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1.  Microscopic measurement of inflammation in synovial tissue: inter‐observer agreement for manual quantitative, semiquantitative and computerised digital image analysis 
Annals of the Rheumatic Diseases  2007;66(12):1656-1660.
To evaluate inter‐observer agreement for microscopic measurement of inflammation in synovial tissue using manual quantitative, semiquantitative and computerised digital image analysis.
Paired serial sections of synovial tissue, obtained at arthroscopic biopsy of the knee from patients with rheumatoid arthritis (RA), were stained immunohistochemically for T lymphocyte (CD3) and macrophage (CD68) markers. Manual quantitative and semiquantitative scores for sub‐lining layer CD3+ and CD68+ cell infiltration were independently derived in 6 international centres. Three centres derived scores using computerised digital image analysis. Inter‐observer agreement was evaluated using Spearman's Rho and intraclass correlation coefficients (ICCs).
Paired tissue sections from 12 patients were selected for evaluation. Satisfactory inter‐observer agreement was demonstrated for all 3 methods of analysis. Using manual methods, ICCs for measurement of CD3+ and CD68+ cell infiltration were 0.73 and 0.73 for quantitative analysis and 0.83 and 0.78 for semiquantitative analysis, respectively. Corresponding ICCs of 0.79 and 0.58 were observed for the use of digital image analysis. All ICCs were significant at levels of p<0.0001. At each participating centre, use of computerised image analysis produced results that correlated strongly and significantly with those obtained using manual measurement.
Strong inter‐observer agreement was demonstrated for microscopic measurement of synovial inflammation in RA using manual quantitative, semiquantitative and computerised digital methods of analysis. This further supports the development of these methods as outcome measures in RA.
PMCID: PMC2095312  PMID: 17604286
2.  Discontinuation of antiviral prophylaxis correlates with high prevalence of hepatitis B virus (HBV) reactivation in rheumatoid arthritis patients with HBV carrier state: a real-world clinical practice 
To investigate the risk of hepatitis B virus (HBV) reactivation in rheumatoid arthritis (RA) patients with HBV carrier state during treatment of disease-modifying antirheumatic drugs (DMARDs) and the use of antiviral prophylaxis in real-world clinical practice.
Consecutive RA patients with HBV carrier state were included. Clinical data including liver evaluation, HBV infection evaluation and the use of antiviral prophylaxis were recorded.
Fifty-three RA patients with HBV carrier state were screened and 36 patients were qualified for analysis. Thirty-six percentage of patients developed HBV reactivation and 17% developed HBV hepatitis together with reactivation, one of which developed decompensate cirrhosis. Only 50% of patients accepted lamivudine although all patients were recommended antiviral prophylaxis with entecavir or tenofovir and only 31% continued during DMARDs therapy. Seventy-one percentage of patients who discontinued antiviral prophylaxis developed HBV reactivation 3 ~ 21 months after discontinuation. Logistic regression analyses showed discontinuation of antiviral prophylaxis (OR: 66, p = 0.027), leflunomide (OR: 64, p = 0.011) and past history of hepatitis (OR: 56, p = 0.013) were risk factors of HBV reactivation. Past history of hepatitis (OR: 10, p = 0.021) was also risk factor of HBV hepatitis together with reactivation.
Our results suggest poor patient acceptance and discontinuation of antiviral prophylaxis should not be ignored for Chinese RA patients with HBV carrier state in real-world clinical practice. Discontinuation of antiviral prophylaxis, past history of hepatitis and LEF might increase risk of HBV reactivation for RA patients with HBV carrier state during DMARDs therapy.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2474-15-449) contains supplementary material, which is available to authorized users.
PMCID: PMC4320507  PMID: 25532827
Rheumatoid arthritis; Hepatitis B virus; Disease-modifying antirheumatic drugs
3.  Application of the OMERACT filter to measures of core outcome domains in recent clinical studies of acute gout 
The Journal of rheumatology  2014;41(3):574-580.
To determine the extent to which instruments that measure core outcome domains in acute gout fulfil the OMERACT filter requirements of truth, discrimination and feasibility.
Patient-level data from four randomised controlled trials of agents designed to treat acute gout and one observational study of acute gout were analysed. For each available measure construct validity, test-retest reliability, within-group change using effect size, between-group change using the Kruskall-Wallis statistic and repeated measures generalised estimating equations were assessed. Floor and ceiling effects were also assessed and MCID was estimated. These analyses were presented to participants at OMERACT 11 to help inform voting for possible endorsement.
There was evidence for construct validity and discriminative ability for 3 measures of pain (0 to 4 Likert, 0 to 10 numeric rating scale, 0 to 100 mm visual analogue scale). Likewise, there appears to be sufficient evidence for a 4-point Likert scale to possess construct validity and discriminative ability for physician assessment of joint swelling and joint tenderness. There was some evidence for construct validity and within-group discriminative ability for the Health Assessment Questionnaire as a measure of activity limitations, but not for discrimination between groups allocated to different treatment.
There is sufficient evidence to support measures of pain (using Likert, numeric rating scale or visual analogue scales), joint tenderness and swelling (using Likert scale) as fulfilling the requirements of the OMERACT filter. Further research on a measure of activity limitations in acute gout clinical trials is required.
PMCID: PMC4212978  PMID: 24429178
gout; outcome measures; psychometrics
4.  New classification criteria for gout: a framework for progress 
Rheumatology (Oxford, England)  2013;52(10):1748-1753.
