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1.  Unilateral vs bilateral symptomatic knee osteoarthritis: associations between pain intensity and function 
Rheumatology (Oxford, England)  2013;52(12):2229-2237.
Objective. The objective of this study was to determine if associations between pain distribution (unilateral vs bilateral) and measures of function (self-report vs performance-based) were influenced by knee pain intensity of the painful knee(s) in persons with moderate to severe symptomatic knee OA.
Methods. Data from persons in the Osteoarthritis Initiative (OAI) dataset (n = 852) with symptomatic knee OA were studied. Key dependent variables were the WOMAC physical function, Knee Injury and Osteoarthritis Outcome Score (KOOS) quality of life, the repeated chair stand test and the 20-m walk test. In addition to covariates, the independent variables were the presence of unilateral or bilateral OA involvement (either Kellgren and Lawrence grade 3 or 4 or a grade <3) and pain category (mild, moderate or severe).
Results. WOMAC physical function scores consistently showed the strongest association with pain intensity for persons with unilateral vs bilateral knee pain. For example, in persons with unilateral severe knee pain, WOMAC scores averaged 19.9 (s.d. = 12.0) points while persons with bilateral knee pain with at least one knee rated as severe had WOMAC scores ranging from 25.3 to 28.9, depending on pain severity of the contralateral knee. These differences were statistically significant (P < 0.001) as was the test for trend (P = 0.001). Self-report measures generally showed larger effect sizes than performance-based measures.
Conclusion. Knee pain intensity influences self-report and performance-based tests differently depending on whether knee pain is unilateral or bilateral. WOMAC scores are most strongly associated with pain intensity in persons with unilateral vs bilateral pain while walking tests are least influenced by pain intensity.
doi:10.1093/rheumatology/ket291
PMCID: PMC3828512  PMID: 24026250
osteoarthritis; knee; pain; quality of life; performance; function; association; self-reported function; walking; validity
2.  Foot posture, foot function and low back pain: the Framingham Foot Study 
Rheumatology (Oxford, England)  2013;52(12):2275-2282.
Objective. Abnormal foot posture and function have been proposed as possible risk factors for low back pain, but this has not been examined in detail. The objective of this study was to explore the associations of foot posture and foot function with low back pain in 1930 members of the Framingham Study (2002–05).
Methods. Low back pain, aching or stiffness on most days was documented on a body chart. Foot posture was categorized as normal, planus or cavus using static weight-bearing measurements of the arch index. Foot function was categorized as normal, pronated or supinated using the centre of pressure excursion index derived from dynamic foot pressure measurements. Sex-specific multivariate logistic regression models were used to examine the associations of foot posture, foot function and asymmetry with low back pain, adjusting for confounding variables.
Results. Foot posture showed no association with low back pain. However, pronated foot function was associated with low back pain in women [odds ratio (OR) = 1.51, 95% CI 1.1, 2.07, P = 0.011] and this remained significant after adjusting for age, weight, smoking and depressive symptoms (OR = 1.48, 95% CI 1.07, 2.05, P = 0.018).
Conclusion. These findings suggest that pronated foot function may contribute to low back symptoms in women. Interventions that modify foot function, such as orthoses, may therefore have a role in the prevention and treatment of low back pain.
doi:10.1093/rheumatology/ket298
PMCID: PMC3828513  PMID: 24049103
low back pain; risk factors; flatfoot; gait
3.  Normative values for the Bath Ankylosing Spondylitis Metrology Index in a UK population 
Rheumatology (Oxford, England)  2013;52(11):2086-2090.
Objective. Spinal mobility is assessed frequently in patients with AS/axial SpA using the BASMI to provide baseline measurement and monitor change over time. The interpretation of BASMI scores has been hindered by the absence of normative values. We aimed to obtain normative values for the BASMI in healthy men and women in a UK population.
Methods. A cross-sectional study of 168 volunteers stratified by gender and age was completed. Exclusion criteria comprised factors potentially influencing spinal mobility. Each component of the BASMI was assessed, with the total score computed using the 10-point scoring system. Measurements were taken by physiotherapists following an agreed protocol. Data were summarized and analysed with age-specific centiles and CIs calculated.
Results. Total BASMI scores ranged from 0 to 4.4, with only 1.2% of the sample having a score of 0. The estimated median score for an individual age 25 years was 0.9, increasing with age to 2.1 for an individual age 65 years. There was a corresponding increase in component BASMI scores, which was more pronounced for some components than others.
Conclusion. Our data indicate that it is unusual for healthy individuals to score zero on the BASMI, which has implications for the interpretation of scores, especially at baseline. The generation of normative values has the potential to inform clinical assessment of spinal mobility and assist patients in understanding how their spinal mobility compares with that of a healthy age-matched population.
doi:10.1093/rheumatology/ket272
PMCID: PMC3798717  PMID: 23962624
ankylosing spondylitis; axial spondyloarthritis; BASMI; spinal mobility; normative; age
4.  Vitamin D deficiency does not predict progression of coronary artery calcium, carotid intima–media thickness or high-sensitivity C-reactive protein in systemic lupus erythematosus 
Rheumatology (Oxford, England)  2013;52(11):2071-2076.
