inception cohort of RA patients in Rochester, MN, we investigated the contribution of traditional and RA-specific risk factors towards this increased risk of CV morbidity and mortality. Several traditional CV risk factors were found to behave differently in RA patients. In addition, their associations with CV disease are weaker in RA patients as increased inflammation associated with RA appears to also contribute substantially to the increased CV mortality. Furthermore, the impact of disease modifying anti-rheumatic drugs (DMARDs) and biologics on CV disease in RA patients is unclear. CV risk scores for the general population may underestimate risk for RA patients. Together with other studies that have demonstrated similar associations between RA and CV mortality, these data suggest that optimal control of CV risk factors is important, but not sufficient in RA patients. RA-specific CV risk prediction tools are needed, as well as clinical trials to assess the impact of therapies and tight control of inflammation in RA patients on CV outcomes and mortality.
doi:10.1136/ard.2009.119404
PMCID: PMC4308040  PMID: 19995747
6.  Ligation of TLR7 by rheumatoid arthritis synovial fluid single strand RNA induces transcription of TNF-α in monocytes 
Annals of the rheumatic diseases  2012;72(3):418-426.
Objective
The aim of the study was to characterize the expression, regulation and pathogenic role of TLR7 and TLR8 in rheumatoid arthritis (RA).
Methods
Expression of TLR7 and TLR8 was demonstrated in RA, osteoarthritis (OA) and normal (NL) synovial tissues (ST) employing immunohistochemistry. We next examined the mechanism by which TLR7 and TLR8 ligation mediates proinflammatory response by Western blot analysis and ELISA. Expression of TLR7 and TLR8 in RA monocytes was correlated to disease activity score (DAS28) and TNF-α levels. Further the effect of TLR7 ligation in RA monocytes was determined on synovial fluid (SF) mediated TNF-α transcription.
Results
TLR7/TLR8 are predominately expressed in RA ST lining and sublining macrophages. We show that NF-κB and/or PI3K pathways are essential for TLR7/TLR8 induction of proinflammatory factors in RA peripheral blood (PB) differentiated macrophages. Expression of TLR7 in RA monocytes shows a strong correlation with DAS28 and TNF-α levels. In contrast, expression of TLR8 in these cells does not correlate with DAS28, TLR7 or TNF-α levels. We further demonstrate that RNA from RA SF but not RA or NL plasma could modulate TNF-α transcription from RA monocytes that can be downregulated by antagonizing TLR7 ligation or degradation of single stand (ss) RNA. Thus, ssRNA present in RA SF may function as a potential endogenous ligand for TLR7.
Conclusions
These results suggest that expression of TLR7 but not TLR8 may be a predictor for RA disease activity and anti-TNF-α responsiveness, and targeting TLR7 may suppress chronic progression of RA.
doi:10.1136/annrheumdis-2011-201203
PMCID: PMC4281889  PMID: 22730373
RA synovial tissue; RA monocytes/macrophages; TLR7; TLR8 and ssRNA
8.  Lymphoma risk in systemic lupus: effects of disease activity versus treatment 
Annals of the rheumatic diseases  2013;73(1):10.1136/annrheumdis-2012-202099.
Objective
To examine disease activity versus treatment as lymphoma risk factors in systemic lupus erythematosus (SLE).
Methods
We performed case–cohort analyses within a multisite SLE cohort. Cancers were ascertained by regional registry linkages. Adjusted HRs for lymphoma were generated in regression models, for time-dependent exposures to immunomodulators (cyclophosphamide, azathioprine, methotrexate, mycophenolate, antimalarial drugs, glucocorticoids) demographics, calendar year, Sjogren’s syndrome, SLE duration and disease activity. We used adjusted mean SLE Disease Activity Index scores (SLEDAI-2K) over time, and drugs were treated both categorically (ever/never) and as estimated cumulative doses.
Results
We studied 75 patients with lymphoma (72 non-Hodgkin, three Hodgkin) and 4961 cancer-free controls. Most lymphomas were of B-cell origin. As is seen in the general population, lymphoma risk in SLE was higher in male than female patients and increased with age. Lymphomas occurred a mean of 12.4 years (median 10.9) after SLE diagnosis. Unadjusted and adjusted analyses failed to show a clear association of disease activity with lymphoma risk. There was a suggestion of greater exposure to cyclophosphamide and to higher cumulative steroids in lymphoma cases than the cancer-free controls.