The definitive classification or diagnosis of gout normally relies upon the identification of MSU crystals in SF or from tophi. Where microscopic examination of SF is not available or is impractical, the best approach may differ depending upon the context. For many types of research, clinical classification criteria are necessary. The increasing prevalence of gout, advances in therapeutics and the development of international research collaborations to understand the impact, mechanisms and optimal treatment of this condition emphasize the need for accurate and uniform classification criteria for gout. Five clinical classification criteria for gout currently exist. However, none of the currently available criteria has been adequately validated. An international project is currently under way to develop new validated gout classification criteria. These criteria will be an essential step forward to advance the research agenda in the modern era of gout management.
PMCID: PMC4047282  PMID: 23611919
gout; classification; urate; research
5.  OMERACT endorsement of measures of outcome for studies of acute gout 
The Journal of rheumatology  2013;41(3):569-573.
To determine the extent to which OMERACT participants agree that instruments that have been used in clinical trials and measure OMERACT core outcome domains in acute gout fulfil the filter requirements of truth, discrimination and feasibility and to determine where future research efforts need to be directed.
The results of a systematic literature review and analysis of individual-level data from recent clinical studies of acute gout were presented to OMERACT participants. The information was discussed in breakout groups and opinion was defined by subsequent voting in a plenary session. Endorsement was defined as at least 70% of participants voting in agreement with the proposition (where the denominator excluded those participants who did not vote or who voted ‘don’t know’).
The following measures were endorsed for use in clinical trials of acute gout: (1) 5-point Likert scale and/or VAS (0 to 100mm) to measure pain; (2) 4-point Likert scale for joint swelling; (3) 4-point Likert scale for joint tenderness; and (4) 5-point Likert scale for patient global assessment of response to treatment. Measures for the activity limitations domain were not endorsed.
Measures of pain, joint swelling, joint tenderness and patient global assessment in acute gout were endorsed at OMERACT-11. These measures should now be used in clinical trials of acute gout.
PMCID: PMC4162875  PMID: 24334651
gout; outcome measures; psychometrics
6.  The Structure of Affective Symptomatology in Older Adults with Osteoarthritis 
to examine the structure of symptoms of affective disorder among older adults with a chronic health problem (osteoarthritis), and to explore cross-sectional and longitudinal associations of obtained affective symptom clusters with key health outcomes (pain, functional disability, perceived health).
One-year longitudinal study of older adults with diagnosed osteoarthritis of the knee. Symptoms of DSM depression and anxiety were assessed in a research diagnostic interview using a DSM-IV symptom checklist; self-reports captured demographic characteristics, objective health, pain, disability, and perceived health. Confirmatory factor analysis tested comparability of affective symptom structure in this sample to findings of previous research; ordinary least squares regression examined cross-sectional and longitudinal associations of affective symptoms with health outcomes, controlling for demographics and objective health.
The current sample displayed an affective symptom structure comparable to that observed in previous research, with symptoms clustering into Depressed Mood, Somatic Symptoms and Psychic Anxiety factors. Depressed Mood was cross-sectionally associated with pain and disability and marginally with perceived health; Somatic Symptoms predicted current pain and perceived health. Only Depressed Mood predicted one-year change in disability and perceived health (but not pain).
This research confirms the role of somatic symptoms of distress in fueling disability and perceived ill health among chronically ill older adults. However, it is depressed mood that drives changes in perceived health and functional ability.
PMCID: PMC3460061  PMID: 22653754
Affective Symptoms; Comorbidity; Depression; Anxiety; Osteoarthritis
7.  Tophus measurement as an outcome measure for clinical trials of chronic gout: progress and research priorities 
The Journal of rheumatology  2011;38(7):10.3899/jrheum.110272.
Despite the recognition that tophus regression is an important outcome measure in clinical trials of chronic gout, there is no agreed method of tophus measurement. A number of methods have been used in clinical trials of chronic gout, from simple physical measurement techniques to complex advanced imaging methods. This paper summarises the methods of tophus measurement that have been used and discusses the properties of these methods. Physical measurement using Vernier calipers fulfils most aspects of the Outcomes Measures in Rheumatology (OMERACT) filter. Rigorous testing of the complex methods, particularly with respect to reliability and sensitivity to change is needed, to determine the appropriate use of these methods. Further information is also required regarding which method of physical measurement is best for use in future clinical trials. The need to develop and test a patient reported measure of tophus burden is also highlighted.
PMCID: PMC3882031  PMID: 21724716
8.  Patient-reported Outcomes in Chronic Gout: A Report from OMERACT 10 
The Journal of rheumatology  2011;38(7):10.3899/jrheum.110271.
To summarize the endorsement of measures of patient-reported outcome (PRO) domains in chronic gout at the 2010 Outcome Measures in Rheumatology Meeting (OMERACT 10).
During the OMERACT 10 gout workshop, validation data were presented for key PRO domains including pain [pain by visual analog scale (VAS)], patient global (patient global VAS), activity limitation [Health Assessment Questionnaire-Disability Index (HAQ-DI)], and a disease-specific measure, the Gout Assessment Questionnaire version 2.0 (GAQ v2.0). Data were presented on all 3 aspects of the OMERACT filters of truth, discrimination, and feasibility. One PRO, health-related quality of life measurement with the Medical Outcomes Study Short-form 36 (SF-36), was previously endorsed at OMERACT 9.
One measure for each of the 3 PRO of pain, patient global, and activity limitation was endorsed by > 70% of the OMERACT delegates to have appropriate validation data. Specifically, pain measurement by VAS was endorsed by 85%, patient global assessment by VAS by 73%, and activity limitation by HAQ-DI by 71%. GAQ v2.0 received 30% vote and was not endorsed due to several concerns including low internal consistency and lack of familiarity with the measure. More validation studies are needed for this measure.