Objective. Vitamin D deficiency is common in SLE. Cardioprotective effects of vitamin D have been postulated due to modulation of inflammatory cytokines. However, the effects of vitamin D supplementation on inflammatory cytokines in trials have been inconsistent. We determined whether levels of vitamin D at baseline were associated with subclinical measures of atherosclerosis, or with changes in subclinical measures over 2 years.
Methods. Of the 200 patients enrolled in the Lupus Atherosclerosis Prevention Study, complete baseline and follow-up data [including coronary artery calcium (CAC), carotid intima–media thickness (IMT), 25-hydroxy vitamin D [25(OH)D] and high-sensitivity CRP (hsCRP) levels] were available for 154 patients. Assessments were repeated 2 years later.
Results. 25(OH)D values ranged from 4 to 79 ng/ml. Among African American patients, 25(OH)D values ranged from 4 to 55 ng/ml. With low 25(OH)D (vitamin D <21 ng/ml), a higher proportion had a CAC score >100 (11%) compared with those with vitamin D insufficiency (21–32 ng/ml) (10%) and normal (≥32 ng/ml) 25(OH)D (3%), which was not statistically significant. 25(OH)D was neither associated with nor did it predict progression of CAC or carotid IMT over 2 years. The mean hsCRP decreased over 2 years.
Conclusion. 25(OH)D was not associated with any measure of subclinical atherosclerosis. 25(OH)D deficiency was associated with higher hsCRP at baseline, but did not predict a change in hsCRP over 2 years.
doi:10.1093/rheumatology/ket271
PMCID: PMC3798716  PMID: 23955647
systemic lupus erythematosus; atherosclerosis; vitamin D
5.  Comorbidities are associated with poorer outcomes in community patients with rheumatoid arthritis 
Rheumatology (Oxford, England)  2013;52(10):1809-1817.
Objective. To evaluate the impact of comorbidities on achieving remission by examining changes in the clinical disease activity index (CDAI) in RA patients in the community-based Consortium of Rheumatology Researchers of North America (CORRONA) registry.
Methods. A subcohort of 1548 RA subjects with varying disease duration met the following inclusion criteria: started a DMARD/biologic agent, continued therapy ≥3 months, CDAI ≥2.8 at study entry and followed longitudinally from baseline to follow-up (mean time 7.46 months). Patients reported comorbidities according to a standardized list of 33 conditions. Entry characteristics were compared across age categories using one-way analysis of variance. Linear and logistic regression models were constructed to assess characteristics [e.g. age, disease duration, number of previous DMARDs/biologics, baseline modified health assessment questionnaire (MHAQ), baseline CDAI and number of comorbidities] associated with primary outcomes: change in CDAI (baseline to follow-up) and CDAI remission (yes/no).
Results. Although disease activity measures at entry were similar across age categories, older patients had more comorbidities, less improvement in CDAI/MHAQ and were less likely to attain remission at follow-up. However, after adjusting covariates an increasing number of patient-reported comorbidities and higher baseline CDAI (but not age) were consistently and independently associated with a lower likelihood of clinical improvement or remission (P < 0.001).
Conclusion. In this observational cohort of community RA patients an increasing number of patients reported comorbidities, independently correlated with less CDAI improvement over time. These results reaffirm that comorbidities may be an important factor in consideration of treat-to-target recommendations and aid in understanding achievable RA therapeutic goals.
doi:10.1093/rheumatology/ket224
PMCID: PMC3775293  PMID: 23813577
comorbidities; rheumatoid arthritis; age; remission
6.  The effect of golimumab on haemoglobin levels in patients with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis 
Rheumatology (Oxford, England)  2013;52(10):1845-1855.
Objective. To evaluate the effect of golimumab on haemoglobin levels in patients with RA, PsA or AS.
Methods. Secondary analysis was performed on integrated data from five randomized controlled studies: three RA, one PsA and one AS (2303 patients total). Golimumab 50 or 100 mg was injected s.c. every 4 weeks with or without MTX. Control groups received placebo injections plus MTX or background therapy. Patients with haemoglobin levels below the age- and sex-specific normal ranges were considered to have anaemia. Ferritin levels were used to distinguish anaemia of mixed aetiology (≥15 and <60 ng/ml) and anaemia of inflammation (≥60 ng/ml). Changes from baseline to weeks 14 and 24 in haemoglobin level were compared between treatment groups using an analysis of variance on the van der Waerden normal scores.
Results. At baseline, 21% of RA patients, 9% of PsA patients and 15% of AS patients had anaemia. Of these, 24%, 57% and 25%, respectively, had anaemia of inflammation. The median increase from baseline to week 14 in the haemoglobin level of anaemic patients was 0.3 g/dl in the control group and 0.9 g/dl in the golimumab group (P < 0.001). Haemoglobin levels improved within the subgroups of patients with anaemia of mixed aetiology (control, 0.4 g/dl vs golimumab, 0.7 g/dl) (P = 0.305) and with anaemia of inflammation (0.2 vs 1.4 g/dl, respectively) (P < 0.001).
