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1.  The diagnostic performance of MRI in osteoarthritis: a systematic review and meta-analysis 
Objective
Osteoarthritis (OA) is currently diagnosed using clinical and radiographic findings. In recent years MRI use in osteoarthritis has increasingly been studied. This study was conducted to determine the diagnostic utility of MRI in OA through a meta-analysis of published studies.
Methods
A systematic literature search was undertaken to include studies that used MRI to evaluate or detect osteoarthritis. MRI was compared to various reference standards: histology, arthroscopy, radiography, CT, clinical evaluation, and direct visual inspection. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and receiver operating characteristic (ROC) area under the curve were calculated. Random effects models were used to pool results.
Results
Of 20 relevant studies identified from the literature, 16 reported complete data and were included in the meta-analysis, with a total of 1220 patients (1071 with OA and 149 without). Overall sensitivity from pooling data of all the included studies was 61% (95% confidence interval [CI] 53 to 68), specificity was 82% (95% CI 77 to 87), PPV was 85% (95% CI 80 to 88), and NPV was 57% (95% CI 43 to 70). The ROC showed an area under the curve of 0.804. There was significant heterogeneity in the above parameters (I2 >83%). With histology as the reference standard, sensitivity increased to 74% and specificity decreased to 76% compared with all reference standards combined. When arthroscopy was used as the reference standard, sensitivity increased to 69% and specificity to 93% compared with all reference standards combined.
Conclusion
MRI can detect OA with an overall high specificity and moderate sensitivity when compared with various reference standards, thus lending more utility to ruling out OA than ruling it in. The sensitivity of MRI is below the current clinical diagnostic standards. At this time standard clinical algorithm for OA diagnosis, aided by radiographs appears to be the most effective method for diagnosing OA.
doi:10.1016/j.joca.2011.10.003
PMCID: PMC3934362  PMID: 22044841
Osteoarthritis; diagnosis; MRI
2.  The association between ANKH promoter polymorphism and chondrocalcinosis is independent of age and osteoarthritis: results of a case–control study 
Introduction
Chondrocalcinosis (CC) most commonly results from calcium pyrophosphate crystal deposition (CPPD). The objective of this study is to examine the association between candidate single-nucleotide polymorphisms (SNPs) and radiographic CC.
Methods
SNPs in ankylosis human (ANKH), high ferritin (HFE), tissue non-specific alkaline phosphatase (TNAP), ecto-neucleotide pyrophosphatase 1 (ENPP1), and transferrin (TE) genes were genotyped in participants of the Genetics of Osteoarthritis and Lifestyle (GOAL) and Nottingham Osteoarthritis Case-Control studies. Adjusted genotype odds ratio (aORGENOTYPE), the OR for association between one additional minor allele and CC, was calculated and adjusted for age, gender, body mass index (BMI), and osteoarthritis (OA) by using binary logistic regression. Statistical significance was set at P ≤0.003 after Bonferroni correction for multiple tests.
Results
The -4bpG > A polymorphism in the 5′ untranslated region (5′ UTR) of ANKH associated with CC after Bonferroni correction. This was independent of age, gender, OA, and BMI; aORGENOTYPE (95% confidence interval, or CI) was 1.39 (1.14-1.69) (P = 0.001). rs3045 and rs875525, two other SNPs in ANKH, associated with CC; aORGENOTYPE (95% CI) values were 1.31 (1.09-1.58) (P = 0.005) and 1.18 (1.03-1.35) (P = 0.015), respectively; however, this was non-significant after Bonferroni correction.
Conclusions
This study validates the association between a functional polymorphism in the 5′ UTR of ANKH and CC and shows for the first time that this is independent of age and OA – the two key risk factors for CC. It shows that other SNPs in ANKH may also associate with CC. This supports the role of extracellular inorganic pyrophosphate in the pathogenesis of CC. The findings of this hospital-based study require replication in a community-based population.
doi:10.1186/ar4453
PMCID: PMC3978851  PMID: 24467728
3.  Individual patient data meta-analysis of trials investigating the effectiveness of intra-articular glucocorticoid injections in patients with knee or hip osteoarthritis: an OA Trial Bank protocol for a systematic review 
Systematic Reviews  2013;2:54.