Conclusions
In this large SLE sample, there was a suggestion of higher lymphoma risk with exposure to cyclophosphamide and high cumulative steroids. Disease activity itself was not clearly associated with lymphoma risk. Further work will focus on genetic profiles that might interact with medication exposure to influence lymphoma risk in SLE.
doi:10.1136/annrheumdis-2012-202099
PMCID: PMC3855611  PMID: 23303389
9.  Association of Medication Beliefs and Self-Efficacy with Adherence in Urban Hispanic and African American Rheumatoid Arthritis Patients 
Annals of the rheumatic diseases  2013;73(1):317-318.
doi:10.1136/annrheumdis-2013-203560
PMCID: PMC3940270  PMID: 23904474
rheumatoid arthritis; medication adherence; minority health; self-efficacy; medication beliefs
10.  Non-viral Opportunistic Infections in New Users of TNF Inhibitor Therapy: Results of the SAfety Assessment of Biologic ThERapy (SABER) Study 
Annals of the rheumatic diseases  2013;73(11):1942-1948.
Objectives
To determine among patients with autoimmune diseases in the United States whether the risk of non-viral opportunistic infections (OIs) was increased among new users of tumor necrosis factor-alpha inhibitors (TNFI), when compared to users of non-biologic agents used for active disease.
Methods
We identified new users of TNFI among cohorts of rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis-psoriatic arthritis-ankylosing spondylitis (PsO-PsA-AS) patients during 1998–2007 using combined data from Kaiser Permanente Northern California, two pharmaceutical assistance programs for the elderly, Tennessee Medicaid, and US Medicaid/Medicare programs. We compared incidence of non-viral OIs among new TNFI users and patients initiating non-biologic disease modifying drugs (DMARDs) overall and within each disease cohort. Cox regression models were used to compare propensity-score and steroid- adjusted OI incidence between new TNFI and non-biologic DMARD users.
Results
Within a cohort of 33,324 new TNFI users we identified 80 non-viral OIs, the most common of which was pneumocystosis (n=16). In the combined cohort, crude rates of non-viral OIs among new users of TNFI as compared to those initiating non-biologic DMARDs was 2.7 verus 1.7 per 1000-person years[adjusted hazard ratio (aHR): 1.6, 95% CI: 1.0, 2.6)]. Baseline corticosteroid use was associated with non-viral OIs (aHR 2.5, 95% CI: 1.5, 4.0). In the RA cohort, rates of non-viral OIs among new users of infliximab were higher when compared to patients newly starting non-biologic DMARDs (aHR 2.6, 95% CI 1.2, 5.6) or new etanercept users (aHR 2.9, 95% CI: 1.5, 5.4).
Conclusions
In the US, the rate of non-viral OIs was higher among new users of TNFI with autoimmune diseases as compared to non-biologic DMARD users.
doi:10.1136/annrheumdis-2013-203407
PMCID: PMC4273901  PMID: 23852763
opportunistic infection; tumor necrosis factor-alpha; Pneumocystis; tuberculosis; rheumatoid arthritis
11.  Relationship between air pollution and positivity of RA-related autoantibodies in individuals without established RA: a report on SERA 
Annals of the rheumatic diseases  2013;72(12):10.1136/annrheumdis-2012-202949.
Introduction
Studies suggest that respiratory exposures including smoking, proximity to traffic and air pollution might be associated with development of rheumatoid arthritis (RA). RA-related autoantibodies are predictive of the development of RA.
Objective
We evaluated the relationship between RA-related autoantibodies and exposure to particulate matter (PM), a measure of air pollution of interest to health, in individuals without RA.
Methods
The Studies of the Etiology of Rheumatoid Arthritis (SERA) is a multicentre study following first-degree relatives (FDRs) of a proband with RA. FDRs are without the 1987 ACR (American College of Rheumatology) classifiable RA at enrolment and are followed for the development of RA-related autoimmunity. RA-related autoantibody outcomes as well as tender and swollen joint outcomes were assessed. Exposure to PM was assigned using ambient air pollution monitoring data and interpolated with inverse distance weighting spatial analyses using Geographic Information Systems. PM exposures were linked to FDR’s residential zip codes.
Results
RA-related autoantibodies as well as tender or swollen joints are not associated with ambient PM concentrations.
Discussion
While other respiratory exposures may be associated with increased risk of RA, our data suggest that ambient PM is not associated with autoantibodies and joint signs among individuals without RA, but at increased risk of developing RA.
doi:10.1136/annrheumdis-2012-202949
PMCID: PMC3818364  PMID: 23572338
12.  New insight on the Xq28 association with systemic sclerosis 
Annals of the rheumatic diseases  2013;72(12):10.1136/annrheumdis-2012-202742.
