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Background: Studies on long-term consequences of COVID-19, commonly referred to as post-COVID condition, in patients with inflammatory rheumatic diseases are scarce and inconclusive. Furthermore, classifying patients with inflammatory rheumatic diseases as having post-COVID condition is complicated because of overlapping symptoms. Therefore, we investigated the risk of post-COVID condition and time until recovery, and compared the prevalence of symptoms seen in post-COVID condition, between patients with inflammatory rheumatic diseases and healthy controls, with and without a history of COVID-19. Methods: In this substudy we used data from an ongoing prospective cohort study in the Netherlands. All adult patients with inflammatory rheumatic diseases from the Amsterdam Rheumatology and Immunology Center in Amsterdam, the Netherlands, were invited to participate in the study between April 26, 2020, and March 1, 2021. All patients were asked, but not obliged, to recruit their own control participant of the same sex, of comparable age (< 5 years), and without an inflammatory rheumatic disease. Demographic and clinical data, including data on the occurrence of SARS-CoV-2 infections, were collected via online questionnaires. On March 10, 2022, all study participants received a questionnaire on the occurrence, onset, severity, and duration of persistent symptoms during the first 2 years of the COVID-19 pandemic, independent of their history of SARS-CoV-2 infection. Additionally, we prospectively monitored a subset of participants who had a PCR or antigen confirmed SARS-CoV-2 infection in the 2-month period surrounding the questionnaire in order to assess COVID-19 sequelae. In line with WHO guidelines, post-COVID condition was defined as persistent symptoms that lasted at least 8 weeks, started after the onset and within 3 months of a PCR or antigen-confirmed SARS-CoV-2 infection, and could not be explained by an alternative diagnosis. Statistical analyses included descriptive statistics, logistic regression analyses, logistic-based causal mediation analyses, and Kaplan-Meier survival analyses for time until recovery from post-COVID condition. In exploratory analyses, E-values were calculated to investigate unmeasured confounding. Findings: A total of 1974 patients with inflammatory rheumatic disease (1268 [64%] women and 706 [36%] men; mean age 59 years [SD 13]) and 733 healthy controls (495 [68%] women and 238 [32%] men; mean age 59 years [12]) participated. 468 (24%) of 1974 patients with inflammatory rheumatic disease and 218 (30%) of 733 healthy controls had a recent SARS-CoV-2 omicron infection. Of those, 365 (78%) of 468 patients with inflammatory rheumatic disease and 172 (79%) of 218 healthy controls completed the prospective follow-up COVID-19 sequelae questionnaires. More patients than controls fulfilled post-COVID condition criteria: 77 (21%) of 365 versus 23 (13%) of 172 (odds ratio [OR] 1·73 [95% CI 1·04–2·87]; p=0·033). The OR was attenuated after adjusting for potential confounders (adjusted OR 1·53 [95% CI 0·90–2·59]; p=0·12). Among those without a history of COVID-19, patients with inflammatory diseases were more likely to report persistent symptoms consistent with post-COVID condition than were healthy controls (OR 2·52 [95% CI 1·92–3·32]; p

Contains fulltext : 251784.pdf (Publisher’s version ) (Closed access) BACKGROUND: Concerns have been raised regarding the risks of SARS-CoV-2 breakthrough infections in vaccinated patients with immune-mediated inflammatory diseases treated with immunosuppressants, but clinical data on breakthrough infections are still scarce. The primary objective of this study was to compare the incidence and severity of SARS-CoV-2 breakthrough infections between patients with immune-mediated inflammatory diseases using immunosuppressants, and controls (patients with immune-mediated inflammatory diseases not taking immunosuppressants and healthy controls) who had received full COVID-19 vaccinations. The secondary objective was to explore determinants of breakthrough infections of the delta (B.1.617.2) variant of SARS-CoV-2, including humoral immune responses after vaccination. METHODS: In this substudy, we pooled data collected in two large ongoing prospective multicentre cohort studies conducted in the Netherlands (Target to-B! [T2B!] study and Amsterdam Rheumatology Center COVID [ARC-COVID] study). Both studies recruited adult patients (age ≥18 years) with immune-mediated inflammatory diseases and healthy controls. We sourced clinical data from standardised electronic case record forms, digital questionnaires, and medical files. We only included individuals who were vaccinated against SARS-CoV-2. For T2B!, participants were recruited between Feb 2 and Aug 1, 2021, and for ARC-COVID, participants were recruited between April 26, 2020, and March 1, 2021. In this study we assessed data on breakthrough infections collected between July 1 and Dec 15, 2021, a period in which the delta SARS-CoV-2 variant was the dominant variant in the Netherlands. We defined a SARS-CoV-2 breakthrough infection as a PCR-confirmed or antigen test-confirmed SARS-CoV-2 infection that occurred at least 14 days after vaccination. All breakthrough infections during this period were assumed to be due to the delta variant due to its dominance during the study period. We analysed post-vaccination serum samples for anti-receptor binding domain (RBD) antibodies to assess the humoral vaccination response (T2B! study only) and anti-nucleocapsid antibodies to identify asymptomatic breakthrough infections (ARC-COVID study only). We used multivariable logistic regression analyses to explore potential clinical and humoral determinants associated with the odds of breakthrough infections. The T2B! study is registered with the Dutch Trial Register, Trial ID NL8900, and the ARC-COVID study is registered with Dutch Trial Register, trial ID NL8513. FINDINGS: We included 3207 patients with immune-mediated inflammatory diseases who receive immunosuppressants, and 1807 controls (985 patients with immune-mediated inflammatory disease not on immunosuppressants and 822 healthy controls). Among patients receiving immunosuppressants, mean age was 53 years (SD 14), 2042 (64%) of 3207 were female and 1165 (36%) were male; among patients not receiving immunosuppressants, mean age was 54 years (SD 14), 598 (61%) of 985 were female and 387 (39%) were male; and among healthy controls, mean age was 57 years (SD 13), 549 (67%) of 822 were female and 273 (33%) were male. The cumulative incidence of PCR-test or antigen-test confirmed SARS-CoV-2 breakthrough infections was similar in patients on immunosuppressants (148 of 3207; 4·6% [95% CI 3·9-5·4]), patients not on immunosuppressants (52 of 985; 5·3% [95% CI 4·0-6·9]), and healthy controls (33 of 822; 4·0% [95% CI 2·8-5·6]). There was no difference in the odds of breakthrough infection for patients with immune-mediate inflammatory disease on immunosuppressants versus combined controls (ie, patients not on immunosuppressants and healthy controls; adjusted odds ratio 0·88 [95% CI 0·66-1·18]). Seroconversion after vaccination (odds ratio 0·58 [95% CI 0·34-0·98]; T2B! cohort only) and SARS-CoV-2 infection before vaccination (0·34 [0·18-0·56]) were associated with a lower odds of breakthrough infections. INTERPRETATION: The incidence and severity of SARS-CoV-2 breakthrough infections in patients with immune-mediated inflammatory diseases on immunosuppressants was similar to that in controls. However, caution might still be warranted for those on anti-CD20 therapy and those with traditional risk factors. FUNDING: ZonMw (the Netherlands Organization for Health Research and Development) and Reade foundation.

Aims Hyperuricaemia and gout are strongly related with traditional cardiovascular risk factors and vascular damage. This study aimed to assess whether febuxostat and allopurinol could differently influence carotid-femoral pulse wave velocity (cfPWV) in patients with gout and elevated serum uric acid (SUA) levels. Methods and results A multi-centre, multinational, phase IV, randomized, parallel-group, active-controlled, open-label trial with blind endpoints evaluation. One hundred and ninety-seven adults with gout and SUA levels ≥8 mg/dL were randomized to febuxostat or allopurinol in a 1:1 ratio for 36 weeks. The primary outcome was the comparison of the effects of febuxostat and allopurinol on changes in cfPWV. The mean cfPWV values at randomization and Week 36 were 8.69 and 9.00 m/s, respectively for subjects randomized to febuxostat and 9.02 and 9.05 m/s for subjects randomized to allopurinol. No statistically significant changes in cfPWV by treatment assignment were observed at any time point for any of the assessed parameters. More subjects who received febuxostat had serum urate concentrations ≤6 mg/dL following treatment (78.3% vs. 61.1% at Week 36, P = 0.0137). Treatment-emergent adverse events were reported by 51 (52.0%) patients randomized to febuxostat and 63 (62.5%) patients randomized to allopurinol. The majority of events were mild in both treatment groups and included gout flares and arthralgia. Conclusion In patients with gout and elevated SUA levels the arterial stiffness remained stable both with febuxostat and allopurinol. Febuxostat was more effective and faster than allopurinol in achieving the SUA target. Both treatments were safe and well tolerated.

