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1.  Validation of Methotrexate-First Strategy in Patients with Early, Poor-Prognosis Rheumatoid Arthritis: Results From a Two-Year Randomized, Double-Blind Trial 
Arthritis and rheumatism  2013;65(8):1985-1994.
Objective
Methotrexate (MTX) taken as monotherapy is recommended as the initial disease-modifying antirheumatic drug for rheumatoid arthritis (RA). The purpose of this study was to examine outcomes of a blinded trial of initial MTX monotherapy with the option to step-up to combination therapy as compared to immediate combination therapy in patients with early, poor-prognosis RA.
Methods
In the Treatment of Early Rheumatoid Arthritis (TEAR) trial, 755 participants with early, poor-prognosis RA were randomized to receive MTX monotherapy or combination therapy (MTX + etanercept or MTX + sulfasalazine + hydroxychloroquine). Participants randomized to receive MTX monotherapy stepped up to combination therapy at 24 weeks if the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) was ≥ 3.2.
Results
Attrition at 24 weeks was similar in the MTX monotherapy and combination groups. Of the 370 evaluable participants in the initial MTX group, 28% achieved low levels of disease activity and did not step-up to combination therapy (MTX monotherapy group). The mean ± SD DAS28-ESR in participants continuing to take MTX monotherapy at week 102 was 2.7 ± 1.2, which is similar to that in participants who were randomized to immediate combination therapy (2.9 ± 1.2). Participants who received MTX monotherapy had less radiographic progression at week 102 as compared to those who received immediate combination therapy (mean ± SD change in modified Sharp score 0.2 ± 1.1 versus 1.1 ± 6.4. Participants assigned to initial MTX who required step-up to combination therapy at 24 weeks (72%) demonstrated similar DAS28-ESR values (3.5 ± 1.3 vs 3.2 ± 1.3 at week 48) and radiographic progression (change in modified Sharp score 1.2 ± 4.1 vs 1.1 ± 6.4 at week 102) as those assigned to immediate combination therapy. The results for either of the immediate combination approaches, whether triple therapy or MTX + etanercept, were similar.
Conclusion
These results in patients with early, poor prognosis RA validate the strategy of starting with MTX monotherapy. This study is the first to demonstrate in a blinded trial that initial MTX monotherapy with the option to step-up to combination therapy results in similar outcomes to immediate combination therapy. Approximately 30% of patients will not need combination therapy, and the 70% who will need it are clinically and radiographically indistinguishable from those who were randomized to receive immediate combination therapy.
doi:10.1002/art.38012
PMCID: PMC4768726  PMID: 23686414
2.  Felty’s Syndrome Autoantibodies Bind to Deiminated Histones and Neutrophil Extracellular Chromatin Traps 
Arthritis and rheumatism  2011;64(4):982-992.
Objective
To test the hypothesis that autoantigen modifications by peptidylarginine deiminase type 4 (PAD-4) increase immunoreactivity.
Methods
We assembled sera from patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Felty’s syndrome (FS), and antineutrophil cytoplasmic antibody–associated vasculitides (AAVs), as well as sera from control subjects without autoimmune diseases. The sera were tested for binding to activated neutrophils, deiminated histones, and neutrophil extracellular chromatin traps (NETs). IgG binding to lipopolysaccharide-activated neutrophils was assessed with confocal microscopy, and binding to in vitro–deiminated histones was measured using enzyme-linked immunosorbent assay (ELISA) and Western blotting. In addition, we quantitated histone deimination in freshly isolated neutrophils from the blood of patients and control subjects.
Results
Increased IgG reactivity with activated neutrophils, particularly binding to NETs, was paralleled by preferential binding to deiminated histones over nondeiminated histones by ELISA in a majority of sera from FS patients but only in a minority of sera from SLE and RA patients. Immunoblotting revealed autoantibody preference for deiminated histones H3, H4, and H2A in most FS patients and in a subset of SLE and RA patients. In patients with AAVs, serum IgG preferentially bound nondeiminated histones over deiminated histones. Increased levels of deiminated histones were detected in neutrophils from RA patients.
Conclusion
Circulating autoantibodies in FS are preferentially directed against PAD-4–deiminated histones and bind to activated neutrophils and NETs. Thus, increased reactivity with modified autoantigens in FS implies a direct contribution of neutrophil activation and the production of NET-associated nuclear autoantigens in the initiation or progression of FS.
doi:10.1002/art.33432
PMCID: PMC4729190  PMID: 22034172
3.  Association of Biomarkers With Pre–Radiographically Defined and Radiographically Defined Knee Osteoarthritis in a Population-Based Study 
Arthritis and rheumatism  2009;60(5):1372-1380.
Objective
To evaluate 10 biomarkers in magnetic resonance imaging (MRI)–determined, pre–radiographically defined osteoarthritis (pre-ROA) and radiographically defined OA (ROA) in a population-based cohort of subjects with symptomatic knee pain.
Methods
Two hundred one white subjects with knee pain, ages 40–79 years, were classified into OA subgroups according to MRI-based cartilage (MRC) scores (range 0–4) and Kellgren/Lawrence (K/L) grades of radiographic severity (range 0–4): no OA (MRC score 0, K/L grade <2), pre-ROA (MRC score ≥1, K/L grade <2), or ROA (MRC score ≥1, K/L grade ≥2). Urine and serum samples were assessed for levels of the following biomarkers: urinary biomarkers C-telopeptide of type II collagen (uCTX-II), type II and types I and II collagen cleavage neoepitopes (uC2C and uC1,2C, respectively), and N-telopeptide of type I collagen, and serum biomarkers sC1,2C, sC2C, C-propeptide of type II procollagen (sCPII), chondroitin sulfate 846 epitope, cartilage oligomeric matrix protein, and hyaluronic acid. Multicategory logistic regression was performed to evaluate the association of OA subgroup with individual biomarker levels and biomarker ratios, adjusted for age, sex, and body mass index.