With the endorsement of one measure each for pain, patient global, SF-36, and activity limitation, all 4 PRO for chronic gout have been endorsed. Future validation studies are needed for the disease-specific measure, GAQ v2.0. Validation for PRO for acute gout will be the focus of the next validation exercise for the OMERACT gout group.
PMCID: PMC3850171  PMID: 21724715
11.  The Relative Composition of the Inflammatory Infiltrate as an Additional Tool for Synovial Tissue Classification 
PLoS ONE  2013;8(8):e72494.
Traditionally, differences in absolute numbers of cells expressing a certain marker (e.g., positive staining cells per mm2) have been used in immunohistological synovial tissue classification. We have begun to evaluate the relative composition of the inflammatory infiltrates, i.e. percentages of inflammatory cell types in inflammatory infiltrates, as an alternate classification tool that may potentially improve tissue diagnostics, subgrouping in clinical trials, and understanding of pathogenesis of inflammatory and noninflammatory arthropathies.
Synovial tissue specimens (normal synovium, n=15; orthopedic arthropathies, n=6; osteoarthritis, n=26; early undifferentiated arthritis, n=10; rheumatoid arthritis, n=26; chronic septic arthritis, n=11) were stained for CD15, CD68, CD3, CD20, and CD38. Densities of cells expressing a given marker were determined in the superficial subintima. Binary and multicategory receiver operating characteristic (ROC) analysis and naïve Bayes classifier were used to compare the abilities of (1) the absolute densities of cells expressing a given marker (absolute method) with (2) the percentages of these cells in the inflammatory cell population (relative method) to differentiate among the six tissue classes.
The inflammatory infiltrates in normal synovium and the orthopedic arthropathies consisted almost exclusively of CD68+ and CD3+ cells. Notable fractions of CD20+ and CD38+ cells appeared in a subset of osteoarthritis samples, and increased further in early, rheumatoid and chronic septic arthritis. ROC analyses and naïve Bayes classifier ranked the absolute method above the relative method in terms of overall discriminatory ability. The relative method became slightly superior when the samples were also stratified according to the total number of inflammatory cells/mm2.
This exploratory investigation featuring a variety of joint disorders revealed that measuring the relative proportions of inflammatory cell types may aid in synovial tissue classification if the samples are also stratified according to the intensity of inflammation.
PMCID: PMC3738641  PMID: 23951325
12.  Rilonacept in the treatment of acute gouty arthritis: a randomized, controlled clinical trial using indomethacin as the active comparator 
In phase-3 clinical trials, the interleukin (IL-1) blocker, rilonacept (IL-1 Trap), demonstrated efficacy for gout flare prevention during initiation of urate-lowering therapy. This trial evaluated rilonacept added to a standard-of-care, indomethacin, for treatment of acute gout flares.
Adults, aged 18-70 years, with gout presenting within 48 hours of flare onset and having at least moderate pain as well as swelling and tenderness in the index joint were randomized to subcutaneous (SC) rilonacept 320 mg at baseline plus oral indomethacin 50 mg TID for 3 days followed by 25 mg TID for up to 9 days (n = 74); SC placebo at baseline plus oral indomethacin as above (n = 76); or SC rilonacept 320 mg at baseline plus oral placebo (n = 75). The primary efficacy endpoint was change in pain in the index joint (patient-reported using a Likert scale (0 = none; 4 = extreme)) from baseline to the average of values at 24, 48 and 72 hours (composite time point) for rilonacept plus indomethacin versus indomethacin alone. Comparison of rilonacept monotherapy with indomethacin monotherapy was dependent on demonstration of significance for the primary endpoint. Safety evaluation included clinical laboratory and adverse event (AE) assessments.
Patient characteristics were comparable among the groups; the population was predominantly male (94.1%), white (75.7%), with mean ± SD age of 50.3 ± 10.6 years. All treatment groups reported within-group pain reductions from baseline (P < 0.0001). Although primary endpoint pain reduction was greater with rilonacept plus indomethacin (-1.55 ± 0.92) relative to indomethacin alone (-1.40 ± 0.96), the difference was not statistically significant (P = 0.33), so formal comparison between monotherapy groups was not performed. Pain reduction over the 72-hour period with rilonacept alone (-0.69 ± 0.97) was less than that in the other groups, but pain reduction was similar among groups at 72 hours. Treatment with rilonacept was well-tolerated with no reported serious AEs related to rilonacept. Across all groups, the most frequent AEs were headache and dizziness.
Although generally well-tolerated, rilonacept in combination with indomethacin and rilonacept alone did not provide additional pain relief over 72 hours relative to indomethacin alone in patients with acute gout flare.
Trial registration registration number NCT00855920.
PMCID: PMC3672764  PMID: 23375025
13.  Functional CCR5 receptor protects arthritis patients from high synovial burden of infecting Chlamydia trachomatis 
The CCR5 chemokine receptor occurs in a wild-type (wt) and a non-functional, deleted form (Δ32). Reports suggested that Chlamydia-induced reproductive tract pathology is attenuated in women bearing Δ32. We asked whether the mutation affects synovial prevalence/burden of C. trachomatis.
PCR defined CCR5 genotype in synovial tissue DNA from 218 individuals: 21 controls, 110 with reactive arthritis (ReA), 83 with undifferentiated oligoarthritis (UO), 4 with osteoarthritis (OA). Disease durations were 0.5–21 yr. Additional PCR assays defined the presence of C. trachomatis DNA. Bacterial load was assessed by real time PCR in selected samples.