Objective To investigate the association between neutrophil activation and cardiovascular risk in gout patients. We hypothesize that neutrophil activation mediates inflammation and therefore takes part in atherogenesis in gout patients. Method Patient data were collected from 75 consecutive gout patients participating in the Reade gout cohort Amsterdam. Levels of neutrophil extracellular traps (NETs) and neutrophil activation (calprotectin and peroxidase activity) were analysed by ELISA and fluorimetry in plasma and compared with healthy controls. Markers of neutrophil activation were related to clinical markers of cardiovascular risk, including BMI, smoking, blood pressure, lipid profile and 10 year risk of cardiovascular mortality (EU-SCORE). Results Increased levels of NETs were found in gout patients, although increased levels were not associated with cardiovascular risk. However, markers of neutrophil activation, including peroxidase activity correlated with waist:hip ratio (β = 0.33, P Conclusion We demonstrated elevated levels of neutrophil activation markers, MPO and calprotectin in gout patients as compared with healthy controls. Of note, neutrophil activation markers were associated with several risk factors for cardiovascular disease, including hyperlipidaemia, hypertension and diabetes. Finally, the presence of a neutrophil activation signature was strongly associated with an increased 10 year risk of cardiovascular mortality. Further studies are needed to determine whether gout-specific factors and/or cardiovascular risk factors contribute to the elevated neutrophil activation observed in these patients.

Objectives To assess whether (i) high-intensity resistance training (RT) leads to increased muscle strength compared to low-intensity RT in patients with knee osteoarthritis (OA); and (ii) RT with vitamin D supplementation leads to increased muscle strength compared to placebo in a subgroup with vitamin D deficiency. Design Randomized controlled trial Setting Outpatient rehabilitation centre Subjects Patients with knee OA Interventions 12 weeks of RT at high-intensity RT (70–80% of 1-repetition maximum (1-RM)) or low-intensity RT (40–50% of 1-RM) and 24 weeks of vitamin D (1200 International units vitamin D3 per day) or placebo supplementation. Main measures Primary outcome measure was isokinetic muscle strength. Other outcome measure for muscle strength was the estimated 1-RM. Secondary outcome measures were knee pain and physical functioning. Results 177 participants with a mean age of 67.6 ± 5.8 years were included, of whom 50 had vitamin D deficiency. Isokinetic muscle strength (in Newton metre per kilogram bodyweight) at start, end and 24 weeks after the RT was 0.98 ± 0.40, 1.11 ± 0.40, 1.09 ± 0.42 in the high-intensity group and 1.02 ± 0.41, 1.15 ± 0.42, 1.12 ± 0.40 in the low-intensity group, respectively. No differences were found between the groups, except for the estimated 1-RM in favour of the high-intensity group. In the subgroup with vitamin D deficiency, no difference on isokinetic muscle strength was found between the vitamin D and placebo group. Conclusions High-intensity RT did not result in greater improvements in isokinetic muscle strength, pain and physical functioning compared to low-intensity RT in knee OA, but was well tolerated. Therefore these results suggest that either intensity of resistance training could be utilised in exercise programmes for patients with knee osteoarthritis. No synergistic effect of vitamin D supplementation and RT was found, but this finding was based on underpowered data.

Objective To investigate the factors associated with discordance between patient and physician on the presence of a gout flare. Methods Patients’ self-reports of current gout flares were assessed with the question, ‘Are you having a gout flare today?’ which was then compared with a concurrent, blinded, physician’s assessment. Based on agreement or disagreement with physicians on the presence of a gout flare, flares were divided into concordant and discordant groups, respectively. Within the discordant group, two subgroups—patient-reported flare but the physician disagreed and physician-reported flare but the patient disagreed—were identified. The factors associated with discordance were analysed with multivariable logistic regression analysis. Results Of 268 gout flares, 81 (30.2%) flares were discordant, with either patient or physician disagreeing on the presence of a flare. Of the discordant flares, in 57 (70.4%) the patient reported a flare but the physician disagreed. In multivariable logistic regression analysis adjusted for demographics, disagreement among patients and physicians on the presence of a gout flare was associated with lower pain scores at rest [odds ratio (OR) for each point increase on 0–10 point pain scale 0.81 (95% Wald CI 0.73, 0.90), P < 0.0001] and less presence of joint swelling [OR 0.24 (95% CI 0.10, 0.61), P = 0.003] or joint warmth [OR 0.39 (95% CI 0.20, 0.75), P = 0.005]. Conclusion Although patients and physicians generally agree about the presence of gout flare, discordance may occur in the setting of low pain scores and in the absence of swollen or warm joints.

Much to the liking of many geographers, Forbes Magazine’s contributor and professor in meteorology at the University of Georgia, J. Marshall Shepherd, wrote in early March 2020 an op‐ed titled ‘Why Geography is a key part of fighting the COVID‐19 Coronavirus outbreak’. In Wired, David Wolman (2020) wrote how the pandemic is redefining our relationship with space in a contribution titled ‘Amid a Pandemic, Geography Returns with a Vengeance’. Notwithstanding the many challenges that the Covid‐19 pandemic poses, both in our private lives and in our professional activities, it offers a great opportunity for analysis through a geographic lens. Geographical knowledge and geospatial data, perhaps best exemplified by the widely used Johns Hopkins University COVID‐19 tracking website, have already proven to be vital for understanding the pandemic’s reach. The uneven distribution of the virus across and within countries raises inherently geographic questions regarding the political, economic, financial, socio‐cultural and demographic dimensions of the pandemic. The aim of this special issue of Tijdschrift voor Economische en Sociale Geografie (TESG) is to present the initial investigations of geographers and socio‐spatial scientists into the emerging spaces of the effects of the COVID‐19 pandemic. Following a call, we have received well over 40 papers, thereby exceeding our expectations. After internal and external review of the papers we here present the papers that were selected for publication. We are thankful to the reviewers who provided fast, yet detailed, feedback on the papers. In addition, we would like to thank Grace Ong, Senior Journals Publishing Editor at Wiley, and Noel Valdivia, Production Editor, for their support in the publication of this special issue. The papers in this special issue present an interesting geographical mix (with case studies from Asia, Europe and the North America) as well as a variety of methodological approaches towards understanding the spatial manifestations and variegated geographic impact of the pandemic. Furthermore, they well represent the different thematic fields in geography. The editors of TESG welcome more papers on the consequences of the COVID‐19 pandemic, which we will have reviewed as we do with any other paper. We will not be able to fast‐track new submissions but we will publish new papers online in ‘Early View’ soon after they have been accepted for publication. Future papers on COVID‐19 will also be added to a Virtual Special Issue, which will consist of all papers published in this issue together with new papers on the geography of the pandemic. As much as possible we aim for the open access publication of these papers. The papers in this special issue are grouped by theme and in the remainder of this editorial we will briefly introduce these different themes.

Objective To investigate the coagulation system in gout patients and associations between disease activity and levels of coagulation markers. Methods A prospective cohort study was performed with data from 30 Dutch gout patients. Levels of coagulation markers including APTT, PT, D-dimer, prothrombin F1 + 2, von Willebrand factor, and thrombin generation parameters were analyzed at baseline and 1-year visit. These markers were related to clinical markers of gout disease activity including the Gout Activity Score (GAS). Our hypothesis was that patients with gout and active disease have increased levels of coagulation markers and that a decrease in disease activity would lead to normalization of coagulation activity. Results A higher GAS was associated with increased levels of thrombin generation parameters including ETP (ß = 0.48, p = 0.01), peak thrombin (ß = 0.60, p = 0.001), and velocity index (ß = 0.57, p = 0.002). Tophaceous gout and higher SUA levels were associated with thrombin generation parameters. After 1 year, thrombin generation parameters showed a small procoagulant trend despite a moderate decrease in disease activity. Prospectively measured changes in disease activity according to the GAS were not associated with any of the coagulation markers. Conclusion Patients with active gout have higher levels of thrombin generation markers, indicating a link between disease activity and coagulation. A change in disease activity after 1 year was not associated with significant changes in coagulation markers, probably due to prolonged low-grade inflammation. Future studies should focus on levels of coagulation markers in comparison with the general population and the effect of adequate gout treatment. Key Points• Patients with gout have an increased risk of cardiovascular events.• High disease activity was associated with higher levels of thrombin generation markers.• Over time, small decreases in inflammation were associated with a decrease in D-dimer and thrombin generation.