Objective
To evaluate whether the systemic sclerosis (SSc)-associated IRAK1 non-synonymous single-nucleotide polymorphism rs1059702 is responsible for the Xq28 association with SSc or whether there are other independent signals in the nearby methyl-CpG-binding protein 2 gene (MECP2).
Methods
We analysed a total of 3065 women with SSc and 2630 unaffected controls from five independent Caucasian cohorts. Four tag single-nucleotide polymorphisms of MECP2 (rs3027935, rs17435, rs5987201 and rs5945175) and the IRAK1 variant rs1059702 were genotyped using TaqMan predesigned assays. A meta-analysis including all cohorts was performed to test the overall effect of these Xq28 polymorphisms on SSc.
Results
IRAK1 rs1059702 and MECP2 rs17435 were associated specifically with diffuse cutaneous SSc (PFDR=4.12×10−3, OR=1.27, 95% CI 1.09 to 1.47, and PFDR=5.26×10−4, OR=1.30, 95% CI 1.14 to 1.48, respectively), but conditional logistic regression analysis showed that the association of IRAK1 rs1059702 with this subtype was explained by that of MECP2 rs17435. On the other hand, IRAK1 rs1059702 was consistently associated with presence of pulmonary fibrosis (PF), because statistical significance was observed when comparing SSc patients PF+ versus controls (PFDR=0.039, OR=1.30, 95% CI 1.07 to 1.58) and SSc patients PF+ versus SSc patients PF− (p=0.025, OR=1.26, 95% CI 1.03 to 1.55).
Conclusions
Our data clearly suggest the existence of two independent signals within the Xq28 region, one located in IRAK1 related to PF and another in MECP2 related to diffuse cutaneous SSc, indicating that both genes may have an impact on the clinical outcome of the disease.
doi:10.1136/annrheumdis-2012-202742
PMCID: PMC3818491  PMID: 23444193
13.  Racial Disparities in Knee and Hip Total Joint Arthroplasty: An 18-year Analysis of National Medicare Data 
Annals of the rheumatic diseases  2013;73(12):2107-2115.
Objective
Examine whether racial disparities in utilization and outcomes of total knee and total hip arthroplasty (TKA and THA) have declined over time.
Methods
We used 1991-2008 Medicare Part A (MedPAR) data to identify four separate cohorts of patients (primary TKA, revision TKA, primary THA, revision THA). For each cohort, we calculated standardized arthroplasty utilization rates for White and Black Medicare beneficiaries for each calendar year and examined changes in disparities over time. We examined unadjusted and adjusted arthroplasty outcomes (30-day readmission rate, discharge disposition etc.) for Whites and Blacks and whether disparities decreased over time.
Results
In 1991 utilization of primary TKA was 36% lower for Blacks compared to Whites (20.6 per 10,000 for Blacks; 32.1 per 10,000 for Whites; p<0.0001); in 2008 utilization of primary TKA for Blacks was 40% lower for Blacks (41.5 per 10,000 for Blacks; 68.8 per 10,000 for Whites; p<0.0001) with similar findings for the other cohorts. Black-White disparities in 30-day hospital readmission increased significantly from 1991-2008 among three patient cohorts. For example in 1991 30-day readmission rates for Blacks receiving primary TKA were 6% higher than for Whites; by 2008 readmission rates for Blacks were 24% higher (p<0.05 for change in disparity). Similarly, Black-White disparities in the proportion of patients discharged-to-home after surgery increased across the study period for all cohorts (p<0.05).
Conclusions
In an 18-year analysis of Medicare data we found little evidence of declines in racial disparities for joint arthroplasty utilization or outcomes.
doi:10.1136/annrheumdis-2013-203494
PMCID: PMC4105323  PMID: 24047869
14.  Large-Vessel Involvement in Giant Cell Arteritis: A Population-Based Cohort Study of the Incidence-Trends and Prognosis 
Annals of the rheumatic diseases  2012;72(12):1989-1994.
Objectives
To evaluate incidence trends and timing of large-vessel (LV) manifestations in patients with giant cell arteritis (GCA), and, to examine the influence of LV manifestations on survival.
Methods
A population-based incident cohort of patients diagnosed with GCA between 1950 and 2004 was used. LV involvement was defined as large artery stenosis or aortic aneurysm/dissection that developed in the 1 year prior to GCA diagnosis or any time thereafter. Patients were followed until death or December 31, 2009.