Background
Based on small to moderate effect sizes for the wide range of symptomatic treatments in osteoarthritis (OA), and on the heterogeneity of OA patients, treatment guidelines for OA have stressed the need for research on clinical predictors of response to different treatments. A meta-analysis to quantify the effect modified by the predictors using individual patient data (IPD) is suggested. The initiative to collect and analyze IPD in OA research is commenced by the OA Trial Bank. The study aims are therefore: to evaluate the efficacy of intra-articular glucocorticoids for knee or hip OA in specific subgroups of patients with severe pain and (mild) inflammatory signs, over both short-term and long-term follow-up, using IPD from existing studies; to reach consensus on the rules for cooperation in a consortium; and to develop and explore the methodological issues of meta-analysis with individual OA patient data.
Methods/Design
For the current IPD analysis we will collect and synthesize IPD from randomized trials studying the effect of intra-articular glucocorticoid injections in patients with hip or knee OA. Subgroup analyses will be performed for the primary outcome of pain at both short-term and long-term follow-up, in the subgroups of patients with and without severe pain and with and without inflammatory signs.
Discussion
This study protocol includes the first study of the OA Trial Bank, an international collaboration that initiates meta-analyses on predefined subgroups of OA patients from existing literature. This approach ensures a widely supported initiative and is therefore likely to be successful in data collection of existing trials. The collaboration developed (that is, the OA Trial Bank) may also lead to future IPD analyses on subgroups of patients with several intervention strategies applied in OA patients.
doi:10.1186/2046-4053-2-54
PMCID: PMC3707758  PMID: 23830482
Osteoarthritis; Individual patient data; Corticosteroid injection
4.  A Role for PACE4 in Osteoarthritis Pain: Evidence from Human Genetic Association and Null Mutant Phenotype 
Annals of the rheumatic diseases  2012;71(6):1042-1048.
Objectives
To assess if genetic variation in the PACE4 gene, PCSK6, influences the risk for symptomatic knee OA.
Methods
Ten PCSK6 single nucleotide polymorphisms (SNP) were tested for association in a discovery cohort of radiographic knee OA (n= 156 asymptomatic and 600 symptomatic cases). Meta-analysis of the minor allele at rs900414 was performed in three additional independent cohorts (total n=674 asymptomatic and 2068 symptomatic). Pcsk6 knockout (KO) mice and wildtype C57BL/6 mice were compared in a battery of algesiometric assays, including hypersensitivity in response to intraplantar substance P; pain behaviours in response to intrathecal substance P; and pain behaviour in the abdominal constriction test.
Results
In the discovery cohort of radiographic knee OA, an intronic SNP at rs900414 was significantly associated with symptomatic OA. Replication in three additional cohorts confirmed that the minor allele at rs900414 was consistently increased among asymptomatic compared to symptomatic radiographic knee OA cases in all four cohorts. A fixed-effects meta-analysis yielded an odds ratio =1.35 (95% CI 1.17, 1.56; p-value 4.3×10−5 and no significant between-study heterogeneity). Studies in mice revealed that Pcsk6 knockout (KO) mice were significantly protected against pain in a battery of algesiometric assays.
Conclusions
These results suggest that a variant in PCSK6 is strongly associated with protection against pain in knee OA, offering some insight as to why in the presence of the same structural damage, some individuals develop chronic pain and others are protected. Studies in Pcsk6 null mutant mice further implicate PACE4 in pain.
doi:10.1136/annrheumdis-2011-200300
PMCID: PMC3603144  PMID: 22440827
Knee osteoarthritis; pain; PACE4; genetic association; SNP
5.  Gene-environment interaction between body mass index and transforming growth factor beta 1 (TGFβ1) gene in knee and hip osteoarthritis 
Introduction
The objective was to investigate potential gene-environment interaction between body mass index (BMI) and each of eight TGFβ1 polymorphisms in knee and hip osteoarthritis (OA).