Results
The risk of ROA versus no OA increased with increasing levels of uCTX-II (odds ratio [OR] 3.12, 95% confidence interval [95% CI] 1.35–7.21), uC2C (OR 2.13, 95% CI 1.04–4.37), and uC1,2C (OR 2.07, 95% CI 1.06–4.04), and was reduced in association with high levels of sCPII (OR 0.53, 95% CI 0.30–0.94). The risk of pre-ROA versus no OA increased with increasing levels of uC2C (OR 2.06, 95% CI 1.05–4.01) and uC1,2C (OR 2.06, 95% CI 1.12–3.77). The ratios of type II collagen degradation markers to collagen synthesis markers were better than individual biomarkers at differentiating the OA subgroups, e.g., the ratio of [uCTXII][uC1,2C] to sCPII was associated with a risk of ROA versus no OA of 3.47 (95% CI 1.34–9.03) and a risk of pre-ROA versus no OA of 2.56 (95% CI 1.03–6.40).
Conclusion
Different cartilage degradation markers are associated with pre-ROA than are associated with ROA, indicating that their use as diagnostic markers depends on the stage of OA. Biomarker ratios contrasting cartilage degradation with cartilage synthesis are better able to differentiate OA stages compared with levels of the individual markers.
doi:10.1002/art.24473
PMCID: PMC4724193  PMID: 19404937
4.  Short-Term Outcome of Neuropsychiatric Events in Systemic Lupus Erythematosus upon Enrollment into an International Inception Cohort Study 
Arthritis and rheumatism  2008;59(5):721-729.
Objective
To determine the short-term outcome of neuropsychiatric (NP) events upon enrollment into an international, inception cohort of SLE patients.
Methods
The study was performed by the Systemic Lupus International Collaborating Clinics. Patients were enrolled within 15 months of diagnosis of SLE and NP events were characterized using the ACR case definitions. Decision rules were derived to identify NP events attributable to SLE. Physician outcome scores of NP events and patient derived mental (MCS) and physical (PCS) component summary scores of the SF-36 were recorded.
Results
There were 890 patients (88.7% female) with a mean (± SD) age of 33.8 ± 13.4 years and mean disease duration of 5.3 ± 4.2 months. Within the enrollment window 271/890 (33. 5%) patients had at least 1 NP event encompassing 15 NP syndromes. NP events attributed to SLE varied from 16.5% – 33.9% using alternate attribution models and occurred in 6.0% – 11.5% of patients. Outcome scores for NP events attributed to SLE were significantly better than for NP events due to non-SLE causes. Higher global disease activity was associated with worse outcomes. MCS scores were lower in patients with NP events, regardless of attribution, and were also lower in patients with diffuse and central NP events. There was a significant association between physician outcome scores and patient MCS scores only for NP events attributed to SLE.
Conclusion
In SLE patients the short-term outcome of NP events is determined by both the characteristics and attribution of the events.
doi:10.1002/art.23566
PMCID: PMC4656032  PMID: 18438902 CAMSID: cams5140
Systemic lupus erythematosus; Neuropsychiatric; Inception cohort; Attribution; Outcome
5.  Cognitive Function In Systemic Lupus Erythematosus, Rheumatoid Arthritis And Multiple Sclerosis Assessed By Computerized Neuropsychological Tests 
Arthritis and rheumatism  2010;62(5):1478-1486.
Objective
Computerized neuropsychological testing may facilitate screening for cognitive impairment in SLE. We used the Automated Neuropsychological Assessment Metrics (ANAM), to compare patients with SLE, rheumatoid arthritis (RA) and multiple sclerosis (MS) with healthy controls.
Methods
Patients with SLE (68), RA (33), and MS (20), were compared to 29 healthy controls. Efficiency of cognitive performance on eight ANAM subtests was examined using throughput (Tp), inverse efficiency (IE) and adjusted IE scores. The latter is more sensitive to higher cognitive functions because it adjusts for the impact of simple reaction time on performance. The results were analyzed using O’Brien’s generalized least squares test.
Results
Control subjects were the most efficient in cognitive performance. MS patients were least efficient overall (Tp and IE scores) and were less efficient than both SLE (p=0.01) and RA (p<0.01) patients, who did not differ. Adjusted IE scores were similar between SLE, RA patients and controls reflecting the impact of simple reaction time on cognitive performance. Thus, 50% of SLE patients, 61% of RA patients and 75% of MS patients were impaired on at least one ANAM subtest. Only 9% of RA patients and 11% of SLE patients were impaired on 4 or more subtests, whereas this was true for 20% of MS patients.
Conclusion
ANAM is sensitive to cognitive impairment. While such computerized testing may be a valuable screening tool, our results emphasize the lack of specificity of slowed performance as a reliable indicator of impairment of higher cognitive function in SLE patients.
doi:10.1002/art.27404
PMCID: PMC4656033  PMID: 20155829 CAMSID: cams5139
Systemic lupus erythematosus; Neuropsychiatric; Cognitive impairment; ANAM
6.  Autoantibodies and Neuropsychiatric events at diagnosis of SLE 
Arthritis and rheumatism  2008;58(3):843-853.
Objective
To examine the association between neuropsychiatric (NP) events with antiphospholipid antibodies (lupus anticoagulant, anticardiolipin), anti-β2 glycoprotein-I, anti-ribosomal P and anti-NR2 glutamate receptor antibodies in an international inception cohort.
Methods
NP events were identified using the ACR case definitions and clustered into central/peripheral and diffuse/focal events. Attribution of NP events was determined using decision rules of different stringency (model A and model B). Autoantibodies were measured without knowledge of NP events or their attribution.