Results
The study included 204 patients, 80% women, mean age at diagnosis of GCA 76.0 years (± 8.2 years). Median length of follow-up was 8.8 years. The cumulative incidence of any LV manifestation at 10 years was 24.9% for patients diagnosed with GCA between 1980–2004 compared to 8.3% for patients diagnosed with GCA between 1950 and 1979. The incidence of any LV event was high within the first year of GCA diagnosis. The incidence of aortic aneurysm/dissection increased 5 years after GCA diagnosis.
Compared to the general population, survival was decreased in patients with an aortic aneurysm/dissection (p<0.001) but not in patients with large-artery stenosis (p=0.11). Patients with GCA and aortic manifestations had higher than expected number of deaths from cardiovascular and pulmonary causes compared to the general population. Among patients with GCA, aortic manifestations were associated with increased mortality (HR: 3.4; 95% CI: 2.2, 5.4).
Conclusions
Screening for aortic aneurysms should be considered in all patients with GCA with vigilance 5 years after incidence. Aortic aneurysm/dissection is associated with increased mortality in GCA.
doi:10.1136/annrheumdis-2012-202408
PMCID: PMC4112513  PMID: 23253927
Giant cell arteritis; aortic aneurysm; aortic dissection; large-artery stenosis; survival
15.  Ankylosing spondylitis is associated with the anthrax toxin receptor 2 gene (ANTXR2) 
Annals of the Rheumatic Diseases  2014;73(11):2054-2058.
Objectives
ANTXR2 variants have been associated with ankylosing spondylitis (AS) in two previous genome-wide association studies (GWAS) (p∼9×10−8). However, a genome-wide significant association (p<5×10−8) was not observed. We conducted a more comprehensive analysis of ANTXR2 in an independent UK sample to confirm and refine this association.
Methods
A replication study was carried out with 2978 cases and 8365 controls. Then, these were combined with non-overlapping samples from the two previous GWAS in a meta-analysis. Human leukocyte antigen (HLA)-B27 stratification was also performed to test for ANTXR2-HLA-B27 interaction.
Results
Out of nine single nucleotide polymorphisms (SNP) in the study, five SNPs were nominally associated (p<0.05) with AS in the replication dataset. In the meta-analysis, eight SNPs showed evidence of association, the strongest being with rs12504282 (OR=0.88, p=6.7×10−9). Seven of these SNPs showed evidence for association in the HLA-B27-positive subgroup, but none was associated with HLA-B27-negative AS. However, no statistically significant interaction was detected between HLA-B27 and ANTXR2 variants.
Conclusions
ANTXR2 variants are clearly associated with AS. The top SNPs from two previous GWAS (rs4333130 and rs4389526) and this study (rs12504282) are in strong linkage disequilibrium (r2≥0.76). All are located near a putative regulatory region. Further studies are required to clarify the role played by these ANTXR2 variants in AS.
doi:10.1136/annrheumdis-2014-205643
PMCID: PMC4215346  PMID: 25169729
Ankylosing Spondylitis; Inflammation; Gene Polymorphism; Epidemiology; Spondyloarthritis
16.  The outcome and cost-effectiveness of nurse-led care in people with rheumatoid arthritis: a multicentre randomised controlled trial 
Annals of the Rheumatic Diseases  2013;73(11):1975-1982.
Objective
To determine the clinical effectiveness and cost-effectiveness of nurse-led care (NLC) for people with rheumatoid arthritis (RA).
Methods
In a multicentre pragmatic randomised controlled trial, the assessment of clinical effects followed a non-inferiority design, while patient satisfaction and cost assessments followed a superiority design. Participants were 181 adults with RA randomly assigned to either NLC or rheumatologist-led care (RLC), both arms carrying out their normal practice. The primary outcome was the disease activity score (DAS28) assessed at baseline, weeks 13, 26, 39 and 52; the non-inferiority margin being DAS28 change of 0.6. Mean differences between the groups were estimated controlling for covariates following per-protocol (PP) and intention-to-treat (ITT) strategies. The economic evaluation (NHS and healthcare perspectives) estimated cost relative to change in DAS28 and quality-adjusted life-years (QALY) derived from EQ5D.
Results
Demographics and baseline characteristics of patients under NLC (n=91) were comparable to those under RLC (n=90). Overall baseline-adjusted difference in DAS28 mean change (95% CI) for RLC minus NLC was −0.31 (−0.63 to 0.02) for PP and -0.15 (−0.45 to 0.14) for ITT analyses. Mean difference in healthcare cost (RLC minus NLC) was £710 (−£352, £1773) and −£128 (−£1263, £1006) for PP and ITT analyses, respectively. NLC was more cost-effective with respect to cost and DAS28, but not in relation to QALY utility scores. In all secondary outcomes, significance was met for non-inferiority of NLC. NLC had higher ‘general satisfaction’ scores than RLC in week 26.