Methods
We conducted a case-control study of Caucasian men and women aged 45 to 86 years from Nottingham, United Kingdom (Genetics of OA and Lifestyle (GOAL) study). Cases had clinically severe symptoms and radiographic knee or hip OA; controls had no symptoms and no radiographic knee/hip OA. We used logistic regression to investigate the association of TGFβ1 polymorphisms and OA when stratifying by BMI. Knee and hip OA were analyzed separately with adjustment for potential confounders. Additive and multiplicative interactions were examined.
Results
2,048 cases (1,042 knee OA, 1,006 hip OA) and 967 controls were studied. For hip OA, the highest risk was in overweight (BMI ≥25 kg/m2) individuals with the variant allele of single-nucleotide polymorphism (SNP) rs1800468 (odds ratio (OR) 2.21, 95% confidence interval (CI) 1.55, 3.15). Evaluation of gene-environment interaction indicated significant synergetic interaction (relative excess risk due to interaction (RERI) = 0.93, synergy index (SI) = 4.33) with an attributable proportion due to interaction (AP) of 42% (AP = 0.42; 95% CI 0.16, 0.68). Multiplicative interaction was also significant (OR for interaction (ORINT) = 2.27, P = 0.015). For knee OA, the highest risk was in overweight individuals with homozygous genotype 11 of SNP rs2278422 (OR = 6.95, P <0.001). In contrast, the variant allele indicated slightly lower risks (OR = 4.72, P <0.001), a significant antagonistic interaction (RERI = -2.66, SI = 0.59), AP = -0.56 (95%CI -0.94, -0.17) and a significant multiplicative interaction (ORINT = 0.47, P = 0.013).
Conclusion
TGFβ1 gene polymorphisms interact with being overweight to influence the risk of large joint OA.
doi:10.1186/ar4214
PMCID: PMC4060375  PMID: 23597094
6.  Chondrocalcinosis is common in the absence of knee involvement 
Arthritis Research & Therapy  2012;14(5):R205.
Introduction
We aimed to describe the distribution of radiographic chondrocalcinosis (CC) and to examine whether metacarpophalangeal joint (MCPJ) calcification and CC at other joints occurs in the absence of knee involvement.
Methods
This was a cross-sectional study embedded in the Genetics of Osteoarthritis and Lifestyle study (GOAL). All participants (n = 3,170) had radiographs of the knees, hands, and pelvis. These were scored for radiographic changes of osteoarthritis (OA), for CC at knees, hips, symphysis pubis, and wrists, and for MCPJ calcification. The prevalence of MCPJ calcification and CC overall, at each joint, and in the presence or absence of knee involvement, was calculated.
Results
The knee was the commonest site of CC, followed by wrists, hips, and symphysis pubis. CC was more likely to be bilateral at knees and wrists but unilateral at hips. MCPJ calcification was usually bilateral, and less common than CC at knees, hips, wrists, and symphysis pubis. Unlike that previously reported, CC commonly occurred without any knee involvement; 44.4% of wrist CC, 45.9% of hip CC, 45.5% of symphysis pubis CC, and 31.3% of MCPJ calcification occurred in patients without knee CC. Those with meniscal or hyaline articular cartilage CC had comparable ages (P = 0.21), and neither preferentially associated with fibrocartilage CC at distant joints.
Conclusions
CC visualized on a plain radiograph commonly occurs at other joints in the absence of radiographic knee CC. Therefore, knee radiographs alone are an insufficient screening test for CC. This has significant implications for clinical practice, for epidemiologic and genetic studies of CC, and for the definition of OA patients with coexistent crystal deposition.
doi:10.1186/ar4043
PMCID: PMC3580517  PMID: 23036436
7.  A Hierarchy of Patient-Reported Outcomes for Meta-Analysis of Knee Osteoarthritis Trials: Empirical Evidence from a Survey of High Impact Journals 
Arthritis  2012;2012:136245.