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Experimentalist forms of governance have burgeoned across policy areas and institutional contexts in recent years. Recognizing that experimentalist forms of governance can evolve along a plethora of distinct pathways, this paper inquires how the evolutionary nature of experimentalism can be explored in greater depth. Linking the framework of experimentalist governance to that of Evolutionary Governance Theory (EGT), the paper identifies three driving mechanisms of contingency in experimentalism: governance being (1) self-referential, (2) rooted in observation, and (3) steered by dependencies. The paper then refers to recent efforts in the realm of energy transition governance in the Netherlands to illustrate how these contingency mechanisms can help to interrogate the variegated evolutionary pathways that experimentalist governance may have in practice. Building on this Dutch empirical context, the paper puts forward evolutionary path- and context-mapping as a fruitful tool for identifying and disentangling the myriad of pathways along which experimentalism may manifest itself.

BackgroundResearch on the disease severity of COVID-19 in patients with rheumatic immune-mediated inflammatory diseases (IMIDs) has been inconclusive, and long-term prospective data on the development of SARS-CoV-2 antibodies in these patients are lacking.MethodsAdult patients with rheumatic IMIDs from the Amsterdam Rheumatology and Immunology Center, Amsterdam were invited to participate. All patients were asked to recruit their own sex-matched and age-matched control subject. Clinical data were collected via online questionnaires (at baseline, and after 1–4 and 5–9 months of follow-up). Serum samples were collected twice and analysed for the presence of SARS-CoV-2-specific antibodies. Subsequently, IgG titres were quantified in samples with a positive test result.FindingsIn total, 3080 consecutive patients and 1102 controls with comparable age and sex distribution were included for analyses. Patients were more frequently hospitalised compared with controls when infected with SARS-CoV-2; 7% vs 0.7% (adjusted OR: 7.33, 95% CI: 0.96 to 55.77). Only treatment with B-cell targeting therapy was independently associated with an increased risk of COVID-19-related hospitalisation (adjusted OR: 14.62, 95% CI: 2.31 to 92.39). IgG antibody titres were higher in hospitalised compared with non-hospitalised patients, and slowly declined with time in similar patterns for patients in all treatment subgroups and controls.InterpretationWe observed that patients with rheumatic IMIDs, especially those treated with B-cell targeting therapy, were more likely to be hospitalised when infected with SARS-CoV-2. Treatment with conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and biological DMARDs other than B-cell targeting agents is unlikely to have negative effects on the development of long-lasting humoral immunity against SARS-CoV-2.

To investigate the coagulation system in gout patients and associations between disease activity and levels of coagulation markers.A prospective cohort study was performed with data from 30 Dutch gout patients. Levels of coagulation markers including APTT, PT, D-dimer, prothrombin F1 + 2, von Willebrand factor, and thrombin generation parameters were analyzed at baseline and 1-year visit. These markers were related to clinical markers of gout disease activity including the Gout Activity Score (GAS). Our hypothesis was that patients with gout and active disease have increased levels of coagulation markers and that a decrease in disease activity would lead to normalization of coagulation activity.A higher GAS was associated with increased levels of thrombin generation parameters including ETP (ß = 0.48, p = 0.01), peak thrombin (ß = 0.60, p = 0.001), and velocity index (ß = 0.57, p = 0.002). Tophaceous gout and higher SUA levels were associated with thrombin generation parameters. After 1 year, thrombin generation parameters showed a small procoagulant trend despite a moderate decrease in disease activity. Prospectively measured changes in disease activity according to the GAS were not associated with any of the coagulation markers.Patients with active gout have higher levels of thrombin generation markers, indicating a link between disease activity and coagulation. A change in disease activity after 1 year was not associated with significant changes in coagulation markers, probably due to prolonged low-grade inflammation. Future studies should focus on levels of coagulation markers in comparison with the general population and the effect of adequate gout treatment. Key Points • Patients with gout have an increased risk of cardiovascular events. • High disease activity was associated with higher levels of thrombin generation markers. • Over time, small decreases in inflammation were associated with a decrease in D-dimer and thrombin generation.

Foot and ankle problems are common in rheumatic disorders and often lead to pain and limitations in functioning, affecting quality of life. There appears to be large variability in the management of foot problems in rheumatic disorders across podiatrists. To increase uniformity and quality of podiatry care for rheumatoid arthritis (RA), osteoarthritis (OA), spondyloarthritis (SpA), and gout a clinical protocol has been developed.[1] to evaluate an educational programme to train podiatrists in the use of the protocol and [2] to explore barriers and facilitators for the use of the protocol in daily practice.This study used a mixed method design and included 32 podiatrists in the Netherlands. An educational programme was developed and provided to train the podiatrists in the use of the protocol. They thereafter received a digital questionnaire to evaluate the educational programme. Subsequently, podiatrists used the protocol for three months in their practice. Facilitators and barriers that they experienced in the use of the protocol were determined by a questionnaire. Semi-structured interviews were held to get more in-depth understanding.The mean satisfaction with the educational programme was 7.6 (SD 1.11), on a 11 point scale. Practical knowledge on joint palpation, programme variation and the use of practice cases were valued most. The protocol appeared to provide support in the diagnosis, treatment and evaluation of foot problems in rheumatic disorders and the treatment recommendations were clear and understandable. The main barrier for use of the protocol was time. The protocol has not yet been implemented in the electronic patient file, which makes it more time consuming. Other experienced barriers were the reimbursement for the treatment and financial compensation.The educational programme concerning the clinical protocol for foot problems in rheumatic disorders appears to be helpful for podiatrists. Podiatrists perceived the protocol as being supportive during patient management. Barriers for use of the protocol were identified and should be addressed prior to large scale implementation. Whether the protocol is also beneficial for patients, needs to be determined in future research.

Background Gout is the most prevalent inflammatory arthritis in developed countries. A gout flare is mediated by phagocytosis of monosodium urate crystals by macrophages and neutrophils leading to subsequent activation of neutrophils contributing to synovitis, local joint destruction, and systemic inflammation. We hypothesize that biomarkers from activated neutrophils reflect gout disease activity. The objective of this study therefore was to investigate the clinical utility of neutrophil-derived biomarkers in gout disease activity. Methods Plasma samples from 75 gout patients participating in the “Reade gout cohort Amsterdam” were compared with 30 healthy controls (HC). Levels of neutrophil extracellular traps (NETs) and neutrophil activation markers (calprotectin and peroxidase activity) were analyzed by ELISA and fluorimetry, compared to healthy controls, and related to markers of inflammation and disease activity. Results Levels of NETs, as well as neutrophil activation markers, were increased in gout patients compared to HC (p p β = 0.35, p β = 0.49, p β = 0.66, p β = 0.25, p = 0.04, and ESR: β = 0.57, p β = 0.34, p β = 0.23, p = 0.05) and morning stiffness, especially in patients with chronic poly-articular gout (β = 0.71, p Conclusions Neutrophil activation markers are associated with characteristics of active, polyarticular gout. Furthermore, NETs are present in the peripheral blood of gout patients. However, NETs do not associate with markers of disease activity or inflammation. Future research should point out if peroxidase and calprotectin could be used in clinical practice as biomarkers for monitoring gout disease activity.