Conclusions
The results provide robust evidence to support non-inferiority of NLC in the management of RA.
Trial registration
ISRCTN29803766
doi:10.1136/annrheumdis-2013-203403
PMCID: PMC4215359  PMID: 23982436
Economic Evaluations; Health services research; Multidisciplinary team-care; Nursing; Rheumatoid Arthritis
17.  Obesity and risk of incident psoriatic arthritis in US women 
Annals of the rheumatic diseases  2012;71(8):1267-1272.
Objectives
Both overall and central obesity has been associated with risk of psoriasis from prospective study. Data on the association between obesity and psoriatic arthritis (PsA) have been very sparse and no evidence on obesity measures and risk of incident PsA is available now. We aimed to evaluate the association between obesity and risk of incident PsA in a large cohort of women.
Methods
A total of 89,049 participants were included from the Nurses Health Study II over a 14-year time period (1991–2005). Information on BMI, weight change, and measures of central obesity (waist circumference, hip circumference, and waist-hip ratio) was collected during the follow-up. Incidence of clinician-diagnosed PsA was ascertained and confirmed by supplementary questionnaires.
Results
We identified 146 incident PsA cases during 1,231,693 person-years’ follow-up. Among total participants, BMI was monotonically associated with an increased risk of incident PsA. Compared with BMI less than 25.0, the relative risk (RR) was 1.83 for BMI 25.0 through 29.9 (95% confidence interval (CI): 1.15–2.89), 3.12 for BMI 30.0 through 34.9 (95% CI: 1.90–5.11), and 6.46 for BMI > 35.0 (95% CI: 4.11–10.16). There was a graded positive association between weight change from age 18, measures of central obesity, and risk of PsA (P for trend <0.001). The analysis among participants developing psoriasis during follow-up revealed a similar association (P for trend <0.01), indicating an increased risk of PsA associated with obesity among psoriatics.
Conclusion
In this study we provide further evidence linking obesity with risk of incident PsA among U.S. women.
doi:10.1136/annrheumdis-2011-201273
PMCID: PMC4183754  PMID: 22562978
obesity; weight change; psoriatic arthritis; epidemiology
18.  Aryl hydrocarbon receptor antagonism mitigates cytokine-mediated inflammatory signalling in primary human fibroblast-like synoviocytes 
Annals of the rheumatic diseases  2013;72(10):1708-1716.
Objectives
Rheumatoid Arthritis (RA) is a chronic inflammatory disease of unclear aetiology, which is associated with inflamed human fibroblast-like synoviocytes (HFLS). Epidemiological studies have identified a positive correlation between tobacco smoking (a rich source of aryl hydrocarbon receptor (AHR) agonists) and aggressive RA phenotype. Thus, we hypothesise that antagonism of AHR activity by a potent AHR antagonist GNF351 can attenuate the inflammatory phenotype of HFLS-RA cells.
Methods
Quantitative PCR was used to examine IL1B-induced mRNA expression in primary HFLS-RA cells. A structurally diverse AHR antagonist CH223191 and transient AHR repression using AHR small interfering RNA (siRNA) in primary HFLS-RA cells were used to demonstrate that effects observed by GNF351 are AHR-mediated. The levels of PTGS2 were determined by western blot and secretory cytokines such as IL1B and IL6 by ELISA. Chromatin-immunoprecipitation was used to assess occupancy of the AHR on the promoters of IL1B and IL6.
Results
Many of the chemokine and cytokine genes induced by IL1B in HFLS-RA cells are repressed by co-treatment with GNF351 at both the mRNA and protein level. Pretreatment of HLFS-RA cells with CH223191 or transient gene ablation of AHR by siRNA confirmed that the effects of GNF351 are AHR-mediated. GNF351 inhibited the recruitment of AHR to the promoters of IL1B and IL6 confirming occupancy of AHR at these promoters is required for enhanced inflammatory signalling.
Conclusions
These data suggest that AHR antagonism may represent a viable adjuvant therapeutic strategy for the amelioration of inflammation associated with RA.
doi:10.1136/annrheumdis-2012-202639
PMCID: PMC4041386  PMID: 23349129
19.  HRES-1/Rab4-mediated depletion of Drp1 impairs mitochondrial homeostasis and represents a target for treatment in SLE 
Annals of the rheumatic diseases  2013;73(10):1888-1897.