Objectives. To develop a prioritised list based on responsiveness for extracting patient-reported outcomes (PROs) measuring pain and disability for performing meta-analyses in knee osteoarthritis (OA). Methods. A systematic search was conducted in 20 highest impact factor general and rheumatology journals chosen a priori. Eligible studies were randomised controlled trials, using two or more PROs measuring pain and/or disability. Results. A literature search identified 402 publications and 38 trials were included, resulting in 54 randomised comparisons. Thirty-five trials had sufficient data on pain and 15 trials on disability. The WOMAC “pain” and “function” subscales were the most responsive composite scores. The following list was developed. Pain: (1) WOMAC “pain” subscale, (2) pain during activity (VAS), (3) pain during walking (VAS), (4) general knee pain (VAS), (5) pain at rest (VAS), (6) other composite pain scales, and (7) other single item measures. Disability: (1) WOMAC “function” subscale, (2) SF-36 “physical function” subscale, (3) SF-36 (Physical composite score), and (4) Other composite disability scores. Conclusions. As choosing the PRO most favourable for the intervention from individual trials can lead to biased estimates, using a prioritised list as developed in this study is recommended to reduce risk of biased selection of PROs in meta-analyses.
doi:10.1155/2012/136245
PMCID: PMC3389647  PMID: 22792458
8.  Large Scale Replication Study of the Association between HLA Class II/BTNL2 Variants and Osteoarthritis of the Knee in European-Descent Populations 
PLoS ONE  2011;6(8):e23371.
Osteoarthritis (OA) is the most common form of arthritis and a major cause of disability. This study evaluates the association in Caucasian populations of two single nucleotide polymorphisms (SNPs) mapping to the Human Leukocyte Antigen (HLA) region and deriving from a genome wide association scan (GWAS) of knee OA in Japanese populations. The frequencies for rs10947262 were compared in 36,408 controls and 5,749 knee OA cases from European-descent populations. rs7775228 was tested in 32,823 controls and 1,837 knee OA cases of European descent. The risk (major) allele at rs10947262 in Caucasian samples was not significantly associated with an odds ratio (OR)  = 1.07 (95%CI 0.94 -1.21; p = 0.28). For rs7775228 the meta-analysis resulted in OR = 0.94 (95%CI 0.81-1.09; p = 0.42) for the allele associated with risk in the Japanese GWAS. In Japanese individuals these two SNPs are in strong linkage disequilibrium (LD) (r2 = 0.86) with the HLA class II haplotype DRB1*1502 DQA1*0103 DQB1*0601 (frequency 8%). In Caucasian and Chinese samples, using imputed data, these SNPs appear not to be in LD with that haplotype (r2<0.07). The rs10947262 and rs7775228 variants are not associated with risk of knee OA in European descent populations and they do not appear tag the same HLA class II haplotype as they do in Japanese individuals.
doi:10.1371/journal.pone.0023371
PMCID: PMC3154440  PMID: 21853121
9.  Are joints affected by gout also affected by osteoarthritis? 
Annals of the Rheumatic Diseases  2007;66(10):1374-1377.
Objectives
To determine whether joints affected by gout are also affected by osteoarthritis (OA).
Methods
A postal questionnaire was sent to all adults aged over 30 years registered with two general practices. The questionnaire assessed a history of gout (doctor diagnosed, or episodes suggestive of acute crystal synovitis) and medication use. Patients who possibly had gout attended for clinical assessment to verify the diagnosis on clinical grounds and assess the distribution of joints affected by acute attacks of gout and OA. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were calculated between the history of an acute attack of gout and the presence of OA at an individual joint adjusted for age, gender, body mass index and prior diuretic use in a binary logistic regression model.
Results
A total of 4249 completed questionnaires were returned (32%). From 359 attendees, 164 cases of gout were clinically confirmed. A highly significant association existed between the site of acute attacks of gout and the presence of OA (aOR 7.94; 95% CI 6.27, 10.05). Analysis at individual joint sites revealed a significant association at the first metatarsophalangeal joint (aOR 2.06; 95% CI 1.28, 3.30), mid‐foot (aOR 2.85; 95% CI 1.34, 6.03), knee (aOR 3.07; 95% CI 1.05, 8.96) and distal interphalangeal joints (aOR 12.67; 95% CI 1.46, 109.91).
Conclusion
Acute attacks of gout at individual joint sites are associated with the presence of clinically assessed OA at that joint suggesting that OA may predispose to the localised deposition of monosodium urate crystals.
doi:10.1136/ard.2006.063768
PMCID: PMC1994292  PMID: 17284542
10.  Concordance of the management of chronic gout in a UK primary‐care population with the EULAR gout recommendations 
Annals of the Rheumatic Diseases  2007;66(10):1311-1315.