Results
412 patients (87.3% female; mean (± SD) age of 34.9 ± 13.5 years; mean disease duration 5.0 ± 4.2 months) were studied. There were 214 NP events in 133 (32.3%) patients. NP events attributed to SLE varied from 15% (model A) to 36% (model B). There was no association between autoantibodies and NP events from all causes. However the frequency of anti-ribosomal P antibodies in patients with NP events due to SLE (model A) was 4/24 (16.6%) compared to 3/109 (2.8%) for all other NP events and 24/279 (8.6%) with no NP events (P=0.07). Furthermore anti-ribosomal P antibodies in patients with central NP events attributed to SLE (model A) was 4/20 (20%) vs. 3/107 (2.8%) for other NP events and 24/279 (8.6%) with no NP events (P = 0.04). For diffuse NP events the antibody frequencies were 3/11 (27%) compared to 4/111 (3.6%) and 24/279 (8.6%) respectively (P=0.02).
Conclusion
NP events at onset of SLE were associated with anti-ribosomal P antibodies, suggesting a pathogenetic role for this autoantibody. There was no association with other autoantibodies.
doi:10.1002/art.23218
PMCID: PMC4656035  PMID: 18311802 CAMSID: cams5142
Systemic lupus erythematosus; Neuropsychiatric; Autoantibodies; Inception cohort; Attribution
7.  ANTIPHOSPHOLIPID ANTIBODIES AFFECT TROPHOBLAST GONADOTROPIN SECRETION AND INVASIVENESS BY BINDING DIRECTLY AND THROUGH ADHERED β2-GLYCOPROTEIN I 
Arthritis and rheumatism  2000;43(1):140-150.
Objective
To investigate the in vitro ability of antiphospholipid antibodies (aPL) to bind human tro-phoblast cells and to affect gonadotropin secretion and invasiveness.
Methods
Antiphospholipid antibody IgG from women with recurrent miscarriages, β2-glycoprotein I (β2GPI)-independent IgG aPL human monoclonal antibody (mAb) (519), and IgM anti-β2GPI human mAb (TM1G2) were investigated for their binding to trophoblasts cultured for various amounts of time, their ability to affect invasiveness of Matrigel-coated filters, and their release of human chorionic gonadotropin (hCG).
Results
Polyclonal IgG aPL, as well as mAb 519 and TM1G2, bound to trophoblasts, the highest binding being found when cells displayed the greatest amount of syncytium formation. TM1G2 binding was found to be β2GPI dependent. Both polyclonal and monoclonal aPL, but not the controls, significantly reduced hCG release and Matrigel invasiveness.
Conclusion
These findings suggest that aPL recognition of both anionic PL and adhered β2GPI on trophoblast cell structures might represent a potential pathogenetic mechanism for defective placentation in women with the antiphospholipid syndrome.
doi:10.1002/1529-0131(200001)43:1<140::AID-ANR18>3.0.CO;2-P
PMCID: PMC4625538  PMID: 10643710
8.  FoxP3+ regulatory T cells increase in number and function during experimental arthritis 
Arthritis and rheumatism  2008;58(12):3730-3741.
Objective
CD4+CD25+FoxP3+ regulatory T cells (TR) are critical regulators of autoimmunity. Yet, TR are paradoxically increased in RA patients and show variable activity in human studies. Our objective is to characterize the expansion and function of TR during the initiation and progression of experimental arthritis.
Methods
To unequivocally identify TR, we crossed FoxP3gfp mice to K/BxN to generate arthritic mice in which TR express green fluorescence protein. We examined the expansion and function of TR and effector T cells (TE) during different stages of arthritis by flow cytometry and cell proliferation.
Results
In K/BxN mice, thymic selection of KRN T cells resulted in an enrichment of FoxP3+ TR. TR numbers increased during arthritis with significant increases in the spleen and draining lymph node, indicating selective tropism to sites of disease. In contrast to the in vitro unresponsiveness when cultured by themselves, substantial fractions of TR proliferated in both non-arthritic and arthritic mice. However, they also underwent greater apoptosis thereby maintaining equilibrium with TE. Similarly, enhanced TR suppressive activity during arthritis was offset by greater resistance by their TE counterparts and antigen presenting cells.
Conclusion
In this well established model of RA, the interplay of TE and TR in K/BxN mice recapitulated many features of human disease. We demonstrated an ordered expansion of TR during arthritis and the dynamic changes in TR and TE functions. By elucidating factors that govern TR and TE development in K/BxNgfp mice, we will gain insight into the pathophysiology and develop novel therapeutics for human RA.
doi:10.1002/art.24048
PMCID: PMC4596710  PMID: 19035490
9.  Novel Proteasome Inhibitors Have a Beneficial Effect in Murine Lupus via the dual inhibition of Type I Interferon and autoantibody secreting cells 
Arthritis and rheumatism  2012;64(2):493-503.
Objective
We postulated that proteasome inhibition (PI) may be useful in the treatment of SLE by targeting plasmacytoid dendritic cells (pDCs) and plasma cells (PCs), both critical to disease pathogenesis.
Methods
Lupus prone mice were treated with the non-selective PIs carfilzomib and bortezomib, the LMP7-selective immunoproteasome inhibitor ONX 0914, or vehicle control. Tissues were harvested and analyzed by flow cytometry using standard markers. Nephritis was monitored by proteinuria and kidney harvest. Serum anti-dsDNA levels were measured by ELISA and total IgG and dsDNA antibody secreting cells (ASC) by ELIspot. Human PBMCs or mouse bone marrow cells were incubated with TLR agonists and PIs and interferon α measured by ELISA and flow cytometry.