5 controls were wt/Δ32, 16 were wt/wt; 2/21 controls (both wt/wt) were PCR-positive for C. trachomatis. 85 (44%) arthritis patients were PCR-positive for C. trachomatis (69 ReA, 16 UO). For ReA patients, 14 (13%) had wt/Δ32, 10 (71%) of whom were PCR-positive. 19 UO patients (23%) were wt/Δ32, with 1 (1%) PCR-positive. No differences existed for gender or other factors. 1 OA patient had wt/Δ32. In ReA and UO samples, wt/Δ32 heterozygotes had a 5–10-fold higher bacterial burden than did wt/wt patients (p = 0.03), regardless of diagnosis.
These results indicate that the wt/wt genotype is associated with attenuated synovial bacterial load compared to loads in wt/Δ32 patients. While no alleles other than Δ32 were assessed, our data suggest that this allele provides little/no protection from ReA in chlamydiae-infected patients but it may provide some protection in UO patients. The basis of this possible differential effect of CCR5 genotype is under study.
PMCID: PMC2995821  PMID: 20811274
Chlamydia trachomatis; reactive arthritis; pathogenesis; inflammation; chemokine receptor
14.  Evaluation of glyceraldehyde-3-phosphate, prolylpeptidyl isomerase A, and a set of stably expressed genes as reference mRNAs in urate crystal inflammation 
BMC Research Notes  2011;4:443.
The murine air pouch membrane represents an easily accessible tissue for studies on gene regulation in acute inflammation. Considering that acute inflammation may affect expression of molecular reference genes, we evaluated the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and prolylpeptidyl isomerase A (PPIA) in the air pouch membrane during a complete time course of urate crystal inflammation and correlated the results with expression of interleukin (IL)-1β and hypoxia inducible factor (HIF)-1α. In addition, we aimed to identify alternate potential reference genes.
Using custom microfluidic real-time PCR arrays, the expression of 96 genes including GAPDH, PPIA, IL-1β, and HIF-1α was determined in dissected air pouch membranes 1, 4, 9, 18, 27, and 50 hours (h) after injecting monosodium urate (MSU) crystals into the pouch. One-way ANOVA was used to detect differential gene expression throughout the time course. Using the genes on these arrays as a convenience sample, alternate candidate reference genes were sought (1) with a biostatistical approach and (2) using the geNorm software tool.
Pouch leukocytes peaked at t = 9h and declined toward t = 50h. PPIA expression was not differentially regulated (p = 0.52, ANOVA). In contrast, GAPDH mRNA increased steadily after crystal injection, reaching a maximal 2.8-fold increase at t = 18h (p = 0.0006, t test), which followed a marked induction of IL-1β (max., 208-fold at t = 4h, p = 8.4 × 10-5, t test) and HIF-1α (max., 6.6-fold at t = 4h, p = 0.00025, t test). Fifteen genes were artifactually identified as "significantly regulated" when Ct values were normalized against GAPDH expression. The biostatistical approach and the geNorm analysis identified overlapping sets of candidate reference genes. Both ranked PPIA as the best candidate, followed by defender against cell death 1 (DAD1) and high-mobility group B1 (HMGB1).
GAPDH mRNA expression is up-regulated in urate crystal inflammation, possibly due to inflammation-associated hypoxia. Using GAPDH mRNA for molecular normalization resulted in significant artifacts in the calculated expression of the target mRNAs. PPIA and other stably expressed genes promise to be more appropriate reference genes in this model.
PMCID: PMC3213070  PMID: 22023915
15.  Patients with Chlamydia-associated arthritis have ocular (trachoma), not genital, serovars of C trachomatis in synovial tissue 
Microbial pathogenesis  2009;48(2):62.
Some individuals with a genital Chlamydia trachomatis infection develop inflammatory arthritis, but it is unknown whether particular chlamydial serovar(s) engender the disease more often than others. We defined serovar in synovial tissues from arthritis patients infected with this organism. DNA from synovial biopsies of 36 patients with PCR-confirmed synovial C. trachomatis was analyzed. Diagnoses included reactive arthritis, undifferentiated oligoarthritis, rheumatoid arthritis, and osteoarthritis. The chlamydial omp1 and trpA genes were amplified, cloned, and 10 or more clones from each sample were sequenced. The cytotoxin locus also was analyzed. omp1 sequences showed 2 patients having only C. trachomatis A serovar, 1 with only B, and 33 having only C, all ocular serovars. Analyses of trpA and the cytotoxin locus uniformly displayed standard ocular serovar characteristics for each patient. Identification of ocular chlamydial serovars in the synovia of arthritis patients is unexpected. These observations suggest that urogenital chlamydial infections, while consisting primarily of organisms of genital serovars, include some of ocular serovar(s). They further suggest that during such infections unknown selection pressures favor establishment of the latter in the synovium to the exclusion of genital serovar chlamydiae.
PMCID: PMC2815210  PMID: 19931374
Chlamydia trachomatis; inflammatory arthritis; infection; genital infection
16.  Detection of changes in articular cartilage proteoglycan by T1ρ magnetic resonance imaging 
The purpose of this work is to demonstrate the feasibility of T1ρ-weighted magnetic resonance imaging (MRI) to quantitatively measure changes in proteoglycan content in cartilage. The T1ρ MRI technique was implemented in an in vivo porcine animal model with rapidly induced cytokine-mediated cartilage degeneration. Six pigs were given an intra-articular injection of recombinant porcine interleukin-1β (IL-1β) into the knee joint before imaging to induce changes in cartilage via matrix metalloproteinase (MMP) induction. The induction of MMPs by IL-1 was used since it has been extensively studied in many systems and is known to create conditions that mimic in part characteristics similar to those of osteoarthritis. The contralateral knee joint was given a saline injection to serve as an internal control. T1ρ-weighted MRI was performed on a 4 T whole-body clinical scanner employing a 2D fast spin-echo-based T1ρ imaging sequence. T1ρ relaxation parameter maps were computed from the T1ρ-weighted image series. The average T1ρ relaxation rate, R1ρ (1/T1ρ) of the IL-1β-treated patellae was measured to be on average 25% lower than that of saline- injected patellae indicating a loss of proteoglycan. There was an average reduction of 49% in fixed charge density, measured via sodium MRI, of the IL-1β-treated patellae relative to control corroborating the loss of proteoglycan. The effects of IL-1β, primarily loss of PG, were confirmed by histological and immunochemical findings. The results from this study demonstrate that R1ρ is able to track proteoglycan content in vivo.