Objectives
To assess concordance of the management of chronic gout in UK primary care with the European League Against Rheumatism (EULAR) gout recommendations.
Methods
A postal questionnaire was sent to all adults aged >30 years registered with two general practices. Patients with possible gout attended for clinical assessment, at which the diagnosis was verified clinically. Aspects of chronic gout management, including provision of lifestyle modification advice, use of urate‐lowering therapies (ULT) including dose titration to serum urate (SUA) level, prophylaxis against acute attacks, and diuretic cessation were assessed in accordance with the EULAR recommendations.
Results
Of 4249 (32%) completed questionnaires returned, 488 reported gout or acute attacks and were invited for clinical assessment. Of 359 attendees, 164 clinically confirmed cases of gout were identified. Advice regarding alcohol consumption was recalled by 59 (41%), weight loss by 36 (25%) and diet by 42 (29%). Allopurinol was the only ULT used and was taken by 44 (30%); 31 (70%) were taking 300 mg daily. Mean SUA was lower in allopurinol users than non‐users (318 vs 434 μmol/l) and was less often >360 μmol/l in allopurinol users (23% vs 75%). Eight patients had recently commenced allopurinol; two of these also were taking prophylactic colchicine or non‐steroidal anti‐inflammatory drugs. Of 25 patients with diuretic‐induced gout, 16 (64%) were still taking a diuretic.
Conclusion
Treatment of chronic gout is often suboptimal and poorly concordant with EULAR recommendations. Lifestyle advice is infrequently offered, and allopurinol is restricted to a minority. Persistent hyperuricaemia was often seen in allopurinol non‐users, but was also in allopurinol users, suggesting that doses >300 mg are often necessary.
doi:10.1136/ard.2007.070755
PMCID: PMC1994300  PMID: 17504843
gout; primary health care; lifestyle risk reduction; allopurinol; EULAR recommendations
11.  Development and validation of self-reported line drawings for assessment of knee malalignment and foot rotation: a cross-sectional comparative study 
Background
For large scale epidemiological studies clinical assessments and radiographs can be impractical and expensive to apply to more than just a sample of the population examined. The study objectives were to develop and validate two novel instruments for self-reported knee malalignment and foot rotation suitable for use in questionnaire studies of knee pain and osteoarthritis.
Methods
Two sets of line drawings were developed using similar methodology. Each instrument consisted of an explanatory question followed by a set of drawings showing straight alignment, then two each at 7.5° angulation and 15° angulation in the varus/valgus (knee) and inward/outward (foot) directions. Forty one participants undertaking a community study completed the instruments on two occasions. Participants were assessed once by a blinded expert clinical observer with demonstrated excellent reproducibility. Validity was assessed by sensitivity, specificity and likelihood ratio (LR) using the observer as the reference standard. Reliability was assessed using weighted kappa (κ). Knee malalignment was measured on 400 knee radiographs. General linear model was used to assess for the presence of a linear increase in knee alignment angle (measured medially) from self-reported severe varus to mild varus, straight, mild valgus and severe valgus deformity.
Results
Observer reproducibility (κ) was 0.89 and 0.81 for the knee malalignment and foot rotation instruments respectively. Self-reported participant reproducibility was also good for the knee (κ 0.73) and foot (κ 0.87) instruments. Validity was excellent for the knee malalignment instrument, with a sensitivity of 0.74 (95%CI 0.54, 0.93) and specificity of 0.97 (95%CI 0.94, 1.00). Similarly the foot rotation instrument was also found to have high sensitivity (0.92, 95%CI 0.83, 1.01) and specificity (0.96, 95%CI 0.93, 1.00). The knee alignment angle increased progressively from self reported severe varus to mild varus, straight, mild valgus and severe valgus knee malalignment (ptrend <0.001).
Conclusions
The two novel instruments appear to provide a valid and reliable assessment of self-reported knee malalignment and foot rotation, and may have a practical use in epidemiological studies.
doi:10.1186/1471-2288-10-57
PMCID: PMC2896354  PMID: 20565825
12.  Chronic health conditions and survival after out‐of‐hospital ventricular fibrillation cardiac arrest 
Heart  2007;93(6):728-731.