Results
Early treatment of lupus prone mice with the dual targeting PIs carfilzomib or bortezomib or the immunoproteasome specific inhibitor ONX 0914 prevented disease progression, and treatment of mice with established disease dramatically abrogated nephritis. Treatment had profound effects on plasma cells with greater reductions in autoreactive than total IgG ASCs, an effect that became more pronounced with prolonged treatment, and was reflected in decreasing serum autoantibodies. Remarkably, proteasome inhibition efficiently suppressed production of interferon α by toll-like receptor activated pDCs in vitro and in vivo, an effect mediated by both an inhibition of pDC survival and function.
Conclusions
Inhibition of the immunoproteasome is equally efficacious to dual targeting agents in preventing lupus disease progression by targeting two critical pathways in disease pathogenesis, type I interferon activation and autoantibody production by plasma cells.
doi:10.1002/art.33333
PMCID: PMC4584406  PMID: 21905015
interferon; plasmacytoid dendritic cells; plasma cells; Systemic Lupus Erythematosus; autoimmunity
10.  Regulation of complement by COMP allows for a novel molecular diagnostic principle in rheumatoid arthritis 
Arthritis and rheumatism  2010;62(12):3574-3583.
Objective
Cartilage oligomeric matrix protein (COMP) is a structural component of cartilage where it catalyzes collagen fibrillogenesis. Elevated amounts of COMP are found in serum during increased turnover of cartilage associated with active joint diseases, such as rheumatoid arthritis (RA) and osteoarthritis (OA). In this study we investigated the ability of COMP to regulate complement. Such capacity was previously shown for some cartilage proteins.
Methods
Regulation of complement by COMP was studied using functional assays in vitro. Interactions between complement proteins and COMP were investigated using direct binding assays and electron microscopy. Circulating COMP and COMP-C3b complexes in serum and synovial fluid from RA and OA patients and healthy controls were measured using a novel ELISA.
Results
We show in vivo evidence of complement activation by released COMP in the general circulation of patients with RA, but not OA patients. We found that COMP induces activation and deposition of C3b and C9 specifically via the alternative pathway of complement, which is attributable to a direct interaction between COMP and properdin. Furthermore, COMP inhibits the classical and the lectin complement pathways due to direct interaction with the stalk region of C1q and mannose-binding lectin, respectively.
Conclusion
COMP is the first extracellular matrix protein for which an active role is demonstrated in inflammation in vivo where it can activate one complement pathway at the same time as it has the potential to inhibit another. The net outcome of these interactions is most likely determined by the type of released COMP-fragments, which may be disease-specific.
doi:10.1002/art.27720
PMCID: PMC4576017  PMID: 20737467
11.  The PTPN22 gene is associated with juvenile and adult UK Caucasian idiopathic inflammatory myopathy independent of the HLA 8.1 haplotype 
Arthritis and rheumatism  2008;58(10):3247-3254.
Objective
To examine single nucleotide polymorphisms (SNPs) from the protein tyrosine phosphatase N22 (PTPN22) gene as part of a large UK adult and juvenile idiopathic inflammatory myopathy (IIM) case-control association study, and to study the relationship of the PTPN22 gene with the HLA region.
Methods
A cross-sectional, case-control study of PTPN22 SNPs, comparing cases of polymyositis (PM, n=114), dermatomyositis (DM, n=102), myositis associated with another connective tissue disorder (myositis/CTD-overlap, n=64) and juvenile DM (JDM, n=101) with 748 control subjects. 17 PTPN22 SNPs were genotyped using the Sequenom MassArray iPLEX platform. Serotyping for myositis specific/associated antibodies (MSA/MAA) was performed by radio-immunoprecipitation.
Results
A significant association was noted between the R620W variant (rs2476601) and IIM, and in the clinical subgroup PM (corrected p [pcorr]=0.0007 for both). A weaker association was noted for JDM (pcorr=0.019). No significant associations were noted after stratification by serological subgroup. The R620W variant association was independent of alleles forming the HLA 8.1 haplotype. No other PTPN22 SNPs were associated with IIM. The PTPN22 haplotype containing the R620W T allele was the only haplotype significantly associated with IIM.
Conclusion
The R620W variant is a significant risk factor in IIM and is independent of the HLA 8.1 haplotype. Unlike the HLA region, risk is not increased in individuals possessing MSA/MAA. This data is further evidence that the PTPN22 gene confers autoimmune susceptibility.
doi:10.1002/art.23900
PMCID: PMC4568569  PMID: 18821667
12.  De Novo CIAS1 Mutations, Cytokine Activation, and Evidence for Genetic Heterogeneity in Patients With Neonatal-Onset Multisystem Inflammatory Disease (NOMID) 
Arthritis and rheumatism  2002;46(12):3340-3348.
Objective
Neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic, cutaneous, articular [CINCA] syndrome) is characterized by fever, chronic meningitis, uveitis, sensorineural hearing loss, urticarial skin rash, and a characteristic deforming arthropathy. We investigated whether patients with this disorder have mutations in CIAS1, the gene which causes Muckle-Wells syndrome and familial cold autoinflammatory syndrome, two dominantly inherited disorders with some similarities to NOMID/CINCA syndrome.
Methods
Genomic DNA from 13 patients with classic manifestations of NOMID/CINCA syndrome and their available parents was screened for CIAS1 mutations by automated DNA sequencing. Cytokine messenger RNA (mRNA) levels were assessed by real-time polymerase chain reaction on peripheral blood leukocyte mRNA, and serum cytokine levels were assayed by enzyme-linked immunosorbent assay. Protein expression was assessed by Western blotting of lysates from plastic-adherent peripheral blood mononuclear cells.