PMCID: PMC2858575  PMID: 15607881
MRI; T1ρ; Cartilage; IL-1; Osteoarthritis; Proteoglycan
17.  The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial 
The purpose of this study was to compare urate-lowering (UL) efficacy and safety of daily febuxostat and allopurinol in subjects with gout and serum urate (sUA) ≥ 8.0 mg/dL in a six-month trial.
Subjects (n = 2,269) were randomized to febuxostat 40 mg or 80 mg, or allopurinol 300 mg (200 mg in moderate renal impairment). Endpoints included the proportion of all subjects with sUA <6.0 mg/dL and the proportion of subjects with mild/moderate renal impairment and sUA <6.0 mg/dL. Safety assessments included blinded adjudication of each cardiovascular (CV) adverse event (AE) and death.
Comorbidities included: renal impairment (65%); obesity (64%); hyperlipidemia (42%); and hypertension (53%). In febuxostat 40 mg, febuxostat 80 mg, and allopurinol groups, primary endpoint was achieved in 45%, 67%, and 42%, respectively. Febuxostat 40 mg UL was statistically non-inferior to allopurinol, but febuxostat 80 mg was superior to both (P < 0.001). Achievement of target sUA in subjects with renal impairment was also superior with febuxostat 80 mg (72%; P < 0.001) compared with febuxostat 40 mg (50%) or allopurinol (42%), but febuxostat 40 mg showed greater efficacy than allopurinol (P = 0.021). Rates of AEs did not differ across treatment groups. Adjudicated (APTC) CV event rates were 0.0% for febuxostat 40 mg and 0.4% for both febuxostat 80 mg and allopurinol. One death occurred in each febuxostat group and three in the allopurinol group.
Urate-lowering efficacy of febuxostat 80 mg exceeded that of febuxostat 40 mg and allopurinol (300/200 mg), which were comparable. In subjects with mild/moderate renal impairment, both febuxostat doses were more efficacious than allopurinol and equally safe. At the doses tested, safety of febuxostat and allopurinol was comparable.
Clinical Trial Registration
PMCID: PMC2888216  PMID: 20370912
18.  Febuxostat Treatment for Gout: What the Clinician Needs to Know 
Febuxostat is a new non-purine based inhibitor of xanthine oxidase that will be a useful addition to the drugs available to treat gout. This short review covers general principles of the management of gout and then focuses on practical aspects and use of febuxostat.
PMCID: PMC3383484  PMID: 22870428
febuxostat; allopurinol; colchicine; probenecid; gout
19.  Identification of novel monosodium urate crystal regulated mRNAs by transcript profiling of dissected murine air pouch membranes 
The murine air pouch is a bursa-like space that resembles the human synovial membrane. Injection of monosodium urate (MSU) crystals into the pouch elicits an acute inflammatory response similar to human gout. We conducted the present study to identify mRNAs that were highly regulated by MSU crystals in the pouch membrane.
Air pouch membranes were meticulously dissected away from the overlying skin. Gene expression differences between MSU crystal stimulated and control membranes were determined by oligonucleotide microarray analysis 9 hours after injection of MSU crystals or buffer only. Differential regulation of selected targets was validated by relative quantitative PCR in time course experiments with dissected air pouch membranes and murine peritoneal macrophages.
Eleven of the 12 most highly upregulated mRNAs were related to innate immunity and inflammation. They included mRNAs encoding histidine decarboxylase (the enzyme that synthesizes histamine), IL-6, the cell surface receptors PUMA-g and TREM-1, and the polypeptides Irg1 and PROK-2. IL-6 mRNA rose 108-fold 1 hour after crystal injection, coinciding with a surge in mRNAs encoding IL-1β, tumour necrosis factor-α and the immediate early transcription factor Egr-1. The other mRNAs rose up to 200-fold within the subsequent 3 to 8 hours. MSU crystals induced these mRNAs in a dose-dependent manner in cultured macrophages, with similar kinetics but lower fold changes. Among the downregulated mRNAs, quantitative PCR confirmed significant decreases in mRNAs encoding TREM-2 (an inhibitor of macrophage activation) and granzyme D (a constituent of natural killer and cytotoxic T cells) within 50 hours after crystal injection.
This analysis identified several genes that were previously not implicated in MSU crystal inflammation. The marked rise of the upregulated mRNAs after the early surge in cytokine and Egr-1 mRNAs suggests that they may be part of a 'second wave' of factors that amplify or perpetuate inflammation. Transcript profiling of the isolated air pouch membrane promises to be a powerful tool for identifying genes that act at different stages of inflammation.