Objective
To investigate whether chronic clinical comorbidity, as collected from emergency medical services (EMS) reports, influences survival after out‐of‐hospital ventricular fibrillation (VF) cardiac arrest.
Methods
In this observational retrospective cohort study in King County, Washington, USA 1043 people who suffered out‐of‐hospital VF arrest due to heart disease between 1 January 1999 and 31 December 2003 were studied. Chronic conditions were ascertained and tallied from EMS reports using a uniform abstraction form by people blinded to outcome status. The outcome was survival to hospital discharge.
Results
75% (776/1043) of patients had at least one chronic health condition and 51% (529/1043) had prior clinically recognised heart disease. Overall, the increasing count of chronic conditions was inversely associated with the odds of survival to hospital discharge after adjustment for potential confounders (OR 0.84 (95% CI 0.74 to 0.95) for each additional chronic condition). The chronic condition–outcome association tended to be more prominent among those with longer EMS response intervals (p = 0.07 for interaction term between condition count and response interval). For example, the OR of survival was 0.72 (95% CI 0.59 to 0.88) for each additional chronic condition when the EMS response interval was 8 min compared with an OR of 0.95 (95% CI 0.79 to 1.14) when the EMS response interval was 3 min.
Conclusion
In this cohort, an increasing burden of clinical comorbidity based on a review of EMS reports was associated with a lower odds of survival after VF arrest. This finding suggests that chronic conditions influence arrest pathophysiology and in turn could help guide resuscitation care.
doi:10.1136/hrt.2006.103895
PMCID: PMC1955210  PMID: 17309904
13.  Performing meta-analysis with incomplete statistical information in clinical trials 
Background
Results from clinical trials are usually summarized in the form of sampling distributions. When full information (mean, SEM) about these distributions is given, performing meta-analysis is straightforward. However, when some of the sampling distributions only have mean values, a challenging issue is to decide how to use such distributions in meta-analysis. Currently, the most common approaches are either ignoring such trials or for each trial with a missing SEM, finding a similar trial and taking its SEM value as the missing SEM. Both approaches have drawbacks. As an alternative, this paper develops and tests two new methods, the first being the prognostic method and the second being the interval method, to estimate any missing SEMs from a set of sampling distributions with full information. A merging method is also proposed to handle clinical trials with partial information to simulate meta-analysis.
Methods
Both of our methods use the assumption that the samples for which the sampling distributions will be merged are randomly selected from the same population. In the prognostic method, we predict the missing SEMs from the given SEMs. In the interval method, we define intervals that we believe will contain the missing SEMs and then we use these intervals in the merging process.
Results
Two sets of clinical trials are used to verify our methods. One family of trials is on comparing different drugs for reduction of low density lipprotein cholesterol (LDL) for Type-2 diabetes, and the other is about the effectiveness of drugs for lowering intraocular pressure (IOP). Both methods are shown to be useful for approximating the conventional meta-analysis including trials with incomplete information. For example, the meta-analysis result of Latanoprost versus Timolol on IOP reduction for six months provided in [1] was 5.05 ± 1.15 (Mean ± SEM) with full information. If the last trial in this study is assumed to be with partial information, the traditional analysis method for dealing with incomplete information that ignores this trial would give 6.49 ± 1.36 while our prognostic method gives 5.02 ± 1.15, and our interval method provides two intervals as Mean ∈ [4.25, 5.63] and SEM ∈ [1.01, 1.24].
Conclusion
Both the prognostic and the interval methods are useful alternatives for dealing with missing data in meta-analysis. We recommend clinicians to use the prognostic method to predict the missing SEMs in order to perform meta-analysis and the interval method for obtaining a more cautious result.
doi:10.1186/1471-2288-8-56
PMCID: PMC2571096  PMID: 18706124
14.  Efficacy of topical non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis: meta-analysis of randomised controlled trials 
BMJ : British Medical Journal  2004;329(7461):324.
Objective To assess the efficacy of topical non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of osteoarthritis.