Objective
Accumulation of mitochondria underlies T-cell dysfunction in systemic lupus erythematosus (SLE). Mitochondrial turnover involves endosomal traffic regulated by HRES-1/Rab4, a small GTPase that is overexpressed in lupus T cells. Therefore, we investigated whether (1) HRES-1/Rab4 impacts mitochondrial homeostasis and (2) Rab geranylgeranyl transferase inhibitor 3-PEHPC blocks mitochondrial accumulation in T cells, autoimmunity and disease development in lupus-prone mice.
Methods
Mitochondria were evaluated in peripheral blood lymphocytes (PBL) of 38 SLE patients and 21 healthy controls and mouse models by flow cytometry, microscopy and western blot. MRL/lpr mice were treated with 125 μg/kg 3-PEHPC or 1 mg/kg rapamycin for 10 weeks, from 4 weeks of age. Disease was monitored by antinuclear antibody (ANA) production, proteinuria, and renal histology.
Results
Overexpression of HRES-1/Rab4 increased the mitochondrial mass of PBL (1.4-fold; p=0.019) and Jurkat cells (2-fold; p=0.000016) and depleted the mitophagy initiator protein Drp1 both in human (−49%; p=0.01) and mouse lymphocytes (−41%; p=0.03). Drp1 protein levels were profoundly diminished in PBL of SLE patients (−86±3%; p=0.012). T cells of 4-week-old MRL/lpr mice exhibited 4.7-fold over-expression of Rab4A (p=0.0002), the murine homologue of HRES-1/ Rab4, and depletion of Drp1 that preceded the accumulation of mitochondria, ANA production and nephritis. 3-PEHPC increased Drp1 (p=0.03) and reduced mitochondrial mass in T cells (p=0.02) and diminished ANA production (p=0.021), proteinuria (p=0.00004), and nephritis scores of lupus-prone mice (p<0.001).
Conclusions
These data reveal a pathogenic role for HRES-1/Rab4-mediated Drp1 depletion and identify endocytic control of mitophagy as a treatment target in SLE.
doi:10.1136/annrheumdis-2013-203794
PMCID: PMC4047212  PMID: 23897774
20.  Global chemokine expression in systemic sclerosis (SSc): CCL19 expression correlates with vascular inflammation in SSc skin 
Annals of the rheumatic diseases  2013;73(10):1864-1872.
Objective
To characterise global chemokine expression in systemic sclerosis (SSc) skin in order to better understand the relationship between chemokine expression and vascular inflammation in this disease.
Methods
We investigated chemokine mRNA expression in the skin through quantitative PCR analysis comparing patients with diffuse cutaneous (dcSSc) or limited cutaneous (lcSSc) disease with healthy controls. We tested correlations between the most regulated chemokines and vascular inflammation and macrophage recruitment. CCL19 expression was examined in human primary immune cells treated with innate immune activators.
Results
The chemokines, CCL18, CCL19 and CXCL13, were upregulated in dcSSc skin, and CCL18 in lcSSc skin. Expression of CCL19 in dcSSc skin correlated with markers of vascular inflammation and macrophage recruitment. Immunofluorescence data showed CCL19 colocalisation with CD163 macrophages in dcSSc skin. In vitro studies on human primary cells demonstrated that CCL19 expression was induced after toll-like receptor activation of peripheral blood mononuclear cells and separated populations of CD14 monocytes.
Conclusions
CCL18, CCL19 and CXCL13—chemoattractants for macrophage and T cell recruitment—were three of six chemokines with the highest expression in dcSSc skin. Increased CCL19 expression in the skin suggests a role for CCL19 in the recruitment of immune cells to the peripheral tissue. Induction of CCL19 in macrophages but not structural cells indicates a role for skin-resident or recruited immune cells in perivascular inflammation. This study demonstrates that CCL19 is a sensitive marker for the perivascular inflammation and immune cell recruitment seen in dcSSc skin disease.
doi:10.1136/annrheumdis-2012-202814
PMCID: PMC4076390  PMID: 23873879
21.  Smoking and risk of incident psoriatic arthritis in US women 
Annals of the rheumatic diseases  2011;71(6):804-808.
Objectives
Psoriatic arthritis (PsA) is an inflammatory arthritis that is associated with psoriasis. Previous studies have found an association between smoking and psoriasis, but the association with PsA is unclear. We aimed to evaluate the association between smoking and risk of incident PsA in a large cohort of women.
Methods
A total of 94,874 participants were included from the Nurses Health Study II over a 14-year time period (1991-2005). Information on smoking was collected biennially during follow-up. Incidence of clinician-diagnosed PsA was ascertained and confirmed by self-reported questionnaires.