Results
In 6 of the 13 patients, we found 6 heterozygous missense substitutions in CIAS1. Five of the 6 mutations are novel. None of these sequence changes was observed in a panel of >900 chromosomes from healthy controls. Two distinct nucleotide changes in a single codon in unrelated patients resulted in the same amino acid change. In 4 mutation-positive children whose parental DNA was available, no mutation was found in the parental DNA, supporting the conclusion that the mutations arose de novo. Consistent with the recently discovered role of CIAS1 in the regulation of interleukin-1 (IL-1), we found evidence of increased IL-1β, as well as tumor necrosis factor, IL-3, IL-5, and IL-6, but not transforming growth factor β, in a mutation-positive patient compared with normal controls.
Conclusion
Our data increase the total number of known germline mutations in CIAS1 to 20, causing a spectrum of diseases ranging from familial cold autoinflammatory syndrome to Muckle-Wells syndrome to NOMID/CINCA syndrome. Mutations in CIAS1 were only found in ~50% of the cases identified clinically as NOMID/CINCA syndrome, which raises the possibility of genetic heterogeneity. IL-1 regulation by CIAS1 suggests that IL-1 receptor blockade may constitute a rational approach to the treatment of NOMID/CINCA syndrome.
doi:10.1002/art.10688
PMCID: PMC4556432  PMID: 12483741
13.  Efficacy and Safety of Rituximab in Moderately-to-Severely Active Systemic Lupus Erythematosus 
Arthritis and rheumatism  2010;62(1):222-233.
Objective
B cells are likely to contribute to the pathogenesis of systemic lupus erythematosus (SLE), and rituximab induces depletion of B cells. The Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial tested the efficacy and safety of rituximab versus placebo in patients with moderately-to-severely active extrarenal SLE.
Methods
Patients entered with ≥1 British Isles Lupus Assessment Group (BILAG) A score or ≥2 BILAG B scores despite background immunosuppressant therapy, which was continued during the trial. Prednisone was added and subsequently tapered. Patients were randomized at a ratio of 2:1 to receive rituximab (1,000 mg) or placebo on days 1, 15, 168, and 182.
Results
In the intent-to-treat analysis of 257 patients, background treatment was evenly distributed among azathioprine, mycophenolate mofetil, and methotrexate. Fifty-three percent of the patients had ≥1 BILAG A score at entry, and 57% of the patients were categorized as being steroid dependent. No differences were observed between placebo and rituximab in the primary and secondary efficacy end points, including the BILAG-defined response, in terms of both area under the curve and landmark analyses. A beneficial effect of rituximab on the primary end point was observed in the African American and Hispanic subgroups. Safety and tolerability were similar in patients receiving placebo and those receiving rituximab.
Conclusion
The EXPLORER trial enrolled patients with moderately-to-severely active SLE and used aggressive background treatment and sensitive cutoffs for nonresponse. No differences were noted between placebo and rituximab in the primary and secondary end points. Further evaluation of patient subsets, biomarkers, and exploratory outcome models may improve the design of future SLE clinical trials.
doi:10.1002/art.27233
PMCID: PMC4548300  PMID: 20039413
16.  Association of Bone Morphogenetic Protein 6 With Exocrine Gland Dysfunction in Patients With Sjögren’s Syndrome and in Mice 
Arthritis and rheumatism  2013;65(12):3228-3238.
Objective
Primary Sjögren’s syndrome (SS) is characterized by autoimmune activation and loss of function in secretory epithelia. The present study was undertaken to investigate and characterize changes in the epithelia associated with the loss of gland function in primary SS.
Methods
To identify changes in epithelial gene expression, custom microarrays were probed with complementary RNA (cRNA) isolated from minor salivary glands (MSGs) of female patients with primary SS who had low focus scores and low salivary flow rates, and the results were compared with those obtained using cRNA from the MSGs of sex-matched healthy volunteers. The effect of bone morphogenetic protein 6 (BMP-6) on salivary gland function was tested using adeno-associated virus–mediated gene transfer to the salivary glands of C57BL/6 mice.
Results
A significant increase in expression of BMP-6 was observed in RNA isolated from SS patients compared with healthy volunteers. Overexpression of BMP-6 locally in the salivary or lacrimal glands of mice resulted in the loss of fluid secretion as well as changes in the connective tissue of the salivary gland. Assessment of the fluid movement in either isolated acinar cells from mice overexpressing BMP-6 or a human salivary gland cell line cultured with BMP-6 revealed a loss in volume regulation in these cells. Lymphocytic infiltration in the submandibular gland of BMP-6 vector–treated mice was increased. No significant changes in the production of proinflammatory cytokines or autoantibodies associated with SS (anti-Ro/SSA and anti-La/SSB) were found after BMP-6 overexpression.
Conclusion
In addition to identifying BMP-6 expression in association with xerostomia and xerophthalmia in primary SS, the present results suggest that BMP-6–induced salivary and lacrimal gland dysfunction in primary SS is independent of the autoantibodies and immune activation associated with the disease.
doi:10.1002/art.38123
PMCID: PMC4527329  PMID: 23982860
17.  Lifetime Risk of Symptomatic Knee Osteoarthritis 
Arthritis and rheumatism  2008;59(9):1207-1213.
Objective
To estimate the lifetime risk of symptomatic knee osteoarthritis (OA), overall and stratified by sex, race, education, history of knee injury, and body mass index (BMI).
Methods
The lifetime risk of symptomatic OA in at least 1 knee was estimated from logistic regression models with generalized estimating equations among 3,068 participants of the Johnston County Osteoarthritis Project, a longitudinal study of black and white women and men age ≥45 years living in rural North Carolina. Radiographic, sociodemographic, and symptomatic knee data measured at baseline (1990–1997) and first followup (1999–2003) were analyzed.
Results
The lifetime risk of symptomatic knee OA was 44.7% (95% confidence interval [95% CI] 40.0–49.3%). Cohort members with history of a knee injury had a lifetime risk of 56.8% (95% CI 48.4–65.2%). Lifetime risk rose with increasing BMI, with a risk of 2 in 3 among those who were obese.