PMCID: PMC2483455  PMID: 18522745
20.  Reduction of urate crystal-induced inflammation by root extracts from traditional oriental medicinal plants: elevation of prostaglandin D2 levels 
Dried roots of the plants Acanthopanax senticosus, Angelica sinensis and Scutellaria baicalensis are used in traditional oriental medicine and reportedly possess anti-inflammatory properties. Using the murine air pouch model of inflammation, we investigated the efficacy and mode of action of an extract from these three plants in crystal-induced inflammation. Air pouches were raised on the backs of 8-week-old BALB/c mice. Mice were fed 100 mg/kg body weight of root extracts (A. senticosus:A. sinensis:S. baicalensis mixed in a ratio of 5:4:1 by weight) or vehicle only on days 3–6. Inflammation was elicited on day 6 by injecting 2 mg of monosodium urate (MSU) crystals into the pouch. Neutrophil density and IL-6 and TNF-α mRNA levels were determined in the pouch membrane, and the leukocyte count and IL-6, prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2) levels were determined in the pouch exudate. Treatment with the root extracts led to a reduction in all inflammatory parameters: the leukocyte count in the pouch exudate decreased by 82%; the neutrophil density in the pouch membrane decreased by 68%; IL-6 and TNF-α mRNA levels in the pouch membrane decreased by 100%; the IL-6 concentration in the pouch fluid decreased by 50%; and the PGE2 concentration in the pouch fluid decreased by 69%. Remarkably, the concentration of the potentially anti-inflammatory PGD2 rose 5.2-fold in the pouch exudate (p < 0.005), which led to a normalization of the PGD2:PGE2 ratio. A 3.7-fold rise in hematopoietic PGD synthase (h-PGDS) mRNA paralleled this rise in PGD2 (p = 0.01).
Thus, the root extracts diminished MSU crystal-induced inflammation by reducing neutrophil recruitment and expression of pro-inflammatory factors and increasing the level of the potentially anti-inflammatory PGD2. These results support a need for further studies of the efficacy of these extracts in the treatment of inflammatory arthropathies and suggest elevation of PGD2 levels as a novel mechanism for an anti-inflammatory agent.
PMCID: PMC2206389  PMID: 17612394
21.  Elimination of rheumatoid synovium in situ using a Fas ligand 'gene scalpel' 
Arthritis Research & Therapy  2005;7(6):R1235-R1243.
Surgical synovectomy to remove the inflammatory synovium can temporarily ameliorate rheumatoid inflammation and delay the progress of joint destruction. An efficient medically induced programmed cell death (apoptosis) in the rheumatoid synovium might play a role similar to synovectomy but without surgical tissue damage. Gene transfer of Fas ligand (FasL) has increased the frequency of apoptotic cells in mouse and rabbit arthritic synovium. In this study, we investigated whether repeated FasL gene transfer could remove human inflammatory synovial tissue in situ and function as a molecular synovectomy. Briefly, specimens of human synovium from joint replacement surgeries and synovectomies of rheumatoid arthritis (RA) patients were grafted subcutaneously into male C.B-17 severe combined immunodeficiency (SCID) mice. Injections of a recombinant FasL adenovirus (Ad-FasL) into the grafted synovial tissue at the dosage of 1011 particles per mouse were performed every two weeks. Three days after the fifth virus injection, the mice were euthanized by CO2 inhalation and the human synovial tissues were collected, weighed and further examined. Compared to the control adenovirus-LacZ (Ad-LacZ) and phosphate buffered saline (PBS) injected RA synovium, the Ad-FasL injected RA synovium was dramatically reduced in size and weight (P < 0.005). The number of both synoviocytes & mononuclear cells was significantly reduced. Interestingly, an approximate 15-fold increased frequency of apoptotic cells was observed in RA synovium three days after Ad-FasL injection, compared with control tissues. In summary, our in vivo investigation of gene transfer to human synovium in SCID mice suggests that repeated intra-articular gene transfer of an apoptosis inducer, such as FasL, may function as a 'gene scalpel' for molecular synovectomy to arrest inflammatory synovium at an early stage of RA.
PMCID: PMC1297566  PMID: 16277676
22.  Randomised double blind trial of etoricoxib and indometacin in treatment of acute gouty arthritis 
BMJ : British Medical Journal  2002;324(7352):1488-1492.
To assess the safety and efficacy of etoricoxib, a selective cyclo-oxygenase-2 inhibitor, in comparison with indometacin in the treatment of acute gouty arthritis.
Randomised, double blind, active comparator controlled trial.
43 outpatient study centres in 11 countries.
142 men and eight women (75 patients per treatment group) aged 18 years or over presenting with clinically diagnosed acute gout within 48 hours of onset.
Etoricoxib 120 mg administered orally once daily versus indometacin 50 mg administered orally three times daily, both for 8 days
Main outcome measures
Patients' assessment of pain in the study joint over days 2 to 5 (primary end point); investigators' and patients' global assessments of response to treatment and tenderness of the study joint (key secondary end points).
Etoricoxib showed efficacy comparable to indometacin. Patients' assessment of pain in the study joint (0-4 point Likert scale, “no pain” to “extreme pain”) over days 2 to 5 showed a least squares mean change from baseline of −1.72 (95% confidence interval −1.90 to −1.55) for etoricoxib and −1.83 (−2.01 to −1.65) for indometacin. The difference between treatment groups met prespecified comparability criteria. All other efficacy end points, including those reflecting reduction in inflammation and analgesia, provided corroborative evidence of comparable efficacy. Significant pain relief was evident at the first measurement, 4 hours after the first dose of treatment. Prespecified safety analyses revealed that drug related adverse experiences occurred significantly less frequently with etoricoxib (22.7%) than with indometacin (46.7%) (P=0.003), although overall adverse experience rates were similar between the two treatment groups.