Purpose: Exercise therapy with a focus on muscle strengthening has proven to be effective for the management of knee osteoarthritis (OA). Yet it is not known whether high-intensity resistance training (RT) is more effective in improving upper leg muscle strength and physical performance than low-intensity RT. Still, there is some controversy regarding the effectiveness of high-intensity RT and whether or not it is harmful, for instance by accelerating cartilage degeneration, osteophyte formation, or increasing synovitis. Any catabolic or anabolic response of musculoskeletal tissue to RT might first be visible on a biochemical level before changes in clinical symptoms are measurable. Serum biomarkers can objectively measure early biochemical changes and assess whether RT leads to a more anabolic or catabolic response. The aim of this study is to assess (i) whether high-intensity RT elicits a different response (e.g. catabolic) on systemic inflammation and musculoskeletal tissues in and surrounding the joint, including bone, cartilage, muscle, and synovial tissue compared to low-intensity RT; and (ii) whether there is an association between changes in serum levels of inflammatory and musculoskeletal tissue-derived biomarkers and improvements in clinical outcomes (performance-based tests and self-reported outcomes on pain and activity limitations).Methods: In a randomized controlled trial, 177 participants with knee OA conducted a high-intensity (70%-80% of the Repetition Maximum (1RM)) or low-intensity (40%-50% 1RM) RT program 3 times a week for 12 weeks. Measures of clinical outcomes and serum samples were collected at the start of RT (pre-intervention), after 3 months at the end of RT (post-intervention), and 6 months after RT (follow-up). As a reflection of systemic inflammation (CRP), synovitis (CRPM, C3M), bone turnover (OC, CTX-I), cartilage turnover (PRO-C2, C2M, huARGS), muscle turnover (PRO-C3, PRO-C6), and cell behaviour (col10neo) a total of eleven serum biomarkers were analysed. With the exception of CRP, which was determined with an immunoturbidimetric assay, ELISA assays were used to quantify serum levels of the other 10 serum biomarkers. The primary outcome measures are the changes in serum biomarker levels. Other outcome measures include upper leg muscle strength, performance-based tests, and self-reported outcomes on pain and activity limitations.Results: High-intensity RT resulted in greater improvements in muscle strength compared to low-intensity RT when measured by the estimated 1RM. No significant differences between groups were found for upper leg muscle strength (Nm/kg) when measured with an isokinetic dynamometer. Both groups showed similar improvements in pain and physical functioning. Although there is no difference between groups in clinical outcomes, except for the estimated 1RM, we expect that participants in the high-intensity RT group are more likely to have enhanced serum levels of catabolic biomarkers than participants in the low-intensity RT group. Since both the high-intensity RT group and low-intensity RT group improved over time, we expect that changes in serum biomarker levels are associated with overall improvements in clinical outcomes. Almost all participants had normal CRP values (Conclusions: The work to date on CRP serum levels suggests that RT did not influence CRP levels. This result may be explained by the high percentage of participants with normal CRP levels (

Background Exercise therapy is the cornerstone of knee osteoarthritis (OA) management. In particular muscle strengthening exercise, targeting the characteristic loss of muscle strength present in knee OA, is a key factor for the beneficial effects reported for exercise therapy. The optimal training intensity for resistance training in patients with knee OA, however, is not known to date. Besides resistance training, vitamin D supplementation in patients with vitamin deficiency may optimize muscle strength. Objectives To assess (i) whether high-intensity resistance training leads to greater improvements in muscle strength compared to moderate-intensity resistance training in patients with knee OA; and (ii) whether vitamin D supplementation in combination with strength training leads to greater improvements in muscle strength compared to placebo in combination with strength training in patients with knee OA and vitamin D deficiency (25 (OH)D level > 15 nmol/L and Methods In a randomized controlled trial, 177 patients with a clinical diagnosis of knee OA were included. All patients were randomly allocated to a high-intensity (70-80% of the Repetition Maximum (1RM)) or a moderate-intensity (40-50% of the 1RM) resistance training program of 12 weeks. Both groups were supervised by a physical therapist twice a week and performed home exercises once a week. In addition, 50 out 177 patients had vitamin D deficiency and received supplementation of vitamin D (1200 IU vitamin D3 per day) or placebo in the 12 weeks prior to and during the resistance training program. The primary outcome measure was isokinetic (60 °/s) upper leg muscle strength (Nm/kg). In addition, the estimated 1 RM for leg press, leg curl and hip abduction were used as measures for muscle strength. Other outcome measures included severity of knee pain (NRS), self-reported and performance based activity limitations (WOMAC physical functioning (WOMAC), Get-up-and-go-test (GUG)). Measurements were performed by a blinded assessor prior to the exercise program (T0), directly after the program (T12) and at 6 months follow-up (T36). Additionally, for patients with vitamin D deficiency, measurements were also taken prior to vitamin supplementation or placebo (T-12). Results Both the high-intensity group and moderate-intensity group improved in upper leg muscle strength over time. No significant differences between groups were found for isokinetic upper leg muscle strength (p = 0.646) (see figure 1). However, when measured by the estimated 1 RM, significant differences were found between groups in favor of the high–intensity group (p = 0.001) (see figure 1). No between-group differences were found on pain (p = 0.885), or on self-reported and performance-based activity limitations (WOMAC p = 0.968; GUG p = 0.800), although both groups improved (see figure 1). An unexpected finding was that, in the (small sample of) patients with vitamin D deficiency, the placebo group showed significant greater isokinetic upper leg muscle strength over time compared to the vitamin D group (p = 0.001). Conclusion No differences between groups were found for isokinetic upper leg muscle strength. With the estimated 1 RM as a measure of muscle strength, high-intensity resistance training led to greater improvements in muscle strength compared to moderate-intensity resistance training in patients with knee OA. This did not result in greater improvements in pain and physical functioning in the high-intensity resistance group; both groups showed similar clinically important improvements. The added value of vitamin D supplementation on muscle strength in knee OA patients with vitamin D deficiency need further study. Disclosure of Interests Arjan de Zwart: None declared, Joost Dekker: None declared, Leo D. Roorda: None declared, Martin van der Esch : None declared, Paul Lips: None declared, Natasja van Schoor: None declared, Annemieke Heijboer: None declared, Franktien Turkstra: None declared, Martijn Gerritsen Grant/research support from: Grunenthal has sponsored the Reade Cohort, Arja Hakkinen: None declared, Kim Bennell: None declared, Martijn Steultjens: None declared, Willem Lems Speakers bureau: Amgen Inc., Merck, Eli Lilly and Pfizer, Marike van der Leeden : None declared

Background Similar to other rheumatic diseases, patients with gout have an increased cardiovascular morbidity and mortality, not fully explained by traditional cardiovascular risk factors. Instead, gout-specific factors, including xanthine oxidase induced oxidative stress, increased lipid oxidization and chronic low-grade inflammation, have been suggested as important contributors.(1) Neutrophils, through formation of neutrophil extracellular traps (NETs), partake in pro-thrombotic and atherogenic processes contributing to cardiovascular disease.(2) However, the role of NETs in cardiovascular disease in human gout is not known. Objectives Our objective is to investigate the association between neutrophil activation and cardiovascular risk in gout patients. We hypothesize that neutrophil activation mediates inflammation, as well as activation and damage to endothelial cells, partaking in atherosclerosis development. Methods Plasma samples from 75 gout patients participating in the ‘Reade gout cohort Amsterdam’ were analyzed. Patient data was collected on disease activity, demographics, gout history, comorbidities, medication use and cardiovascular risk assessments. Measurements included anthropometry, vital parameters (RR, HF), ECG and lab variables. Levels of NETs, and NET-derived markers (cell-free DNA and peroxidase activity) were analyzed using a MPO-DNA ELISA, as well as fluorimetry. Levels of calprotectin (S100A8/A9) were analyzed by ELISA. Markers of NETosis were related to clinical markers of cardiovascular risk, including BMI, smoking, blood pressure, lipid profile and 10 year risk of cardiovascular mortality (SCORE EU). Results No associations were found between markers of cell death (cfDNA and NETs) and cardiovascular risk. However, markers of neutrophil activation, including peroxidase activity correlated with BMI (r=0.31, p=0.008), waist-hip ratio (r=0.52, p Conclusion We have demonstrated, for the first time, that neutrophil activation markers are associated with several risk factors of cardiovascular disease, including hyperlipidemia, hypertension and diabetes in a large cohort of gout patients. Furthermore, the presence of a neutrophil activation signature is strongly associated with a 10-year risk of cardiovascular comorbidity. References [1] Krishnan E. Inflammation, oxidative stress and lipids: the risk triad for atherosclerosis in gout. Rheumatology (Oxford). 2010;49(7):1229-38. [2] Doring Y, et al. Neutrophil Extracellular Traps in Atherosclerosis and Atherothrombosis. Circ Res. 2017;120(4):736-43. Disclosure of Interests Daisy Vedder Speakers bureau: Novartis, Martijn Gerritsen Grant/research support from: Grunenthal has sponsored the Reade Cohort, Michael Nurmohamed Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Menarini, MSD, Mundipharma, Pfizer, Roche, Sanofi and UCB, Consultant for: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Menarini, MSD, Mundipharma, Pfizer, Roche, Sanofi and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Menarini, MSD, Mundipharma, Pfizer, Roche, Sanofi and UCB, Ronald van Vollenhoven: None declared, Christian Lood: None declared