Conclusion
Nearly half of the adults in Johnston County will develop symptomatic knee OA by age 85 years, with lifetime risk highest among obese persons. These current high risks in Johnston County may suggest similar risks in the general US population, especially given the increase in 2 major risk factors for knee OA, aging, and obesity. This underscores the immediate need for greater use of clinical and public health interventions, especially those that address weight loss and self-management, to reduce the impact of having knee OA.
doi:10.1002/art.24021
PMCID: PMC4516049  PMID: 18759314
18.  A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Oral Type I Collagen Treatment in Patients With Diffuse Cutaneous Systemic Sclerosis 
Arthritis and rheumatism  2008;58(6):1810-1822.
Objective
To investigate the safety and efficacy of oral bovine type I collagen (CI) treatment in patients who have had diffuse cutaneous systemic sclerosis (dc-SSc; scleroderma) for ≤10 years.
Methods
One hundred sixty-eight patients with dcSSc were enrolled in a double-blind, placebo-controlled trial of oral CI (500 µg/day) or placebo administered over 12 months, with a followup visit at month 15. The primary outcome was the modified Rodnan skin thickness score (MRSS). Other clinical and immune system parameters were also assessed.
Results
Intent-to-treat and modified intent-to-treat analyses showed that for the total population of patients with dcSSc, there were no significant differences in the mean change in MRSS or other key clinical parameters between the CI and placebo treatment groups at 12 months or at 15 months. However, in a subanalysis of the available data at month 15, the CI-treated group of patients with late-phase dcSSc experienced a significant reduction in the MRSS compared with that in the placebo-treated patients with late-phase dcSSc (change in MRSS at month 15 –7.9 versus −2.9; P = 0.0063).
Conclusion
Although the results from this trial did not meet the primary outcome goals, the findings from exploratory analyses indicated that CI treatment may benefit patients with late-phase dcSSc. This new treatment strategy and preliminary clinical observations in patients with dcSSc need to be corroborated.
doi:10.1002/art.23501
PMCID: PMC4511098  PMID: 18512816
19.  Effects of Glucocorticoids on Weight Change During the Treatment of Wegener's Granulomatosis 
Arthritis and rheumatism  2008;59(5):746-753.
Objective
Weight gain is a side effect of glucocorticoid (GC) use, but the natural history and health implications of changes in weight that occur during the treatment of inflammatory disease are not understood.
Methods
We evaluated data from the Wegener's Granulomatosis Etanercept Trial. Patients were categorized according to clinical outcome at 1 year: remission (no disease flares), single flare, or multiple flares. Risk factors for gaining ≥10 kg were examined in multivariate models.
Results
Weights at baseline and 1 year were available for 157 (93%) of the 168 patients analyzed. During year 1, the mean cumulative prednisone dosage in the multiple flares subgroup was 7.9 gm, compared with 6.0 gm and 3.9 gm in the single flare and remission subgroups, respectively (P < 0.001). Patients in these subgroups gained an average of 2.6 kg, 4.1 kg, and 5.8 kg, respectively (P = 0.005). Weight gain did not correlate with cumulative GC dose (R = 0.10, P = 0.25). Thirty-five patients (22.3%) gained and maintained ≥10 kg in the first year. New diagnosis of Wegener's granulomatosis at baseline was an independent predictor of gaining ≥10 kg at 1 year (odds ratio 19.7, 95% confidence interval 2.4–162.6, P = 0.006). Among the 78 patients in the remission subgroup, 40 sustained remissions through the 2-year time point. For these 40 patients, the mean weight gained at year 1 did not regress by the end of year 2, despite the absence of continued GC use.
Conclusion
Disease control was associated with lower cumulative GC doses but greater weight gain. More than one-fifth of patients gained >10 kg in the first year of treatment. The quantity of weight gained by patients during treatment has potential future health implications.
doi:10.1002/art.23561
PMCID: PMC4508273  PMID: 18438908
20.  Expansion of autoreactive unresponsive CD21-/low B cells in Sjögren's syndrome associated lymphoproliferation 
Arthritis and rheumatism  2013;65(4):1085-1096.
Background
Primary Sjögren's syndrome (pSS) is the autoimmune disease associated with the higher risk of developing non-Hodgkin lymphoma.
Objective
To determine the nature of B cells driving lymphoproliferation in pSS.
Methods
B cell subsets and function were analyzed in peripheral blood from 66 adult patients with pSS [including 14 patients with B-cell lymphoproliferative disorder (LPD)] and 30 healthy donors, using flow cytometry, calcium mobilization, and gene array analysis. We tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from pSS-LPD.
Results
We report here the expansion of an unusual CD21-/low B-cell population which correlates with lymphoproliferation in pSS patients. A majority of CD21–/low B cells from pSS patients expressed autoreactive antibodies, which recognized nuclear and cytoplasmic structures. These B cells belonged to the memory compartment because their immunoglobulin genes were mutated. They were unable to induce calcium flux, become activated, or proliferate in response to B-cell receptor and/or CD40 triggering, suggesting that these autoreactive B cells may be anergic. However, CD21–/low B cells from pSS remained responsive to TLR stimulation. Gene array analyses of CD21–/low B cells revealed molecules specifically expressed in these B cells and that are likely to induce their unresponsive stage.
Conclusion
pSS patients who display high frequencies of autoreactive and unresponsive CD21-/low B cells are susceptible for developing lymphoproliferation. These cells remain in peripheral blood controlled by functional anergy instead of being eliminated, and chronic antigenic stimulation through TLR stimulation may create a favorable environment for breaking tolerance and activating these cells.
doi:10.1002/art.37828
PMCID: PMC4479193  PMID: 23279883
Sjögren's syndrome; CD21-/low B cells; lymphoproliferation; autoimmunity; anergy
21.  Acetylcholine Regulation of Synoviocyte Cytokine Expression by the α7 Nicotinic Receptor 
Arthritis and rheumatism  2008;58(11):3439-3449.