Etoricoxib 120 mg once daily provides rapid and effective treatment for acute gouty arthritis comparable to indometacin 50 mg three times daily. Etoricoxib was generally safe and well tolerated in this study.
What is already known on this topicAcute gouty arthritis is an extremely painful inflammatory arthritis resulting from deposition of monosodium urate in the affected joint spaceThe most common treatment is a non-selective non-steroidal anti-inflammatory drug, with indometacin being the standard treatmentCurrent treatment modalities are based on limited, small studiesWhat this study addsEtoricoxib, a cyclo-oxygenase-2 selective inhibitor, has comparable efficacy to indometacin in the treatment of acute gouty arthritisEtoricoxib provides rapid relief of pain and effectively treats the inflammation of acute gout; it is an effective treatment alternative to indometacin
PMCID: PMC116444  PMID: 12077033
23.  Rheumatoid arthritis associated autoantibodies in patients with synovitis of recent onset 
Arthritis Research  2000;2(3):236-243.
An inception cohort of 238 patients having peripheral joint synovitis of less than 12 months duration was evaluated clinically and followed prospectively for 1 year to determine the clinical significance of a number of rheumatoid arthritis (RA) associated autoantibodies. Serum samples collected at the time of the initial evaluation were tested for rheumatoid factor (RF) and antibodies to Sa (anti-Sa), RA-33, (pro)filaggrin [antifilaggrin antibody (AFA)], cyclic citrullinated peptide (anti-CCP), calpastatin, and keratin [antikeratin antibody (AKA)]. RF had a sensitivity of 66% and a specificity of 87% for RA. Anti-Sa, AFA, and anti-CCP all had a specificity of more than 90%, but a sensitivity of less than 50% for this diagnosis. Overall, there was a high degree of correlation between AFA, AKA, anti-Sa or anti-CCP, this being highest between anti-Sa and anti-CCP (odds ratio, 13.3; P < 0.001). Of the 101 patients who were positive for at least one of these four autoantibodies, 57% were positive for only one. Finally, anti-SA identified a subset of predominantly male RA patients with severe, erosive disease. Anti-SA, AFA and anti-CCP are all specific for early RA but, overall, have little additional diagnostic value over RF alone. Although these antibodies may preferentially recognize citrullinated antigens, the modest degree of concordance between them in individual patient sera suggests that it is unlikely a single antigen is involved in generating these responses.
A spectrum of autoantibodies is now known to be specifically associated with RA. There continues to be uncertainty as to what stage of the disease each of these autoantibodies develop, and whether they are associated with unique clinical features.
To help address these questions, a spectrum of autoantibodies known to be associated with RA in a cohort of patients with early synovitis was evaluated.
An inception cohort of 238 patients having peripheral joint synovitis of less than 12 months duration was evaluated clinicially then followed prospectively for 1 year. Patients were classified as having RA on the basis of fulfilling the 1987 criteria. Serum samples collected at the time of the initial evaluation were tested for anti-Sa and anti-RA-33 using immunoblotting, and to (pro)filaggrin (AFA), anti-CCP, and calpastatin (anti-RA-1) using enzyme-linked immunosorbent assay techniques. AKA were detected using immunoflurescence on human epidermal tissue. RF was tested by nephelometry. HLA-DRB1 alleles were determined using sequence specific primers. Initial and 1 year radiographs were evaluated for the presence of erosions.
Of the 238 patients with synovitis of recent onset in the cohort, 106 (45%) met RA criteria, 102 (96%) of whom met the criteria on their initial visit. Diagnoses in the remaining patients included 22 (9%) with reactive arthritis, 14 (6%) with psoriatic arthritis or another form of spondylarthropathy, 11 (5%) with another well-defined rheumatic diagnosis, and 85 (36%) with undifferentiated arthritis. The RA patients were significantly older than the nonRA patients (46 ± 13 versus 39 ± 13; P < 0.001), had higher mean swollen joint count (13.8 ± 9.7 versus 2.3 ± 2.3; P < 0.001), and higher C-reactive protein (CRP) level (1.9 ± 1.9 versus 1.6 ± 2.4; P < 0.01). Table 1 summarizes the prevalence of the various RA associated antibodies in patients diagnosed as having RF-positive (RF+) RA, RF-negative (RF-) RA, and nonRA. Regarding the characteristics of these tests, RF had the highest sensitivity at 66%, and all the other antibodies individually were less than 50% sensitive. AFA, anti-Sa, anti-CCP were greater than 90% specific for RA, while RF and AKA were 80-90% specific, and anti-RA-33 and anti-RA-1 was not specific for this diagnosis. The data further indicate that adding any one of AFA, AKA, anti-Sa, or anti-CCP to RF increases the specificity for RA from 80 to 90%. In the absence of RF, the presence of one or more of these antibodies carried a sensitivity of only 31% for RF- RA, with anti-Sa being the most specific at 98%. Overall, there was a high degree of correlation between AFA, AKA, anti-Sa or anti-CCP, this being highest between anti-Sa and anti-CCP (odds ratio, 13.3; P < 0.001). Despite this high level of correlation, of the 101 patients who were positive for at least one of these four autoantibodies, 57% were positive for only one, suggesting considerable variability in individual reactivity patterns.
RA has been shown in multiple populations to be associated with HLA-DRB1 alleles encoding for the shared epitope (SE). In this study, as illustrated in Table 2, the presence of each of these autoantibodies was significantly associated with having two shared epitope alleles, even when only the RA patients were considered.