Conclusion. Compared with the control group, patients receiving golimumab treatment had significantly improved haemoglobin levels, particularly among patients with anaemia of inflammation.
doi:10.1093/rheumatology/ket233
PMCID: PMC3775295  PMID: 23838027
rheumatoid arthritis; anaemia; anti-TNF-α agent; golimumab; psoriatic arthritis; ankylosing spondylitis
7.  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.
doi:10.1093/rheumatology/ket154
PMCID: PMC4047282  PMID: 23611919
gout; classification; urate; research
8.  Associations between preoperative functional status and functional outcomes of total joint replacement in the Dominican Republic 
Rheumatology (Oxford, England)  2013;52(10):1802-1808.
Objective. In developed countries, the functional status scores of patients with poor preoperative scores undergoing total joint replacement (TJR) improve more following TJR than those for patients with better preoperative scores. However, those with better preoperative scores achieve the best postoperative functional outcomes. We determined whether similar associations exist in a developing country.
Methods. Dominican patients undergoing total hip or knee replacement completed WOMAC and SF-36 surveys preoperatively and at 12-month follow-up. Patients were stratified into low-, medium- and high-scoring preoperative groups based on their preoperative WOMAC function scores. We examined the associations between the baseline functional status of these groups and two outcomes—improvement in functional status over 12 months and functional status at 12 months—using analysis of variance with multivariable linear regression.
Results. Patients who scored the lowest preoperatively made the greatest gains in function and pain relief following their TJRs. However, there were no significant differences in pain or function at 12-month follow-up between patients who scored low and those who scored high on preoperative WOMAC and SF-36 surveys.
Conclusion. Patients with poor preoperative functional status had greater improvement but similar 12-month functional outcomes compared with patients who had a higher level of function before surgery. These results suggest that a policy of focusing scarce resources on patients with worse functional status in developing countries may optimize improvement following TJR without threatening functional outcome. Additional research is needed to confirm these findings in other developing countries and to understand why these associations vary between patients in the Dominican Republic and patients from developed countries.
doi:10.1093/rheumatology/ket180
PMCID: PMC3775292  PMID: 23748412
international; joint replacement; medical mission; knee hip arthroplasty; improvement patterns
9.  Predictors of self-reported health-related quality of life in systemic lupus erythematosus 
Rheumatology (Oxford, England)  2013;52(9):1651-1657.
Objective. The Medical Outcomes Short Form-36 Survey (SF-36) has been widely used as a measure of health-related quality of life (HRQOL) in different populations. SLE patients have consistently reported lower scores compared with the general population. The objective of our study was to identify predictors of HRQOL using SF-36 among patients with SLE enrolled in a 2-year randomized controlled trial (RCT).
Methods. We analysed 200 SLE patients enrolled in the Lupus Atherosclerosis Prevention Study (LAPS), an RCT of atorvastatin vs placebo, who completed SF-36 at qualifying, 12- and 24-month (final) visits.
Results. At baseline, mean SF-36 domain scores were lower than those of age- and gender-matched population norms. There was no statistical difference reported between Physical Component Summary (PCS), Mental Component Summary and eight domain scores in the atorvastatin vs placebo group at 2 years. In multiple regression analyses, African American patients reported significantly lower scores in Physical Functioning compared with Caucasians. The presence of FM was significantly associated with lower scores in physical functioning, role physical, bodily pain, general health, vitality, social functioning and lower overall mean PCS scores. The Physician’s Global Assessment of disease activity was associated with multiple SF-36 domains in univariate analysis.
Conclusion. This longitudinal study confirmed lower scores reported across all SF-36 domains. No one explanatory variable was independently associated with all domain scores. FM was independently associated with poorer HRQOL in most domains, underscoring the need for effective treatments for FM in SLE.
doi:10.1093/rheumatology/ket171
PMCID: PMC3741477  PMID: 23681396
SLE; SF-36; HRQOL; fibromyalgia; statins; disease activity; PCS; MCS; disease activity indices; spydergram
10.  Persistent antiphospholipid antibodies do not contribute to adverse pregnancy outcomes 
Rheumatology (Oxford, England)  2013;52(9):1642-1647.
Objective. To determine whether women with persistent aPL (>12 weeks apart on at least two separate occasions) without a history of thrombosis or adverse pregnancy outcome had the same adverse pregnancy outcomes as those with obstetric APS or unmatched controls.
Methods. This was a case–control study between 2005 and 2011 where we identified 73 women with persistent aPL and coincidentally the same number with obstetric APS. Unmatched controls were identified from low-risk clinics (ratio 1:4). Women with multiple pregnancies, fetal anomalies, SLE, thrombotic APS and other thrombophilias were excluded.
Results. Cases and controls were demographically similar, with the exception of younger controls with fewer medical comorbidities. aPL profiles were similar between aPL and APS. In women with aPL, risk of APS-type complications (odds ratio 1.3; 95% CI 0.6, 2.9) and birthweight distribution (median birthweight on a customized centile was 50.8, interquartile range 26.4–68.9; P < 0.05) were similar to controls. These findings persisted even after adjustment for maternal age and medical comorbidities.
Conclusion. Women with persistent aPL on aspirin had pregnancy outcomes that were similar to controls. These data suggest that in the absence of other risk factors, women with aPL do not need intense antenatal surveillance or modified management in pregnancy.
doi:10.1093/rheumatology/ket173
PMCID: PMC3741478  PMID: 23681394
anti-phospholipid antibodies; antiphospholipid syndrome; pregnancy outcomes; placental insufficiency; pre-eclampsia; small for gestational age; adverse outcomes; intrauterine death; fetal growth; pregnancy loss
11.  Primary care providers’ knowledge, beliefs and treatment practices for gout: results of a physician questionnaire 
Rheumatology (Oxford, England)  2013;52(9):1623-1629.