Background: Neutrophils are key immune cells participating in host defense through several mechanisms, including the formation of neutrophil extracellular traps (NETs). Although beneficial from a host-pathogen perspective, excessive neutrophil activation has been linked to inflammation and autoimmunity, including systemic lupus erythematosus (SLE) and gout.(1) In gout models, uric acid crystals induce NETosis. Though NETs are known to induce marked inflammation through TLR9- and cGAS-dependent pathways, as well as partake in induction of tissue damage and thrombotic events, the role of NETs in human gout has not been carefully investigated. Objectives: Our objective is to investigate evidence of systemic neutrophil activation, and the clinical utility of neutrophil-derived biomarkers in gout. We hypothesize that uric acid crystals will activate neutrophils to undergo NET formation, with these processes contributing to immune cell activation, and local joint destruction. Methods: Plasma samples from 75 gout patients participating in the ‘Reade gout cohort Amsterdam’ were compared with 30 healthy controls (HC). Levels of NETs, and NET-derived markers (cell-free DNA and peroxidase activity) were analyzed using a MPO-DNA ELISA, as well as fluorimetry.(2) Levels of calprotectin (S100A8/A9) were analyzed by ELISA. Mitochondrial (mt, COXII), as well as genomic (n, RPLP0) DNA levels were analyzed by qPCR. All of the analyzed markers were compared between gout patients and healthy individuals, and related to markers of inflammation and disease activity. Results: Levels of NETs, as well as other neutrophil biomarkers, were significantly increased in gout patients as compared to healthy subjects (p Conclusion: To our knowledge, this is the first report demonstrating presence of NETs in the peripheral blood of gout patients. Although markedly elevated, levels of NETs did not associate with markers of disease activity or inflammation, possibly due to the lack of inflammatory mitochondrial DNA within the NETs. Even so, our data demonstrate an important role of neutrophils in gout pathogenesis, with neutrophil activation markers associating with characteristics of active, and more pronounced polyarticular disease. References [1] Lee KH, Kronbichler A, Park DD, Park Y, Moon H, Kim H, et al. Neutrophil extracellular traps (NETs) in autoimmune diseases: A comprehensive review. Autoimmun Rev. 2017;16(11):1160-73. [2] Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C, De Ravin SS, Smith CK, et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med. 2016;22(2):146-53. Disclosure of Interests: Daisy Vedder Speakers bureau: Novartis, Martijn Gerritsen Grant/research support from: Grunenthal has sponsored the Reade Cohort, Michael Nurmohamed Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Menarini, MSD, Mundipharma, Pfizer, Roche, Sanofi and UCB, Consultant for: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Menarini, MSD, Mundipharma, Pfizer, Roche, Sanofi and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Menarini, MSD, Mundipharma, Pfizer, Roche, Sanofi and UCB, Ronald van Vollenhoven: None declared, Christian Lood: None declared

Objective: To examine the performance of ultrasound (US) for the diagnosis of gout using the presence of monosodium urate monohydrate (MSU) crystals as the gold standard. Methods: We analyzed data from the Study for Updated Gout Classification Criteria (SUGAR), a large, multicenter observational cross-sectional study of consecutive subjects with at least 1 swollen joint who conceivably may have gout. All subjects underwent arthrocentesis; cases were subjects with confirmed MSU crystals. Rheumatologists or radiologists who were blinded with regard to the results of the MSU crystal analysis performed US on 1 or more clinically affected joints. US findings of interest were double contour sign, tophus, and snowstorm appearance. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Multivariable logistic regression models were used to examine factors associated with positive US results among subjects with gout. Results: US was performed in 824 subjects (416 cases and 408 controls). The sensitivity, specificity, PPV, and NPV for the presence of any 1 of the features were 76.9%, 84.3%, 83.3%, and 78.2%, respectively. Sensitivity was higher among subjects with a disease duration of ≥2 years and among subjects with subcutaneous nodules on examination (suspected tophus). Associations with a positive US finding included suspected clinical tophus (odds ratio [OR] 4.77 [95% confidence interval (95% CI) 2.23–10.21]), any abnormality on plain radiography (OR 4.68 [95% CI 2.68–8.17]), and serum urate level (OR 1.31 [95% CI 1.06–1.62]). Conclusion: US features of MSU crystal deposition had high specificity and high PPV but more limited sensitivity for early gout. The specificity remained high in subjects with early disease and without clinical signs of tophi. (Less)

Objective To identify the best-performing survey definition of gout from items commonly available in epidemiologic studies. Methods Survey definitions of gout were identified from 34 epidemiologic studies contributing to the Global Urate Genetics Consortium (GUGC) genome-wide association study. Data from the Study for Updated Gout Classification Criteria (SUGAR) were randomly divided into development and test data sets. A data-driven case definition was formed using logistic regression in the development data set. This definition, along with definitions used in GUGC studies and the 2015 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) gout classification criteria were applied to the test data set, using monosodium urate crystal identification as the gold standard. Results For all tested GUGC definitions, the simple definition of “self-report of gout or urate-lowering therapy use” had the best test performance characteristics (sensitivity 82%, specificity 72%). The simple definition had similar performance to a SUGAR data-driven case definition with 5 weighted items: self-report, self-report of doctor diagnosis, colchicine use, urate-lowering therapy use, and hyperuricemia (sensitivity 87%, specificity 70%). Both of these definitions performed better than the 1977 American Rheumatism Association survey criteria (sensitivity 82%, specificity 67%). Of all tested definitions, the 2015 ACR/EULAR criteria had the best performance (sensitivity 92%, specificity 89%). Conclusion A simple definition of “self-report of gout or urate-lowering therapy use” has the best test performance characteristics of existing definitions that use routinely available data. A more complex combination of features is more sensitive, but still lacks good specificity. If a more accurate case definition is required for a particular study, the 2015 ACR/EULAR gout classification criteria should be considered.

Gout is one of the most prevalent inflammatory rheumatic disease. It is preceded by hyperuricemia and associated with an increased risk for cardiovascular disease, both related to unhealthy diets. The objective of this systematic review is to better define the most appropriate diet addressing both disease activity and traditional cardiovascular risk factors in hyperuricemic patients. We included clinical trials with patients diagnosed with hyperuricemia or gout, investigating the effect of dietary interventions on serum uric acid (SUA) levels, gout flares and—if available—cardiovascular risk factors. Eighteen articles were included, which were too heterogeneous to perform a meta-analysis. Overall, the risk of bias of the studies was moderate to high. We distinguished four groups of dietary interventions: Calorie restriction and fasting, purine-low diets, Mediterranean-style diets, and supplements. Overall, fasting resulted in an increase of SUA, whilst small (SUA change +0.3 to −2.9 mg/dL) but significant effects were found after low-calorie, purine-low, and Mediterranean-style diets. Studies investigating the effect on cardiovascular risk factors were limited and inconclusive. Since Mediterranean-style diets/DASH (Dietary Approach to Stop Hypertension) have shown to be effective for the reduction of cardiovascular risk factors in other at-risk populations, we recommend further investigation of such diets for the treatment of gout.