Data sources Medline, Embase, Scientific Citation Index, CINAHL, Cochrane Library, and abstracts from conferences.
Review methods Inclusion criterion was randomised controlled trials comparing topical NSAIDs with placebo or oral NSAIDs in osteoarthritis. Effect size was calculated for pain, function, and stiffness. Rate ratio was calculated for dichotomous data such as clinical response rate and adverse event rate. Number needed to treat to obtain the clinical response was estimated. Quality of trial was assessed, and sensitivity analyses were undertaken.
Results Topical NSAIDs were superior to placebo in relieving pain due to osteoarthritis only in the first two weeks of treatment. Effect sizes for weeks 1 and 2 were 0.41 (95% confidence interval, 0.16 to 0.66) and 0.40 (0.15 to 0.65), respectively. No benefit was observed over placebo in weeks 3 and 4. A similar pattern was observed for function, stiffness, and clinical response rate ratio and number needed to treat. Topical NSAIDs were inferior to oral NSAIDs in the first week of treatment and associated with more local side effects such as rash, itch, or burning (rate ratio 5.29, 1.14 to 24.51).
Conclusion Randomised controlled trials of short duration only (less than four weeks) have assessed the efficacy of topical NSAIDs in osteoarthritis. After two weeks there was no evidence of efficacy superior to placebo. No trial data support the long term use of topical NSAIDs in osteoarthritis.
doi:10.1136/bmj.38159.639028.7C
PMCID: PMC506853  PMID: 15286056
15.  Predictors of Change in Bodily Pain in Early Rheumatoid Arthritis: An Inception Cohort Study 
Arthritis Care & Research  2012;64(10):1505-1513.
Objective
To investigate possible predictors for lack of pain improvement after 1 year of treatment for early rheumatoid arthritis (RA).
Methods
The Early Rheumatoid Arthritis Network (ERAN) database was used for analysis of baseline and 1-year pain data. The ERAN is a hospital-based inception cohort of 1,189 people. Short Form 36 questionnaire bodily pain scores were used to calculate change in pain at 1 year as the outcome. The proportion of the Disease Activity Score in 28 joints (DAS28) attributable to patient-reported components (joint tenderness and visual analog scale score; DAS28-P) at baseline was derived as a predictor. Predictors of less improvement in pain were investigated using adjusted odds ratios (ORadj) generated by logistic regression, adjusting for 14 additional clinical and demographic covariates.
Results
Greater pain at baseline was associated with sex, high DAS28, worse mental health, and smoking. Most patients with early RA reported incomplete improvement in bodily pain after 1 year. The DAS28-P index did not significantly change in the patients whose disease remained active. Less improvement in pain was predicted by female sex (ORadj 3.41, 95% confidence interval [95% CI] 1.35–8.64) and a high DAS28-P index at baseline (ORadj for tertiles 2.09, 95% CI 1.24–3.55). Other conventional RA risk factors did not predict pain changes.
Conclusion
The factors most likely to predict less improvement in pain in early RA are female sex and a high DAS28-P index. A high DAS28-P index may reflect greater contributions of noninflammatory factors, such as central sensitization, to pain. Strategies in addition to inflammatory disease suppression may be required to adequately treat pain.
doi:10.1002/acr.21723
PMCID: PMC3770924  PMID: 22556121
16.  The genetic contribution to severe post-traumatic osteoarthritis 
Annals of the Rheumatic Diseases  2013;72(10):1687-1690.
Objective
to compare the combined role of genetic variants loci associated with risk of knee or hip osteoarthritis (OA) in post-traumatic (PT) and non-traumatic (NT) cases of clinically severe OA leading to total joint replacement.
Methods
A total of 1590 controls, 2168 total knee replacement (TKR) cases (33.2% PT) and 1567 total hip replacement (THR) cases (8.7% PT) from 2 UK cohorts were genotyped for 12 variants previously reported to be reproducibly associated with risk of knee or hip OA. A genetic risk score was generated and the association with PT and NT TKR and THR was assessed adjusting for covariates.