Objective. We sought to examine primary care providers’ gout knowledge and reported treatment patterns in comparison with current treatment recommendations.
Methods. We conducted a national survey of a random sample of US primary care physicians to assess their treatment of acute, intercritical and tophaceous gout using published European and American gout treatment recommendations and guidelines as a gold standard.
Results. There were 838 respondents (response rate of 41%), most of whom worked in private practice (63%) with >16 years experience (52%). Inappropriate dosing of medications in the setting of renal disease and lack of prophylaxis when initiating urate-lowering therapy (ULT) accounted for much of the lack of compliance with treatment recommendations. Specifically for acute podagra, 53% reported avoidance of anti-inflammatory drugs in the setting of renal insufficiency, use of colchicine at a dose of ≤2.4 mg/day and no initiation of a ULT during an acute attack. For intercritical gout in the setting of renal disease, 3% would provide care consistent with the recommendations, including initiating a ULT at the appropriate dose with dosing titration to a serum urate level of ≤6 mg/dl and providing prophylaxis. For tophaceous gout, 17% reported care consistent with the recommendations, including ULT use with dosing titration to a serum urate level of ≤6 mg/dl and prophylaxis.
Conclusion. Only half of primary care providers reported optimal treatment practices for the management of acute gout and <20% for intercritical or tophaceous gout, suggesting that care deficiencies are common.
doi:10.1093/rheumatology/ket158
PMCID: PMC3741476  PMID: 23620554
gout knowledge; medication use; treatment practices
12.  Inadequate pain relief and large functional loss among patients with knee osteoarthritis: evidence from a prospective multinational longitudinal study of osteoarthritis real-world therapies 
Rheumatology (Oxford, England)  2014;54(2):270-277.
Objective. To estimate the prevalence of inadequate pain relief (IPR) among patients with symptomatic knee OA prescribed analgesic therapy and to characterize patients with IPR.
Methods. Patients ≥50 years old with physician-diagnosed knee OA who had taken topical or oral pain medication for at least 14 days were recruited for this prospective non-interventional study in six European countries. Pain and function were assessed using the Brief Pain Inventory (BPI) and the WOMAC; quality of life (QoL) was assessed using the 12-item short form. IPR was defined as an average pain score of >4 out of 10 on BPI question 5.
Results. Of 1187 patients enrolled, 68% were female and the mean age was 68 years (s.d. 9); 639 (54%) met the definition of IPR. Patient responses for the BPI average pain question were well correlated with responses on the WOMAC pain subscale (Spearman r = 0.64, P < 0.001). In multivariate logistic regression, patients with IPR had greater odds of being female [adjusted odds ratio (adjOR) 1.90 (95% CI 1.46, 2.48)] and having OA in both knees [adjOR 1.48 (95% CI 1.15, 1.90)], higher BMI, longer OA duration, depression or diabetes. Patients with IPR (vs non-IPR) were more likely to have worse QoL, greater function loss and greater pain interference.
Conclusion. IPR is common among patients with knee OA requiring analgesics and is associated with large functional loss and impaired QoL. Patients at particular risk of IPR, as characterized in this study, may require greater attention towards their analgesic treatment options.
Trial registration: https://clinicaltrials.gov/ (NCT01294696).
doi:10.1093/rheumatology/keu332
PMCID: PMC4301711  PMID: 25150513
analgesic therapy; inadequate pain relief; knee; osteoarthritis
13.  Impact of musculoskeletal pain on insomnia onset: a prospective cohort study 
Rheumatology (Oxford, England)  2014;54(2):248-256.
Objective. Pain, the most common manifestation of rheumatological conditions, is highly prevalent among older adults, with worse health outcomes found in those with co-morbid insomnia. Proactive prevention of insomnia may reduce the overall disease burden of pain and rheumatological conditions. To inform such development, this study examined the role of pain, physical limitation and reduced social participation in predicting and mediating insomnia onset.
Methods. A prospective cohort study was conducted involving 6676 individuals ≥50 years of age who completed questionnaires at baseline and a 3-year follow-up. Participants were classified into none, some and widespread pain according to the ACR criteria. Logistic regression was used to examine the relationship between baseline pain and insomnia onset at 3 years. Path analysis was used to test for the mediating role of physical limitation and social participation restriction.
Results. Some [adjusted odds ratio (AOR) 1.57 (95% CI 1.15, 2.13)] and widespread [2.13 (1.66, 3.20)] pain increased the risk of insomnia onset at 3 years, after adjusting for age, gender, socio-economic class, education, anxiety, depression, sleep and co-morbidity at baseline. The combination of physical limitation and reduced social participation explained up to 68% of the effect of some pain on insomnia onset and 66% of the effect of widespread pain on insomnia onset.