Objective Severe pain in patients with knee osteoarthritis (OA) hampers the ability to exercise. A protocol for the standardized optimization of analgesics in combination with exercise therapy was developed. The purpose of this protocol was to reduce pain, thereby allowing the patient to participate in exercise therapy. The objective of the present study was to evaluate the feasibility and outcome of the protocol. Methods Forty-nine patients with knee OA and severe knee pain (numerical rating scale for pain ≥7) were included. Analgesics were prescribed following an incremental protocol. After 6 weeks, a 12-week exercise therapy program was added. Information about analgesic use and exercise therapy content was recorded. Knee pain and activity limitations were assessed at baseline, after 6 weeks, and after 18 weeks. Results Statistically significant improvements in pain and activity limitations were found in intent-to-treat analysis after 6 weeks of analgesic use and after the intervention was completed. Mean improvements from baseline were 30% (P < 0.001) for pain and 17% (P < 0.001) for activity limitations after the intervention was completed. Seventy-eight percent of the patients were able to exercise according to the protocol. In these patients, exercise therapy following 6 weeks of analgesic use resulted in a further improvement of activity limitations of 10% (P = 0.004). Conclusion The combined intervention of standardized analgesic prescription and exercise therapy allows most patients with knee OA and severe pain to participate in exercise therapy, leading to reduction of pain and activity limitations. These promising results need to be confirmed in a randomized controlled trial.

Objective.To determine the frequency of adverse events of diagnostic arthrocentesis in patients with possible gout.Methods.Consecutive patients underwent arthrocentesis and were evaluated at 6 weeks to determine adverse events. The 95% CI were obtained by bootstrapping.Results.Arthrocentesis was performed in 910 patients, and 887 (97.5%) were evaluated for adverse events. Any adverse event was observed in 12 participants (1.4%, 95% CI 0.6–2.1). There was 1 case (0.1%, 95% CI 0–0.34) of septic arthritis.Conclusions.Diagnostic arthrocentesis is associated with a low frequency of adverse events. Septic arthritis rarely occurs.

OBJECTIVE: To perform external validation of a provisional definition of disease flare in patients with gout. METHODS: Five hundred nine patients with gout were enrolled in a cross-sectional study during a routine clinical care visit at 17 international sites. Data were collected to classify patients as experiencing or not experiencing a gout flare, according to a provisional definition. A local expert rheumatologist performed the final independent adjudication of gout flare status. Sensitivity, specificity, predictive values, and receiver operating characteristic (ROC) curves were used to determine the diagnostic performance of gout flare definitions. RESULTS: The mean ± SD age of the patients was 57.5 ± 13.9 years, and 89% were male. The definition requiring fulfillment of at least 3 of 4 criteria (patient-defined gout flare, pain at rest score of >3 on a 0-10-point numerical rating scale, presence of at least 1 swollen joint, and presence of at least 1 warm joint) was 85% sensitive and 95% specific in confirming the presence of a gout flare, with an accuracy of 92%. The ROC area under the curve was 0.97. The definition based on a classification and regression tree algorithm (entry point, pain at rest score >3, followed by patient-defined flare "yes") was 73% sensitive and 96% specific. CONCLUSION: The definition of gout flare that requires fulfillment of at least 3 of 4 patient-reported criteria is now validated to be sensitive, specific, and accurate for gout flares, as demonstrated using an independent large international patient sample. The availability of a validated gout flare definition will improve the ascertainment of an important clinical outcome in studies of gout.

The objective of this study was to evaluate whether self-reported knee instability is associated with activity limitations in patients with knee osteoarthritis (OA), in addition to knee pain and muscle strength. A cohort of 248 patients diagnosed with knee OA was examined. Self-reported knee instability was defined as the perception of any episode of buckling, shifting, or giving way of the knee in the past 3 months. Knee pain was assessed using a numeric rating scale, and knee extensor and flexor strength were measured using an isokinetic dynamometer. Activity limitations were measured by using the Western Ontario and McMasters Universities Osteoarthritis Index physical function questionnaire, the timed Get Up and Go, and the timed stair climbing and three questionnaires evaluating walking, climbing stairs, and rising from a chair. Other potential determinants of activity limitations were also collected, including joint proprioception, joint laxity, age, sex, body mass index (BMI), disease duration, and radiographic disease severity. Regression analyses evaluated the effect of adding self-reported knee instability to knee pain and muscle strength, when examining associations with the activity limitations measures. Self-reported knee instability was common (65 %) in this cohort of patients with knee OA. Analyses revealed that self-reported knee instability is significantly associated with activity limitations, even after controlling for knee pain and muscle strength. Joint proprioception, joint laxity, age, sex, BMI, duration of complaints, and radiographic severity did not confound the associations. In conclusion, self-reported knee instability is associated with activity limitations in patients with knee OA, in addition to knee pain and muscle strength. Clinically, self-reported knee instability should be assessed in addition to knee pain and muscle strength.

Item does not contain fulltext OBJECTIVES: To compare the sensitivity and specificity of different classification criteria for gout in early and established disease. METHODS: This was a cross-sectional study of consecutive rheumatology clinic patients with joint swelling in which gout was defined by presence or absence of monosodium urate crystals as observed by a certified examiner at presentation. Early disease was defined as patient-reported onset of symptoms of 2 years or less. RESULTS: Data from 983 patients were collected and gout was present in 509 (52%). Early disease was present in 144 gout cases and 228 non-cases. Sensitivity across criteria was better in established disease (95.3% vs 84.1%, p

OBJECTIVE: To determine which clinical, laboratory, and imaging features most accurately distinguished gout from non-gout. METHODS: We performed a cross-sectional study of consecutive rheumatology clinic patients with =1 swollen joint or subcutaneous tophus. Gout was defined by synovial fluid or tophus aspirate microscopy by certified examiners in all patients. The sample was randomly divided into a model development (two-thirds) and test sample (one-third). Univariate and multivariate association between clinical features and monosodium urate-defined gout was determined using logistic regression modeling. Shrinkage of regression weights was performed to prevent overfitting of the final model. Latent class analysis was conducted to identify patterns of joint involvement. RESULTS: In total, 983 patients were included. Gout was present in 509 (52%). In the development sample (n = 653), the following features were selected for the final model: joint erythema (multivariate odds ratio [OR] 2.13), difficulty walking (multivariate OR 7.34), time to maximal pain 6 mg/dl (0.36 mmoles/liter; multivariate OR 3.35), ultrasound double contour sign (multivariate OR 7.23), and radiograph erosion or cyst (multivariate OR 2.49). The final model performed adequately in the test set, with no evidence of misfit, high discrimination, and predictive ability. MTP1 joint involvement was the most common joint pattern (39.4%) in gout cases. CONCLUSION: Ten key discriminating features have been identified for further evaluation for new gout classification criteria. Ultrasound findings and degree of uricemia add discriminating value, and will significantly contribute to more accurate classification criteria.

Severe pain in patients with knee osteoarthritis (OA) hampers the ability to exercise. A protocol for the standardized optimization of analgesics in combination with exercise therapy was developed. The purpose of this protocol was to reduce pain, thereby allowing the patient to participate in exercise therapy. The objective of the present study was to evaluate the feasibility and outcome of the protocol.Forty-nine patients with knee OA and severe knee pain (numerical rating scale for pain ≥7) were included. Analgesics were prescribed following an incremental protocol. After 6 weeks, a 12-week exercise therapy program was added. Information about analgesic use and exercise therapy content was recorded. Knee pain and activity limitations were assessed at baseline, after 6 weeks, and after 18 weeks.Statistically significant improvements in pain and activity limitations were found in intent-to-treat analysis after 6 weeks of analgesic use and after the intervention was completed. Mean improvements from baseline were 30% (P0.001) for pain and 17% (P0.001) for activity limitations after the intervention was completed. Seventy-eight percent of the patients were able to exercise according to the protocol. In these patients, exercise therapy following 6 weeks of analgesic use resulted in a further improvement of activity limitations of 10% (P = 0.004).The combined intervention of standardized analgesic prescription and exercise therapy allows most patients with knee OA and severe pain to participate in exercise therapy, leading to reduction of pain and activity limitations. These promising results need to be confirmed in a randomized controlled trial.

This chapter summarizes therapeutic options in osteoarthritis of the knee or hip. Treatment options include nonpharmacological, pharmacological, and surgical interventions.