Objective
The central nervous system can regulate peripheral inflammation, but the efferent neuronal routes and the mediators remain poorly defined. One candidate is the cholinergic pathway, which releases acetylcholine (ACh). This neurotransmitter can bind to the α7 cholinergic receptor (α7R) expressed by nonneuronal cells and reduce inflammation. To test this possibility, we evaluated the expression of α7R and its potential role as a target in rheumatoid arthritis (RA).
Methods
The expression of α7R in human synovium and fibroblast-like synoviocytes (FLS) was determined using immunohistochemical, Western blot, and quantitative polymerase chain reaction (PCR) analyses. The effects of ACh in vitro were determined in interleukin-1 (IL-1)–stimulated FLS using immunoassays for protein, quantitative PCR for messenger RNA (mRNA), luciferase reporter constructs for IL-6 and NF-κB promoter activity, and electrophoretic mobility shift assays. Expression of α7R was knocked down with small interfering RNA (siRNA) or was inhibited with the selective α7R antagonist methyllycaconitine (MLA).
Results
Protein and mRNA for α7R were demonstrated in RA and osteoarthritis synovium and cultured synoviocytes. Expression in synovium was mainly in the intimal lining. ACh significantly reduced the production of IL-6, CXCL8, CCL2, CCL3, CCL5, and granulocyte colony-stimulating factor by IL-1–stimulated FLS. This effect was blocked by the α7R antagonist MLA or by using α7R siRNA to knock down receptor expression. The selective α7R agonist PNU-282,987 decreased the production of IL-6 by IL-1–stimulated FLS. ACh did not reduce IL-6 transcription, but it decreased IL-6 mRNA half-life and reduced IL-6 mRNA steady-state levels.
Conclusion
The α7 receptor is expressed in the synovium and by synoviocytes. Receptor ligation inhibits cytokine expression in FLS through a posttranscriptional mechanism. Therefore, α7R is a potential therapeutic target for inflammatory diseases.
doi:10.1002/art.23987
PMCID: PMC4476299  PMID: 18975306
22.  Association of Granulomatosis With Polyangiitis (Wegener’s) With HLA–DPB1*04 and SEMA6A Gene Variants Evidence From Genome-Wide Analysis 
Arthritis and rheumatism  2013;65(9):2457-2468.
Objective
To identify genetic determinants of granulomatosis with polyangiitis (Wegener’s) (GPA).
Methods
We carried out a genome-wide association study (GWAS) of 492 GPA cases and 1,506 healthy controls (white subjects of European descent), followed by replication analysis of the most strongly associated signals in an independent cohort of 528 GPA cases and 1,228 controls.
Results
Genome-wide significant associations were identified in 32 single-nucleotide polymorphic (SNP) markers across the HLA region, the majority of which were located in the HLA–DPB1 and HLA–DPA1 genes encoding the class II major histocompatibility complex (MHC) DPβ chain 1 and DPα chain 1 proteins, respectively. Peak association signals in these 2 genes, emanating from SNPs rs9277554 (for DPβ chain 1) and rs9277341 (DPα chain 1) were strongly replicated in an independent cohort (in the combined analysis of the initial cohort and the replication cohort, P = 1.92 × 10−50 and 2.18 × 10−39, respectively). Imputation of classic HLA alleles and conditional analyses revealed that the SNP association signal was fully accounted for by the classic HLA–DPB1*04 allele. An independent single SNP, rs26595, near SEMA6A (the gene for semaphorin 6A) on chromosome 5, was also associated with GPA, reaching genome-wide significance in a combined analysis of the GWAS and replication cohorts (P = 2.09 × 10−8).
Conclusion
We identified the SEMA6A and HLA–DP loci as significant contributors to risk for GPA, with the HLA–DPB1*04 allele almost completely accounting for the MHC association. These two associations confirm the critical role of immunogenetic factors in the development of GPA.
doi:10.1002/art.38036
PMCID: PMC4471994  PMID: 23740775
23.  Thymic Stromal Lymphopoietin Is Up-Regulated in the Skin of Patients With Systemic Sclerosis and Induces Profibrotic Genes and Intracellular Signaling That Overlap With Those Induced by Interleukin-13 and Transforming Growth Factor β 
Arthritis and rheumatism  2013;65(5):1335-1346.
Objective
To explore the expression of thymic stromal lymphopoietin (TSLP) in patients with diffuse cutaneous systemic sclerosis (dcSSc) and compare its effects in vivo and in vitro with those of interleukin-13 (IL-13) and transforming growth factor β (TGFβ).
Methods
Skin biopsy specimens from patients with dcSSc (n = 14) and healthy controls (n = 13) were analyzed by immunohistochemistry and immunofluorescence for TSLP, TSLP receptor, CD4, CD8, CD31, and CD163 markers. Wild-type, IL-4Rα1–, and TSLP-deficient mice were treated with TGFβ, IL-13, poly(I-C), or TSLP by osmotic pump. Human fibroblasts and peripheral blood mononuclear cells (PBMCs) were stimulated with TGFβ, IL-13, poly(I-C), or TSLP. Microarray analysis and quantitative polymerase chain reaction were performed to determine gene expression, and protein levels of phospho-Smad2 and macrophage marker CD163 were tested.