Conclusion. There was a dose–response association between the extent of pain at baseline and insomnia onset at 3 years that was substantially mediated by physical limitation and reduced social participation. Targeting physical limitation and social participation in older people with pain may buffer co-morbid insomnia, reducing the overall disease burden.
doi:10.1093/rheumatology/keu283
PMCID: PMC4301708  PMID: 25125589
musculoskeletal; widespread pain; insomnia; sleep; cohort study; physical function; social participation
14.  A central role of plasmin in cardiac injury initiated by fetal exposure to maternal anti-Ro autoantibodies 
Rheumatology (Oxford, England)  2013;52(8):1448-1453.
Objective. Cardiac neonatal lupus (cardiac-NL), initiated by surface binding of anti-Ro60 autoantibodies to apoptotic cardiocytes during development, activates the urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) system. Subsequent accumulation of apoptotic cells and plasmin generation facilitates increased binding of anti-Ro60 by disrupting and cleaving circulating β2-glycoprotein I (β2GPI) thereby eliminating its protective effect. The association of soluble levels of components of the uPA/uPAR system with cardiac-NL was examined.
Methods. Levels of the uPA/uPAR system were assessed by ELISA in cord blood and immunohistological evaluation of autopsies.
Results. uPA, uPAR and plasminogen levels were each significantly higher in cord blood from cardiac-NL (n = 35) compared with non-cardiac-NL (n = 26) anti-Ro-exposed neonates: 3.3 ± 0.1 vs 1.9 ± 0.05 ng/ml (P < 0.0001), 6.6 ± 0.3 vs 2.1 ± 0.2 ng/ml (P < 0.0001) and 435 ± 34 vs 220 ± 19 ng/ml (P < 0.0001), respectively. In three twin pairs discordant for cardiac-NL, the twin with cardiac-NL had higher levels of uPA, uPAR and plasminogen than the unaffected twin (3.1 ± 0.1 vs 1.9 ± 0.05 ng/ml; P = 0.0086, 6.2 ± 1.4 vs 2.2 ± 0.7 ng/ml; P = 0.147 and 412 ± 61 vs 260 ± 27 ng/ml; P = 0.152, respectively). Immunohistological evaluation of three hearts from fetuses dying with cardiac-NL revealed macrophages and giant cells expressing uPA and plasminogen in the septal region.
Conclusion. Increased soluble uPA, uPAR and plasminogen in cord blood and expression in affected tissue of fetuses with cardiac-NL supports the hypothesis that fetal cardiac injury is in part mediated by plasmin generation initiated by anti-Ro binding to the apoptotic cardiocyte.
doi:10.1093/rheumatology/ket156
PMCID: PMC3708522  PMID: 23598443
apoptosis; fibrosis; inflammation
16.  Calcinosis in juvenile dermatomyositis is influenced by both anti-NXP2 autoantibody status and age at disease onset 
Rheumatology (Oxford, England)  2014;53(12):2204-2208.
Objective. Calcinosis is a major cause of morbidity in JDM and has previously been linked to anti-NXP2 autoantibodies, younger age at disease onset and more persistent disease activity. This study aimed to investigate the clinical associations of anti-NXP2 autoantibodies in patients with JDM stratified by age at disease onset.
Methods. A total of 285 patients with samples and clinical data were recruited via the UK Juvenile Dermatomyositis Cohort and Biomarker Study. The presence of anti-NXP2 was determined by both immunoprecipitation and ELISA. Logistic regression analysis was performed to assess the age-dependent relationship between anti-NXP2 and the development of calcinosis and disease activity measures.
Results. We identified anti-NXP2 autoantibodies in 56 patients (20%). While in all patients younger age at disease onset was associated with an increased risk of calcinosis and this relationship was nearly linear, anti-NXP2 autoantibodies substantially increased the risk of calcinosis across all ages (P = 0.025) and were detectable prior to calcinosis development. Children with anti-NXP2 autoantibodies had a greater degree of weakness (median lowest ever Childhood Myositis Assessment Score 29.6 vs 42) and were less likely to be in remission at 2 years post-diagnosis. No difference in disease activity was seen 4 years post-diagnosis.
Conclusion. Children diagnosed at a young age have a high risk of calcinosis regardless of autoantibody status. However, the presence of anti-NXP2 autoantibodies substantially increases the risk of calcinosis across all ages and is associated with disease severity.
doi:10.1093/rheumatology/keu259
PMCID: PMC4241891  PMID: 24987158
juvenile dermatomyositis; autoantibody; calcinosis; age
17.  Pain at multiple body sites and health-related quality of life in older adults: results from the North Staffordshire Osteoarthritis Project 
Rheumatology (Oxford, England)  2014;53(11):2071-2079.
Objectives. Number of pain sites (NPS) is a potentially important marker of health-related quality of life (HRQoL) but remains unexplored in older people. This cross-sectional study investigated whether, in older people including the oldest old, NPS was independently associated with poorer mental and physical HRQoL and if the association was moderated by age.
Methods. A postal questionnaire sent to a population sample of adults aged ≥50 years in North Staffordshire, UK, included the 12-item Short Form Health Survey (SF-12) mental component summary (MCS) and physical component summary (PCS), a blank body pain manikin, socio-demographic, health behaviour and morbidity questions. Participants shaded sites of pain lasting ≥1 day in the past 4 weeks on the manikin. OA consultation data were obtained for participants consenting to medical records review.