Results
For THR, each additional genetic risk variant conferred lower risk among PT cases (OR=1.07, 95% CI 0.96 to 1.19; p=0.24) than NT cases (OR 1.11, 95% CI 1.06 to 1.17; p=1.55×10−5). In contrast, for TKR, each risk variant conferred slightly higher risk among PT cases (OR 1.12, 95% CI 1.07 to 1.19; p=1.82×10−5) than among NT cases (OR 1.08, 95% CI 1.03 to 1.1; p=0.00063).
Conclusions
Based on the variants reported to date PT TKR cases have at least as high a genetic contribution as NT cases.
doi:10.1136/annrheumdis-2012-202562
PMCID: PMC3786638  PMID: 23355107
Osteoarthritis; Gene Polymorphism; Epidemiology
17.  The Ile585Val TRPV1 variant is involved in risk of painful knee osteoarthritis 
Annals of the Rheumatic Diseases  2011;70(9):1556-1561.
Objective
To assess if a coding variant in the gene encoding transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is associated with genetic risk of painful knee osteoarthritis (OA).
Methods
The Ile585Val TRPV1 variant encoded by rs8065080 was genotyped in 3270 cases of symptomatic knee OA, 1098 cases of asymptomatic knee OA and 3852 controls from seven cohorts from the UK, the USA and Australia. The genetic association between the low-pain genotype Ile–Ile and risk of symptomatic and asymptomatic knee OA was assessed.
Results
The TRPV1 585 Ile–Ile genotype, reported to be associated with lower thermal pain sensitivity, was associated with a lower risk of symptomatic knee OA in a comparison of symptomatic cases with healthy controls, with an odds ratio (OR) of 0.75 (95% CI 0.64 to 0.88; p=0.00039 by meta-analysis) after adjustment for age, sex and body mass index. No difference was seen between asymptomatic OA cases and controls (OR=1.02, 95% CI 0.82 to 1.27 p=0.86) but the Ile–Ile genotype was associated with lower risk of symptomatic versus asymptomatic knee OA adjusting for covariates and radiographic severity (OR=0.73, 95% CI 0.57 to 0.94 p=0.0136). TRPV1 expression in articular cartilage was increased by inflammatory cytokines (tumour necrosis factor α and interleukin 1). However, there were no differences in TRPV1 expression in healthy and arthritic synovial tissue.
Conclusions
A genotype involved in lower peripheral pain sensitivity is significantly associated with a decreased risk of painful knee OA. This indicates a role for the pro-nociceptive gene TRPV1 in genetic susceptibility to symptomatic knee OA, which may also be influenced by a role for this molecule in cartilage function.
doi:10.1136/ard.2010.148122
PMCID: PMC3147243  PMID: 21616913
18.  Genetic contribution to radiographic severity in osteoarthritis of the knee 
Annals of the Rheumatic Diseases  2012;71(9):1537-1540.
Objective
Knee osteoarthritis (OA) has a significant genetic component. The authors have assessed the role of three variants reported to influence risk of knee OA with p<5×10–8 in determining patellofemoral and tibiofemoral Kellgren Lawrence (K/L) grade in knee OA cases.
Methods
3474 knee OA cases with sky-line and weight-bearing antero-posterior x-rays of the knee were selected based on the presentation of K/L grade ≥2 at either the tibiofemoral or patellofemoral compartments for one or both knees. Patients belonging to three UK cohorts, were genotyped for rs143383, rs4730250 and rs11842874 mapping to the GDF5, COG5 and MCF2L genes, respectively. The association between tibiofemoral K/L grade and patellofemoral K/L grade was assessed after adjusting for age, gender and body mass index.
Results
No significant association was found between the rs4730250 and radiographic severity. The rs11842874 mapping to MCF2L was found to be nominally significantly associated with patellofemoral K/L grade as a quantitative trait (p=0.027) but not as a binary trait. The GDF5 single nucleotide polymorphism rs143383 was associated with tibiofemoral K/L grade (β=0.05 (95% CI 0.02 to 0.08) p=0.0011).
Conclusions
Our data indicate that within individuals affected by radiographic knee OA, OAGDF5 has a modest but significant effect on radiographic severity after adjustment for the major risk factors.
doi:10.1136/annrheumdis-2012-201382
PMCID: PMC3414227  PMID: 22615457

Results 1-18 (18)