Results
During 1,303,970 person-years’ follow-up, we identified 157 incident PsA cases. Among total participants, smoking was associated with an elevated risk of incident PsA. Compared with never smokers, the relative risk (RR) was 1.54 for past smokers (95% confidence interval (CI): 1.06-2.24), and 3.13 for current smokers (95% CI: 2.08-4.71). With increasing smoking duration or pack-years, risk of PsA increased monotonically (P for trend <0.0001). The increase in risk was particularly significant for PsA cases with more severe phenotypes. Secondary analysis among participants developing psoriasis during the follow-up replicated the association, demonstrating an increased risk of PsA among psoriasis cases, especially for those with higher cumulative measures of smoking or PsA cases with more severe phenotypes.
Conclusion
In this study of US women, we found that smoking was an independent risk factor for PsA and cumulative measures of smoking were also associated with a higher risk of PsA.
doi:10.1136/annrheumdis-2011-200416
PMCID: PMC4179887  PMID: 22067198
smoking; psoriatic arthritis; epidemiology
22.  Assessment of synovitis with contrast-enhanced MRI using a whole-joint semiquantitative scoring system in people with, or at high risk of, knee osteoarthritis: the MOST study 
Annals of the rheumatic diseases  2010;70(5):805-811.
Objectives
To introduce a comprehensive and reliable scoring system for the assessment of whole-knee joint synovitis based on contrast-enhanced (CE) MRI.
Methods
Multicenter Osteoarthritis Study (MOST) is a cohort study of people with, or at high risk of, knee osteoarthritis (OA). Subjects are an unselected subset of MOST who volunteered for CE-MRI. Synovitis was assessed at 11 sites of the joint. Synovial thickness was scored semiquantitatively: grade 0 (<2 mm), grade 1 (2–4 mm) and grade 2 (>4 mm) at each site. Two musculoskeletal radiologists performed the readings and inter- and intrareader reliability was evaluated. Whole-knee synovitis was assessed by summing the scores from all sites. The association of Western Ontario and McMaster Osteoarthritis Index pain score with this summed score and with the maximum synovitis grade for each site was assessed.
Results
400 subjects were included (mean age 58.8±7.0 years, body mass index 29.5±4.9 kg/m2, 46% women). For individual sites, intrareader reliability (weighted κ) was 0.67–1.00 for reader 1 and 0.60–1.00 for reader 2. Inter-reader agreement (κ) was 0.67–0.92. For the summed synovitis scores, intrareader reliability (intraclass correlation coefficient (ICC)) was 0.98 and 0.96 for each reader and inter-reader agreement (ICC) was 0.94. Moderate to severe synovitis in the parapatellar subregion was associated with the higher maximum pain score (adjusted OR (95% CI), 2.8 (1.4 to 5.4) and 3.1 (1.2 to 7.9), respectively).
Conclusions
A comprehensive semiquantitative scoring system for the assessment of whole-knee synovitis is proposed. It is reliable and identifies knees with pain, and thus is a potentially powerful tool for synovitis assessment in epidemiological OA studies.
doi:10.1136/ard.2010.139618
PMCID: PMC4180232  PMID: 21187293
23.  Microarray-based gene expression profiling in patients with cryopyrin-associated periodic syndromes defines a disease-related signature and IL-1-responsive transcripts 
Annals of the rheumatic diseases  2012;72(6):1064-1070.
Objective
To analyse gene expression patterns and to define a specific gene expression signature in patients with the severe end of the spectrum of cryopyrin-associated periodic syndromes (CAPS). The molecular consequences of interleukin 1 inhibition were examined by comparing gene expression patterns in 16 CAPS patients before and after treatment with anakinra.
Methods
We collected peripheral blood mononuclear cells from 22 CAPS patients with active disease and from 14 healthy children. Transcripts that passed stringent filtering criteria (p values ≤ false discovery rate 1%) were considered as differentially expressed genes (DEG). A set of DEG was validated by quantitative reverse transcription PCR and functional studies with primary cells from CAPS patients and healthy controls. We used 17 CAPS and 66 non-CAPS patient samples to create a set of gene expression models that differentiates CAPS patients from controls and from patients with other autoinflammatory conditions.
Results
Many DEG include transcripts related to the regulation of innate and adaptive immune responses, oxidative stress, cell death, cell adhesion and motility. A set of gene expression-based models comprising the CAPS-specific gene expression signature correctly classified all 17 samples from an independent dataset. This classifier also correctly identified 15 of 16 postanakinra CAPS samples despite the fact that these CAPS patients were in clinical remission.