Results. A total of 13 986 individuals (adjusted response 70.6%) completed a questionnaire, of which 12 408 provided complete pain data. The median NPS reported was 4 [interquartile range (IQR) 0–8]. General linear models showed that an increasing NPS was significantly associated with poorer MCS (β = −0.43, 95% CI −0.46, −0.40) and PCS (β = −0.87, 95% CI −0.90, −0.84). Adjustment for covariates attenuated the associations but they remained significant (MCS: β = −0.28, 95% CI −0.31, −0.24; PCS: β = −0.63, 95% CI −0.66, −0.59). The association between NPS and MCS or PCS was moderated by age, but the strongest associations were not in the oldest old.
Conclusion. NPS appears to be a potentially modifiable target for improving physical and mental HRQoL in older people. Future analyses should investigate the influence of NPS on HRQoL over time in older people.
doi:10.1093/rheumatology/keu240
PMCID: PMC4202023  PMID: 24925881
aged; cross-sectional survey; health-related quality of life; mental health; multisite pain; pain sites; physical health
18.  Cardiovascular risk in rheumatoid arthritis: recent advances in the understanding of the pivotal role of inflammation, risk predictors and the impact of treatment 
Rheumatology (Oxford, England)  2014;53(12):2143-2154.
Risk of cardiovascular (CV) disease is increased among RA patients. High inflammatory burden associated with RA appears to be a key driver of the increased cardiovascular risk. Inflammation is linked with accelerated atherosclerosis and associated with a paradoxical inversion of the relationship between CV risk and lipid levels in patients with untreated RA, recently coined the lipid paradox. Furthermore, the inflammatory burden is also associated with qualitative as well as quantitative changes in lipoproteins, with the anti-inflammatory and atheroprotective roles associated with high-density lipoprotein cholesterol significantly altered. RA therapies can increase lipid levels, which may reflect the normalization of lipids due to their inflammatory-dampening effects. However, these confounding influences of inflammation and RA therapies on lipid profiles pose challenges for assessing CV risk in RA patients and interpretation of traditional CV risk scores. In this review we examine the relationship between the increased inflammatory burden in RA and CV risk, exploring how inflammation influences lipid profiles, the impact of RA therapies and strategies for identifying and monitoring CV risk in RA patients aimed at improving CV outcomes.
doi:10.1093/rheumatology/keu224
PMCID: PMC4241890  PMID: 24907149
rheumatoid arthritis; cardiovascular disease; inflammation; atherosclerosis; dyslipidaemias; anti-rheumatic agents
19.  Delphinidin inhibits IL-1β-induced activation of NF-κB by modulating the phosphorylation of IRAK-1Ser376 in human articular chondrocytes 
Rheumatology (Oxford, England)  2013;52(6):998-1008.
Objective. In OA, there is enhanced expression of pro-inflammatory cytokines such as IL-1β in the affected joint. Delphinidin, an anthocyanidin found in pigmented fruits and vegetables, has been shown to possess anti-inflammatory and antioxidant properties. In the present study we determined whether delphinidin would inhibit the IL-1β-induced activation of NF-κB in human chondrocytes and determined the mechanism of its action.
Methods. PGE2 levels and activation of NF-κB p65 in human OA chondrocytes were determined by ELISA-based assays. Protein expression of cyclo-oxygenase-2 (COX-2) and phosphorylation of kinases was determined by western immunoblotting. Expression level of mRNAs was determined by TaqMan assays.
Results. Delphinidin inhibited IL-1β-induced expression of COX-2 and production of PGE2 in human chondrocytes. Delphinidin also inhibited IL-1β-mediated phosphorylation of IL-1 receptor-associated kinase-1Ser376, phosphorylation of IKKα/β, expression of IKKβ, degradation of IκBα, and activation and nuclear translocation of NF-κB/p65. Phosphorylation of TGF-β-activated kinase 1 was not observed but NF-κB-inducing kinase (NIK) was phosphorylated and phosphorylation of NIK was blocked by delphinidin in IL-1β-treated human chondrocytes.
Conclusion. These data identify delphinidin as a novel inhibitor of IL-1β-induced production of cartilage-degrading molecule PGE2 via inhibition of COX-2 expression and provide new insight into the mechanism of its action. Our results also identify inhibition of IRAK1Ser376 phosphorylation by delphinidin in IL-1β-induced activation of NF-κB in human chondrocytes. Given the important role played by IL-1β-induced NF-κB activation, COX-2 expression and PGE2 production in OA, our results may have important implications for the development of novel therapeutic strategies for the prevention/treatment of OA.
doi:10.1093/rheumatology/kes363
PMCID: PMC3651611  PMID: 23392593
osteoarthritis; IL-1β; delphinidin; chondrocytes; NF-κB; COX-2; PGE2
20.  Patient-level clinically meaningful improvements in activities of daily living and pain after total hip arthroplasty: data from a large US institutional registry 
Rheumatology (Oxford, England)  2013;52(6):1109-1118.
Objective. To characterize patient-level clinically meaningful improvements in pain and limitation of key activities of daily living (ADLs) after primary or revision total hip arthroplasty (THA).