OBJECTIVE: To investigate whether an exercise program, initially focusing on knee stabilization and subsequently on muscle strength and performance of daily activities is more effective than an exercise program focusing on muscle strength and performance of daily activities only, in reducing activity limitations in patients with knee osteoarthritis (OA) and instability of the knee joint.DESIGN: A single-blind, randomized, controlled trial involving 159 knee OA patients with self-reported and/or biomechanically assessed knee instability, randomly assigned to two treatment groups. Both groups received a supervised exercise program for 12 weeks, consisting of muscle strengthening exercises and training of daily activities, but only in the experimental group specific knee joint stabilization training was provided. Outcome measures included activity limitations (Western Ontario and McMaster Universities Osteoarthritis Index - WOMAC physical function, primary outcome), pain, global perceived effect and knee stability.RESULTS: Both treatment groups demonstrated large (∼20-40%) and clinically relevant reductions in activity limitations, pain and knee instability, which were sustained 6 months post-treatment. No differences in effectiveness between experimental and control treatment were found on WOMAC physical function (B (95% confidence interval - CI) = -0.01 (-2.58 to 2.57)) or secondary outcome measures, except for a higher global perceived effect in the experimental group (P = 0.04).CONCLUSIONS: Both exercise programs were highly effective in reducing activity limitations and pain and restoring knee stability in knee OA patients with instability of the knee. In knee OA patients suffering from knee instability, specific knee joint stabilization training, in addition to muscle strengthening and functional exercises, does not seem to have any additional value. Dutch Trial Register (NTR) registration number: NTR1475.

BACKGROUND: Osteoarthritis (OA) of the knee is characterized by pain and activity limitations. In knee OA, proprioceptive accuracy is reduced and might be associated with pain and activity limitations. Although causes of reduced proprioceptive accuracy are divergent, medial meniscal abnormalities, which are highly prevalent in knee OA, have been suggested to play an important role. No study has focussed on the association between proprioceptive accuracy and meniscal abnormalities in knee OA. OBJECTIVE: To explore the association between reduced proprioceptive accuracy and medial meniscal abnormalities in a clinical sample of knee OA subjects. METHODS: Cross-sectional study in 105 subjects with knee OA. Knee proprioceptive accuracy was assessed by determining the joint motion detection threshold in the knee extension direction. The knee was imaged with a 3.0 T magnetic resonance (MR) scanner. Number of regions with medial meniscal abnormalities and the extent of abnormality in the anterior and posterior horn and body were scored according to the Boston-Leeds Osteoarthritis Knee Score (BLOKS) method. Multiple regression analyzes were used to examine whether reduced proprioceptive accuracy was associated with medial meniscal abnormalities in knee OA subjects. RESULTS: Mean proprioceptive accuracy was 2.9degree + 1.9degree. Magnetic resonance imaging (MRI)-detected medial meniscal abnormalities were found in the anterior horn (78%), body (80%) and posterior horn (90%). Reduced proprioceptive accuracy was associated with both the number of regions with meniscal abnormalities (P < 0.01) and the extent of abnormality (P = 0.02). These associations were not confounded by muscle strength, joint laxity, pain, age, gender, body mass index (BMI) and duration of knee complaints. CONCLUSION: This is the first study showing that reduced proprioceptive accuracy is associated with medial meniscal abnormalities in knee OA. The study highlights the importance of meniscal abnormalities in understanding reduced proprioceptive accuracy in persons with knee OA. Copyright 2013 Osteoarthritis Research Society International. All rights reserved

Objective. To examine the association of serum CRP and ESR with muscle strength in patients with knee OA.Methods. Cross-sectional data from 285 patients with knee OA from the Amsterdam Osteoarthritis (AMS-OA) cohort were analysed. CRP (mg/l) and ESR (mm/l) were measured in serum from patients' blood samples and the values were dichotomized for the analyses. Strength of quadriceps and hamstring muscles was assessed using an isokinetic dynamometer. Univariable and multivariable linear regression analyses were used to assess the association of CRP and ESR with muscle strength, adjusting for relevant confounders.Results. Elevated levels of serum CRP (β = -0.10; P = 0.04) and ESR (β = -0.12; P = 0.02) were associated with lower muscle strength after adjustment for age, sex, comorbidities and NSAID use. The associations were no longer significant when BMI was incorporated in the adjusted model.Conclusion. Inflammation might influence muscle strength in patients with knee OA. Moreover, the link between inflammation and obesity might explain the effect that BMI has in the associations between inflammatory markers (i.e. CRP and ESR) and muscle strength. © The Author 2012.Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

Contains fulltext : 172681.pdf (Publisher’s version ) (Closed access) Importance: Eosinophilic fasciitis (EF) is a connective tissue disorder in which conventional treatment leads to disappointing results in a proportion of patients. Therefore, we investigated high-dose intravenous (IV) pulse methotrexate (MTX) as a treatment for EF. Objective: To examine safety and effects of monthly high-dose IV pulse MTX in EF. Design, Setting, and Participants: For this prospective single-arm study, we recruited 12 patients diagnosed with biopsy specimen-proven EF between 2006 and 2009 from the Department of Dermatology and Rheumatology at the Radboud University Medical Centre. Interventions: Intravenous MTX (4 mg/kg) monthly for 5 months with folinic acid rescue 24 hours after MTX administration. Main Outcomes and Measures: The primary outcome was improvement of the modified skin score at month 5 vs baseline. Secondary outcomes were durometry, range of motion, visual analog scale scores for disease activity, and 36-Item Short Form Survey health questionnaires. Results: Overall, 12 patients (11 women between 37-69 years old) received a median (range) monthly dose of 288 (230-336) mg MTX. Median (range) modified skin score improved from 17.5 (8.0-24.0) at baseline to 8.5 (1.0-20.0) at month 5 (P = .001). Secondary outcome measures improved significantly, except for durometer scores and range of motion of the elbows. Adverse events included gastrointestinal symptoms (n = 9), mild stomatitis (n = 5), and alopecia (n = 4). Conclusions and Relevance: High-dose IV pulse MTX is a safe and effective treatment option in EF. Trial Registration: clinicaltrials.gov Identifier: NCT00441961.

Objective: To establish whether proprioception and varusvalgus laxity moderate the association between muscle strength and activity limitations in patients with early symptomatic knee osteoarthritis. Design: A cross-sectional study. Subjects: A sample of 151 participants with early symptomatic knee osteoarthritis from the Cohort Hip and Cohort Knee study. Methods: Regression analyses were performed to establish the associations between muscle strength, proprioception (knee joint motion detection threshold in the anterior- posterior direction), varus-valgus laxity and activity limitations (selfreported and performance-based). Interaction terms were used to establish whether proprioception and laxity moderated the association between muscle strength and activity limitations. Results: Proprioception moderated the association between muscle strength and activity limitations: the negative association between muscle strength and activity limitations was stronger in participants with poor proprioception than in participants with accurate proprioception (performancebased activity limitations p = 0.02; self-reported activity limitations p = 0.08). The interaction between muscle strength and varus-valgus laxity was not significantly associated with activity limitations. Conclusion: The results of the present study support the theory that in the absence of adequate proprioceptive input, lower muscle strength affects a patient’s level of activities to a greater degree than in the presence of adequate proprioceptive input.

Purpose: To explore associations between tissue abnormalities (bone marrow lesions, effusion, synovitis, cartilage loss and osteophytes) visualised by MRI, with both biomechanical impairments (proprioceptive inaccuracy, laxity, quadriceps and hamstrings weakness) and clinical symptoms (pain, stiffness, activity limitations and crepitus) in a cohort of patients with knee osteoarthritis (OA). Methods: Cross-sectional study in 105 patients with knee OA from the Amsterdam Osteoarthritis cohort. Multivariable regression analyses were used to explore associations between MRI features in each compartment with OA symptoms. Results: Associations were found between presence of synovitis with quadriceps weakness (p1⁄4.004) and between severity of cartilage loss in the patellafemoral compartment with quadriceps weakness (p1⁄4.035). No associations were found for proprioceptive inaccuracy, laxity and hamstrings weakness. Medial tibiofemoral cartilage loss was the only MRI feature associated with pain and activity limitations. In contrary, all MRI features, except for synovitis, were found to be associated with the presence of crepitus. Conclusions: As we far as we know, this is the first study to find a significant association between synovitis and quadriceps weakness. This relationship was independent of pain severity. It may imply that strategies that decrease inflammation might be valuable to prevent clinical deterioration in OA patients. Since inflammation had not been identified by physical examination in most cases with MRI-assessed synovitis, MRI can play an important role in clinical assessment of knee OA patients.