Results
TSLP was highly expressed in the skin of dcSSc patients, more strongly in perivascular areas and in immune cells, and was produced mainly by CD163+ cells. The skin of TSLP-treated mice showed up-regulated clusters of gene expression that overlapped strongly with those in IL-13– and TGFβ-treated mice. TSLP up-regulated specific genes, including CXCL9, proteasome, and interferon (IFN)–regulated genes. TSLP treatment in IL-4Rα1–deficient mice promoted similar cutaneous inflammation as in wild-type mice, though TSLP-induced arginase 1, CCL2, and matrix metalloproteinase 12 messenger RNA levels were blocked. In PBMCs, TSLP up-regulated tumor necrosis factor α, Mx-1, IFNγ, CXCL9, and mannose receptor 1 gene expression. TSLP-deficient mice treated with TGFβ showed less fibrosis and blocked expression of plasminogen activator inhibitor 1 and osteopontin 1. Poly(I-C)–treated mice showed high levels of cutaneous TSLP.
Conclusion
TSLP is highly expressed in the skin of dcSSc patients and interacts in a complex manner with 2 other profibrotic cytokines, TGFβ and IL-13, strongly suggesting that it might promote SSc fibrosis directly or indirectly by synergistically stimulating pro-fibrotic genes, or production of these cytokines.
doi:10.1002/art.37859
PMCID: PMC4437575  PMID: 23335246
24.  Blocking of Interferon Regulatory Factor 1 Reduces Tumor Necrosis Factor α–Induced Interleukin-18 Bioactivity in Rheumatoid Arthritis Synovial Fibroblasts by Induction of Interleukin-18 Binding Protein a 
Arthritis and rheumatism  2011;63(11):3253-3262.
Objective
To examine the role of interferon regulatory factor 1 (IRF-1) in tumor necrosis factor α (TNFα)–induced interleukin-18 binding protein a (IL-18BPa) expression in rheumatoid arthritis synovial fibroblasts (RASFs).
Methods
TNFα-induced IRF-1 expression was assessed by real-time quantitative polymerase chain reaction and Western blotting. The effect of TNFα on IRF-1 was assessed using nuclear and cytoplasmic extracts, Western blots, and immunofluorescence. Chemical inhibitors of NF-κB or MAP kinases were used to analyze the signaling pathways of TNFα-induced IRF-1 expression and IRF-1 nuclear translocation. Control and IRF-1 small interfering RNA (siRNA) were used to analyze the effect of IRF-1 down-regulation on TNFα-induced IL-18BP expression. IL-18BPa expression was assessed by enzyme-linked immunosorbent assay, and IL-18 was assessed at the transcription and bioactivity levels using KG-1 cells.
Results
TNFα induced RASF IRF-1 expression at the messenger RNA and protein levels, with a maximal effect at 2 hours (P < 0.05; n ≥ 3). Furthermore, TNFα induced nuclear translocation of IRF-1, with maximal translocation at 2 hours (~6 fold-induction) (P < 0.05; n = 4). Blocking of the NF-κB or JNK-2 pathways reduced TNFα-induced IRF-1 nuclear translocation by 35% and 50%, respectively (P < 0.05; n ≥ 4). Using siRNA to knock down IRF-1, we observed reduced IL-18BPa expression. Additionally, IL-18 bioactivity was higher when siRNA was used to knock down IRF-1 expression.
Conclusion
These results show that IRF-1 is a key regulator of IL-18BPa expression and IL-18 bioactivity in RASFs. Regulation of IRF-1 will be a new therapeutic target in RA.
doi:10.1002/art.30583
PMCID: PMC4416229  PMID: 21834067
25.  Large-Scale Analysis of Association Between GDF5 and FRZB Variants and Osteoarthritis of the Hip, Knee, and Hand 
Arthritis and rheumatism  2009;60(6):1710-1721.
Objective
GDF5 and FRZB have been proposed as genetic loci conferring susceptibility to osteoarthritis (OA); however, the results of several studies investigating the association of OA with the rs143383 polymorphism of the GDF5 gene or the rs7775 and rs288326 polymorphisms of the FRZB gene have been conflicting or inconclusive. To examine these associations, we performed a large-scale meta-analysis of individual-level data.
Methods
Fourteen teams contributed data on polymorphisms and knee, hip, and hand OA. For rs143383, the total number of cases and controls, respectively, was 5,789 and 7,850 for hip OA, 5,085 and 8,135 for knee OA, and 4,040 and 4,792 for hand OA. For rs7775, the respective sample sizes were 4,352 and 10,843 for hip OA, 3,545 and 6,085 for knee OA, and 4,010 and 5,151 for hand OA, and for rs288326, they were 4,346 and 8,034 for hip OA, 3,595 and 6,106 for knee OA, and 3,982 and 5,152 for hand OA. For each individual study, sex-specific odds ratios (ORs) were calculated for each OA phenotype that had been investigated. The ORs for each phenotype were synthesized using both fixed-effects and random-effects models for allele-based effects, and also for haplotype effects for FRZB.
Results
A significant random-effects summary OR for knee OA was demonstrated for rs143383 (1.15 [95% confidence interval 1.09–1.22]) (P = 9.4 × 10−7), with no significant between-study heterogeneity. Estimates of effect sizes for hip and hand OA were similar, but a large between-study heterogeneity was observed, and statistical significance was borderline (for OA of the hip [P = 0.016]) or absent (for OA of the hand [P = 0.19]). Analyses for FRZB polymorphisms and haplotypes did not reveal any statistically significant signals, except for a borderline association of rs288326 with hip OA (P = 0.019).
Conclusion
Evidence of an association between the GDF5 rs143383 polymorphism and OA is substantially strong, but the genetic effects are consistent across different populations only for knee OA. Findings of this collaborative analysis do not support the notion that FRZB rs7775 or rs288326 has any sizable genetic effect on OA phenotypes.
doi:10.1002/art.24524
PMCID: PMC4412885  PMID: 19479880

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