Methods. We analysed prospectively collected data from the Mayo Clinic Total Joint Registry to study clinically meaningful improvements in index hip pain severity and limitation in seven key ADLs (walking, climbing stairs, putting on shoes/socks, picking up objects, getting in/out of car, rising from a chair and sitting), from preoperative to 2- and 5-year post-THA.
Results. The primary THA cohort consisted of 6168 responders preoperatively, 5707 at 2 years and 3289 at 5 years postoperatively. The revision THA cohort consisted of 2063 responders preoperatively, 2682 at 2 years and 1627 at 5 years postoperatively. In the primary THA cohort, clinically meaningful pain reduction to mild or no hip pain at 2 years was reported by 94% with moderate and 91% with severe preoperative pain; respective proportions were 91% and 89% at 5-year follow-up. For revision THA, respective proportions were 84% and 77% at 2 years and 80% and 78% at 5 years. In the primary THA cohort, up to 4% with moderate and 17% with severe preoperative ADL limitation reported severe limitation in the respective activity 2 years post-primary THA; at 5 years, the respective proportions were up to 7% and 20%. Respective proportions for revision THA were up to 10% and 26% at 2 years and 13% and 30% at 5 years.
Conclusions. These comprehensive data for patient-level clinically meaningful improvements in pain and seven key ADLs can help patients set realistic goals for improvement after THA.
doi:10.1093/rheumatology/kes416
PMCID: PMC3651614  PMID: 23382362
pain; activity limitation; activities of daily living; function; functional limitation; total hip replacement; arthroplasty; joint replacement; outcomes; patient-reported outcomes; primary; revision
21.  Telomere length in patients with systemic lupus erythematosus and its associations with carotid plaque 
Rheumatology (Oxford, England)  2013;52(6):1101-1108.
Objective. To evaluate telomere length (TL) between patients with SLE and healthy controls and to test if TL is associated with carotid plaque.
Methods. A pilot study of 154 patients with SLE and 152 controls was performed from the SOLVABLE (Study of Lupus Vascular and Bone Long-Term Endpoints) cohort. Demographic and cardiovascular disease (CVD) factors were collected at baseline. The presence or absence of plaque was evaluated by B-mode US. Genomic DNA was isolated from whole peripheral blood. TL was quantified using real-time quantitative PCR.
Results. SLE women had a short TL compared with healthy controls (4.57 vs 5.44 kb, P = 0.03). SLE women showed shorter TL than controls across all age groups: <35 years (4.38 vs 6.37 kb), 35–44 years (4.52 vs 5.30 kb), 45–54 years (4.77 vs 5.68 kb) and ≥55 years (4.60 vs 4.71 kb). Among patients with SLE and carotid plaque there was a trend towards shorter TL at a younger age and it was significantly lower in the 35- to 44-year age group when compared with controls (P = 0.025). Multiple logistic regression analysis indicated a risk of carotid plaque with older age [odds ratio (OR) 1.09; 95% CI 1.06, 1.12] but not with TL (OR 1.05; 95% CI 0.97, 1.13).
Conclusion. SLE women had significantly shorter TL than controls. SLE women trended towards shorter TL at a younger age. When carotid plaque was identified, the younger SLE women had shorter TL. Only older age but not shorter TL was independently associated with carotid plaque. Additional studies are needed to confirm if TL is a novel biomarker for cardiovascular disease in SLE.
doi:10.1093/rheumatology/kes424
PMCID: PMC3651615  PMID: 23382361
systemic lupus erythematosus; cardiovascular disease; telomere length
22.  Medical and psychological comorbidity predicts poor pain outcomes after total knee arthroplasty 
Rheumatology (Oxford, England)  2013;52(5):916-923.
Objective. To study comorbidity correlates of moderate to severe pain after total knee arthroplasty (TKA).
Methods. We analysed prospectively collected Total Joint Registry data to examine whether medical (heart disease, peripheral vascular disease, renal disease, chronic obstructive pulmonary disease, diabetes and CTD) and psychological (anxiety and depression) comorbidity is associated with moderate to severe pain after primary or revision TKA. Multivariable-adjusted logistic regression simultaneously adjusted for all comorbidities, age, sex, BMI, underlying diagnosis, American Society of Anesthesiologist (ASA) class, distance from medical centre and implant fixation (only for primary TKA) was used to analyse primary and revision TKA separately.
Results. The primary TKA cohort consisted of 7139 and 4234 TKAs (response rates 65% and 57%) and the revision TKA cohort consisted of 1533 and 881 TKAs at 2 and 5 years (response rates 57% and 48%), respectively. In the primary TKA cohort, anxiety was associated with 1.4 higher odds (95% CI 1.0, 2.0) of moderate to severe index knee pain at 2 years; at 5 years, heart disease (OR 1.7; 95% CI 1.1, 2.6), depression (OR 1.7; 95% CI 1.1, 2.5) and anxiety (OR 1.9; 95% CI 1.2, 3.1) were significantly associated with moderate to severe pain. For revision TKA, CTD (OR 0.5; 95% CI 0.2, 0.9) and depression (OR 1.8; 95% CI 1.1, 3.1) were significantly associated with moderate to severe pain.