Patients with anti-Sa antibodies were predominantly male (61% versus 28%; P<0.01), had significantly higher swollen joint counts (18 ± 12 versus 13 ± 9; P=0.02), and higher CRP levels (2.6 ± 3 mg/dl versus 1.6 ± 1.4 mg/dl; P=0.03) at the initial visit. Despite subsequently begin treated with significantly higher doses of prednisone (4.8 ± 6.0 mg/day versus 1.8 ± 3.3 mg/day; P<0.01), and more disease modifying antirheumatic drug therapy (1.4 ± 0.8 versus 0.9 ± 0.7 disease modifying antirheumatic drugs; P<0.01), the anti-Sa-positive RA patients had a higher frequency of erosions than the rest of the RA patients (60% versus 33%; P=0.03). Neither RF nor SE were associated with the disease severity measures, and analyses evaluating all the other autoantibodies failed to reveal a similar trend.
Despite a well-documented lack of specificity, RF continues to be a central part of the definition of RA, primarily because of its favourable sensitivity profile. In our cohort, RF had a sensitivity of 66%, a specificity of 87%, and an overall accuracy of 78% for the diagnosis of RA. AFA, anti-Sa, anti-CCP were all highly specific for this diagnosis, and when any of them were present in conjunction with RF, the specificity for RA approached 100%. Potentially of more importance to the clinician is the diagnostic value of these antibodies when RF is not detectable. Our data indicate that only 31% of RF- RA patients had any of AKA, AFA, anti-Sa or anti-CCP, and that anti-Sa was the most specific for this diagnosis. This modest level of sensitivity suggests that testing for this spectrum of autoantibodies carries little advantage over RF alone in diagnosing early RA.
AFA, AKA, and antiperinuclear factor (APF) have all been proposed to identify a common antigen present in the skin protein (pro)filaggrin. It has continued to be puzzling why a skin antigen would be targeted relatively specifically in a disorder that is primarily articular. A potential explanation for this may relate to the demonstration that citrulline appears to be an essential constituent of the antigenic determinants recognized by AKA, APF, and AFA. The citrulline rich (pro)filaggrin molecule makes an ideal substrate for detecting this reactivity. Moreover, the SA antigen, which, unlike (pro)filaggrin, is detectable in rheumatoid synovium, has recently been shown to also be citrullinated. It is thus possible that AKA, AFA, APE, and anti-Sa all recognize one or more citrullinated antigens. Despite this possibility, the modest degree of concordance between them in individual patient sera suggests that it is unlikely that a single antigen is involved in generating these responses.
This study provides evidence suggesting that anti-Sa antibodies appear to be a marker for a subset of early RA patients whose disease may be more severe and erosive. Moreover, it was determined that anti-Sa, AFA, and anti-CCP were all highly associated with SE, particularly two copies. We examined a spectrum of potential RA severity indicators including the number of swollen joints, CRP level, and presence of early radiographic erosions. Our data indicate that anti-Sa was more highly associated with these measures of RA severity than any other parameter, including the most accepted prognostic indicators, RF and SE.
In conclusion, it is demonstrated that antibodies directed against putatively citrullinated antigens including SA, filaggrin, keratin, and CCP are the most specific for RA, and are detectable early in the disease course. It will be of interest to find out whether the cumulative prevalence of specific autoantibody subsets tends to increase over time, as this would suggest that the mechanisms underlying the development of these reactivities continue to evolve over the course of the arthropathy.
PMCID: PMC17811  PMID: 11056669
autoantibodies; early synovitis; human leukocyte antigen; rheumatoid arthritis; spondylarthropathy
24.  Gamma Interferon and Interleukin-10 Gene Expression in Synovial Tissues from Patients with Early Stages of Chlamydia-Associated Arthritis and Undifferentiated Oligoarthritis and from Healthy Volunteers 
Infection and Immunity  1999;67(5):2682-2686.
Genetically determined differences in interleukin-10 (IL-10) and gamma interferon (IFN-γ) responses in mice correlate with clearance of Chlamydia pneumonitis infection. We measured the synovial expression of IL-10 and IFN-γ and additional cytokine genes in patients who had recent-onset Chlamydia-associated arthritis (Chl-AA). IL-10 and IFN-γ mRNA were relatively abundant in recent-onset Chl-AA.
PMCID: PMC116026  PMID: 10225943
25.  Phagocytic Function of Polymorphonuclear Leukocytes in Rheumatic Diseases 
Journal of Clinical Investigation  1973;52(7):1632-1635.
Phagocytosis of yeast particles by peripheral blood and synovial fluid neutrophils was compared in the sera and synovial fluids from 16 osteoarthritis, 23 rheumatoid arthritis, and 12 miscellaneous arthritis patients. Phagocytosis by normal peripheral blood neutrophils was decreased equally and significantly in all synovial fluids. All synovial fluid neutrophils demonstrated decreased phagocytic capacity in all media. Rheumatoid arthritis synovial fluid neutrophils showed significantly less phagocytosis than miscellaneous arthritis synovial fluid neutrophils. Normal peripheral blood neutrophils which in vitro had previously ingested monosodium urate crystals or oil red O, subsequently exhibited a normal yeast phagocytic capacity. Normal peripheral blood neutrophils, which had ingested preformed immunoglobulin G-rheumatoid factor complexes exhibited significantly less yeast phagocytic capacity than control cells or cells preincubated with the individual complex components. There was a significant correlation between the log of the reciprocal of the rheumatoid factor titer in sera used to produce complexes and the phagocytic capacity exhibited by test neutrophils. Ingestion of immunoglobulin G-rheumatoid factor complexes may be important in the production of the cellular phagocytic defect which this study has demonstrated in rheumatoid arthritis synovial fluid neutrophils.
PMCID: PMC302436  PMID: 4578156

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