Conclusions
We identified a gene expression signature that clearly distinguished CAPS patients from controls. A number of DEG were in common with other systemic inflammatory diseases such as systemic onset juvenile idiopathic arthritis. The CAPS-specific gene expression classifiers also suggest incomplete suppression of inflammation at low doses of anakinra.
doi:10.1136/annrheumdis-2012-202082
PMCID: PMC4174357  PMID: 23223423
24.  MRP8 and MRP14, phagocyte-specific danger signals, are sensitive biomarkers of disease activity in cryopyrin-associated periodic syndromes 
Annals of the rheumatic diseases  2011;70(12):2075-2081.
Objectives
To assess the sensitivity of the phagocyte-specific molecules myeloid-related protein (MRP) 8 and MRP14 (calprotectin) for monitoring disease activity during anti-interleukin (IL)-1 therapies in patients with cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS) and chronic infantile neurological, cutaneous and articular (CINCA) syndrome.
Methods
A total of 39 patients with CAPS, including 5 FCAS, 16 MWS and 18 CINCA syndrome, received anti-IL-1 therapy. All patients with CINCA and 12 with MWS were treated with IL-1Ra (anakinra), 14 patients with MWS with a monoclonal anti-IL-1β antibody (canakinumab) and patients with FCAS received IL-1 Trap (rilonacept). During serial clinical visits serum amyloid A, C-reactive protein, erythrocyte sedimentation rate and MRP8/14 serum levels were analysed.
Results
Untreated patients with CAPS had significantly elevated MRP8/14 values. In response to treatment there was a significant reduction of MRP8/14 levels in CINCA (2,830 (range 690 – 8,480) ng/ml to 670 ng/ml, p < 0.001) and MWS patients (anakinra-treated: 4,390 (1790 – 9780) ng/ml to 1,315 ng/ml (p = 0.003); canakinumab-treated: 3,000 (500 – 13060) ng/ml to 630 ng/ml (p=0.001)). However, in many patients with CAPS, MRP8/14 levels were still elevated compared with healthy individuals, reflecting residual disease activity. However, canakinumab-treated patients with CAPS showed normalised MRP8/14 levels, suggesting control of phagocyte activation.
Conclusions
Monitoring of cellular systems involved in inflammatory cascades of the innate immunity was successfully applied to the IL-1-driven CAPS diseases. This is the first study illustrating different states of subclinical disease activity in all types of CAPS depending on the type of anti-IL-1 therapy. MRP8/14 is a sensitive biomarker for monitoring disease activity, status of inflammation and response to IL-1 blockade in patients with CAPS.
doi:10.1136/ard.2011.152496
PMCID: PMC4174360  PMID: 21908452
25.  Genome-wide association analysis of anti-TNF drug response in rheumatoid arthritis patients 
Annals of the rheumatic diseases  2012;72(8):1375-1381.
Background
Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA). However, a significant subset of patients does not respond for unknown reasons. Currently there are no means of identifying these patients prior to treatment. This study was aimed at identifying genetic factors predicting anti-TNF treatment outcome in patient with RA using a genome-wide association approach.
Methods
We conducted a multi-stage, genome-wide association study with a primary analysis of 2,557,253 single nucleotide polymorphisms (SNPs) in 882 RA patients receiving anti-TNF therapy included through the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry and the database of Apotheekzorg. Linear regression analysis of changes in the Disease Activity Score in 28 joints after 14 weeks of treatment was performed using an additive model. Markers with a p<10−3 were selected for replication in 1,821 RA patients from three independent cohorts. Pathway analysis including all SNPs with a p-value < 10−3 was performed using Ingenuity.
Results
Seven hundred seventy two markers demonstrated evidence of association with treatment outcome in the initial stage. Eight genetic loci showed improved p-value in the overall meta-analysis compared to the first stage, three of which (rs1568885, rs1813443 and rs4411591) showed directional consistency over all four studied cohorts. We were unable to replicate markers previously reported to be associated with anti-TNF outcome. Network analysis indicated strong involvement of biological processes underlying inflammatory response and cell morphology.
Conclusion
Using a multi-stage strategy, we have identified 8 genetic loci associated with response to anti-TNF treatment. Further studies are required to validate these findings in additional patient collections.
doi:10.1136/annrheumdis-2012-202405
PMCID: PMC4169706  PMID: 23233654
anti-TNF; gene polymorphism; pharmacogenetics; rheumatoid arthritis; genome-wide association study

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