Conclusion. This study identified medical and psychological comorbidity risk factors for moderate to severe pain after primary and revision TKA. This information can be used to provide realistic outcome expectations for patients before undergoing primary or revision TKA.
doi:10.1093/rheumatology/kes402
PMCID: PMC3630396  PMID: 23325037
pain; function; functional limitation; total knee replacement; primary; arthroplasty; joint replacement; outcomes; patient-reported outcomes
23.  Low prevalence of coeliac disease in patients with systemic sclerosis: a cross-sectional study of a registry cohort 
Rheumatology (Oxford, England)  2013;52(5):939-943.
Objectives. Two prior studies suggested that coeliac disease (CD) has a higher prevalence rate (8%) in SSc than in the general population (1%), but these studies were limited by small numbers and the use of traditional coeliac screening antibody tests, where newer ones with improved accuracy have since emerged. Our aim was to determine the prevalence of CD in a larger SSc population using a more modern serological approach to coeliac testing and to correlate coeliac antibody status with gastrointestinal symptoms.
Methods. Stored sera from 72 SSc patients in the Scleroderma Registry at the Hospital for Special Surgery were tested for anti-tissue transglutaminase (traditional) and anti-deamidated gliadin peptide (novel) antibodies. If any of these antibodies were positive, anti-endomysial antibodies were tested and confirmatory small-bowel endoscopy and biopsy were obtained. Registry clinical data were used to determine whether antibody status correlated with gastrointestinal symptoms.
Results. The prevalence of coeliac antibodies in our SSc population was 3/72 (4%). No significant differences with respect to gastrointestinal symptoms were seen in the coeliac antibody-positive compared with -negative SSc patients. No cases of confirmed CD were seen in our cohort.
Conclusion. Contrary to the only two previously published studies, the low prevalence of CD that we found does not suggest that concurrent CD is a common cause of gastrointestinal complaints in SSc patients.
doi:10.1093/rheumatology/kes390
PMCID: PMC3716334  PMID: 23335635
scleroderma; systemic; coeliac disease; signs and symptoms; digestive; gastrointestinal diseases
24.  Benefits and risks of low-dose glucocorticoid treatment in the patient with rheumatoid arthritis 
Rheumatology (Oxford, England)  2014;53(10):1742-1751.
Glucocorticosteroids (GCs) have been employed extensively for the treatment of rheumatoid arthritis (RA) and other autoimmune and systemic inflammatory disorders. Their use is supported by extensive literature and their utility is reflected in their incorporation into current treatment guidelines for RA and other conditions. Nevertheless, there is still some concern regarding the long-term use of GCs because of their potential for clinically important adverse events, particularly with an extended duration of treatment and the use of high doses. This article systematically reviews the efficacy for radiological and clinical outcomes for low-dose GCs (defined as ≤10 mg/day prednisone equivalent) in the treatment of RA. Results reviewed indicated that low-dose GCs, usually administered in combination with synthetic DMARDs, most often MTX, significantly improve structural outcomes and decrease symptom severity in patients with RA. Safety data indicate that GC-associated adverse events are dose related, but still occur in patients receiving low doses of these agents. Concerns about side effects associated with GCs have prompted the development of new strategies aimed at improving safety without compromising efficacy. These include altering the structure of existing GCs and the development of delayed-release GC formulations so that drug delivery is timed to match greatest symptom severity. Optimal use of low-dose GCs has the potential to improve long-term outcomes for patients with RA.
doi:10.1093/rheumatology/keu135
PMCID: PMC4165844  PMID: 24729402
rheumatoid arthritis; glucocorticoids; prednisone; disease modifying; treatment strategies; benefit–risk
25.  Reporting of patient-perceived impact of rheumatoid arthritis and axial spondyloarthritis over 10 years: a systematic literature review 
Rheumatology (Oxford, England)  2014;53(7):1274-1281.
Objective. RA and axial SpA have an important impact on patients’ lives. The objective of this study was to explore the reporting of different aspects of that impact in publications, with a focus on differences between diseases and over time.
Methods. A systematic literature review retrieved all articles reporting on the life impact of RA or axial radiographic SpA in adults published within the last 10 years and issued from European research. The data were classified into physical impact (including pain, functional assessment and fatigue), psychological impact (including psychological distress and coping) and social impact (including relationships, family and social life). The number of articles published over time was analysed by linear regression.
Results. In all, 1352 abstracts were screened and 149 publications (40 056 patients) were analysed: 129 articles (86.5%) concerned RA and 16 (10.7%) concerned axial SpA. The mean number of articles reporting on the physical aspects of impact was 11.4 (s.d. 4.8) per 2-year period, but increased more than 2-fold (from 7 articles in 2001–3 to 15 in 2010–11), in particular due to recent publications on fatigue, whereas the number of articles on psychological aspects [mean 12.4 (s.d. 4.0)] decreased markedly after 2006. Publications reporting on social aspects [mean 8.2 (s.d. 4.1)] remained globally stable.
Conclusion. In the era of biologics, there is an interest in the patient-perceived life impact of RA and axial SpA in the European literature, but the impact of RA has been the subject of greater exploration. There are clearly trends over time in the reporting of impact.
doi:10.1093/rheumatology/ket480
PMCID: PMC4065006  PMID: 24602920
rheumatoid arthritis; spondyloarthritis; impact; quality of life; pain; fatigue; social; coping

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