Objective To determine whether muscle strength, proprioceptive accuracy, and laxity are associated with self-reported knee instability in a large cohort of knee osteoarthritis (OA) patients, and to investigate whether muscle strength may compensate for impairment in proprioceptive accuracy or laxity, in order to maintain knee stability. Methods. Data from 283 knee OA patients from the Amsterdam Osteoarthritis cohort were used. Univariable and multivariable logistic regression analyses were performed to assess the association between muscle strength, proprioceptive accuracy (motion sense), frontal plane varus-valgus laxity, and self-reported knee instability. Additionally, effect modification between muscle strength and proprioceptive accuracy and between muscle strength and laxity was determined. Results. Self-reported knee instability was present in 67% of the knee OA patients and mainly occurred during walking. Lower muscle strength was significantly associated with the presence of self-reported knee instability, even after adjusting for relevant confounding. Impaired proprioceptive accuracy and high laxity were not associated with self-reported knee instability. No effect modification between muscle strength and proprioceptive accuracy or laxity was found. Conclusion. Lower muscle strength is strongly associated with self-reported knee instability in knee OA patients, while impairments in proprioceptive accuracy and laxity are not. A compensatory role of muscle strength for impaired proprioceptive accuracy or high laxity, in order to stabilize the knee, could not be demonstrated. (Less)

Purpose: Although a number of bioreductive agents are substrates for purified DT-diaphorase the role of this enzyme in either activation or detoxification of these agents in the whole cell is unclear. The aim of this study was to determine the role of DT-diaphorase in the metabolic activation of E09 under both aerobic and hypoxic conditions. Methods and Materials: A panel of lung cancer cell lines was used and drug sensitivity was determined by clonogenic or tetrazolium-dye-based assays. Activities of DT-diaphorase, cytochrome P450 and cytochrome b5 reductase were determined spectrophotometrically by following the reduction of cytochrome c. Results: Small-cell lung cancer cell lines showed a 600-fold range in DT-diaphorase activities but levels were much higher in three of the four non-small-cell lines. Activities of cytochromes P450 and b5 reductase were much lower than those of DT-diaphorase and showed much less variation between cell lines. There was no relationship between the activities of any of the enzymes and aerobic sensitivity to SR 4233, BCNU and cis-platin. Under aerobic conditions there was a clear correlation between DT-diaphorase activity and sensitivity to E09. The small-cell lines were much more resistant to E09 than the DT-diaphorase rich non-small-cell lines. A doxorubicin resistant variant of one of the small-cell lines (H69LX10) did not show cross resistance to E09 but did show a small degree (3-fold) of cross resistance to SR 4233. Under hypoxic conditions, cell lines with high levels of DT-diaphorase showed only a small increase in sensitivity to E09 (1.5-7 fold); cell lines with low levels of activity showed a 10- 37-fold increase in sensitivity. Conclusion: These results suggest that under hypoxic conditions, E09 is metabolized by 1-electron reducing enzymes to a toxic species. This reduction product is oxygen sensitive but a similar degree of activation is obtained under aerobic conditions in cell lines with high levels of 2-electron reducing DT-diaphorase.

Background Recently, an American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) collaboration developed new classification criteria for rheumatoid arthritis (RA). Objective To evaluate the diagnostic and discriminative ability of these new criteria compared with the 1987 ACR criteria and the Visser decision rule. Methods 455 patients with early arthritis were studied. The diagnostic performance of the criteria was evaluated using methotrexate treatment within 1 year, expert opinion RA and erosive disease as ‘gold standards’. Erosive disease was defined as a 0–3 year change in radiographic score of ≥5. Results The discriminative ability of the three criteria sets (2010 ACR/EULAR, 1987 ACR criteria and Visser algorithm) was similar with areas under the curve of 0.71–0.78 (‘gold standard’ methotrexate), 0.74–0.80 (gold standard expert opinion RA) and 0.63–0.67 (gold standard erosive disease after 3 years). The sensitivity of the 2010 ACR/EULAR criteria was highest with 0.85 (gold standard methotrexate). 86% of patients with RA and 51% of ‘non-RA’ patients according to the new criteria used methotrexate. Conclusion The 2010 ACR/EULAR criteria were slightly more sensitive, but otherwise performed similarly to the older criteria. A high percentage of ‘non-RA’ patients used methotrexate, the gold standard for RA. The ability of the new criteria to identify patients with erosive disease was low, possibly owing to the effect of intensive treatment.

Background Prescription of analgesics is complex in patients with knee OA and severe pain. We developed a protocol for the standardized prescription of analgesics based on the World Health Organization analgesic ladder (1) and the Beating osteoARTritis (BART) strategy for stepped care in hip and knee OA (2). Objectives The aim of this study was to evaluate the feasibility and outcome of the analgesic protocol. Methods Forty-nine patients with knee OA and severe knee pain (NRS≥7; range 0-10) were included. Analgesics were prescribed following an incremental protocol (Figure 1) for a period of six weeks. Pain intensity was evaluated every two weeks. When there was insufficient pain reduction (NRS-pain>5), a consultation at the rheumatologist was planned to offer an analgesic of the next step. Analgesics of the next step were added to analgesics of the previous step(s). Analgesic use was recorded. Knee pain (NRS-pain) and activity limitations (WOMAC-PF) were measured. Data were collected at baseline and after six weeks. Subsequently, patients started with exercise therapy. Results At baseline 84% of the patients used analgesics. Of all patients, 77% used acetaminophen, 36% used NSAIDs and 16% used weak opioids. At baseline, analgesics were used irregularly and at an suboptimal dose. Analgesic use after six weeks is described in Figure 1. The maximal daily dosage was used in 93% of the patients that used acetaminophen, in 66% of the patients that used NSAIDs, and in 44% of the patients that used weak opioids. Combinations of analgesics were common. No serious adverse events occurred. In 39% of the patients NRS-pain was ≤5 after six weeks. Despite NRS-pain>5, a further step in the analgesic protocol was not accepted by the patient (n=14) or not prescribed by the rheumatologist (n=13), the latter mostly due to contra-indications or side effects. Statistically significant and clinically relevant mean improvements from baseline were 19% (p Conclusions After six weeks, patients used analgesics regularly and often at a preferential dose. Prescription of analgesics following an incremental protocol reduces pain and activity limitations in patients with knee OA and severe pain. References World Health Organization. Cancer pain relief: with a guide to opioid availability. Available at: http://whqlibdoc.who.int/publications/9241544821.pdf (accessed 14 January 2014). Smink AJ, et al. Clin Rheumatol 2011;30:1623-9. Disclosure of Interest None declared

Background Severe pain in patients with knee OA hampers the ability to exercise. A protocol for the optimization of analgesics in combination with exercise therapy was developed. The purpose of this protocol is to reduce pain and thereby allowing the patient to participate in exercise therapy. Objectives The objective of the present study was to evaluate the feasibility and outcome of the protocol. Methods Forty-nine patients with knee OA and severe knee pain (NRS-pain≥7, range 0-10) were included in this study. Analgesics were prescribed following an incremental protocol. The incremental steps were (1) acetaminophen, (2) NSAIDs, (3) weak opioids and (4) intra-articular steroid injections. After six weeks of analgesic use a supervised exercise therapy program for 12 weeks was added, consisting of muscle strengthening exercises and training of daily activities. Knee pain was assessed with NRS-pain and activity limitations were assessed with WOMAC-PF. Data were collected at baseline, after six weeks, and after 18 weeks. Results In intention-to-treat analyses statistically significant improvements in pain and activity limitations were found after six weeks of analgesic use and after the complete intervention. Mean improvements from baseline were 30% (p Conclusions The combined intervention of analgesics and exercise therapy allows most patients with knee osteoarthritis and severe pain to participate in exercise therapy, leading to reduction of pain and activity limitations. These promising results need to be confirmed in a randomized controlled trial. Disclosure of Interest None declared

Background Osteoarthritis (OA) of the knee is a leading cause of activity limitations (e.g. stair-climbing, walking) in Western countries (1), and an important physical determinant of activity limitations is muscle strength (2;3). Recent evidence points out that proprioception and varus-valgus laxity moderate (i.e. alter the strength of) the association between muscle strength and activity limitations (2;3). In early OA the moderating roles of proprioception and laxity have not yet been examined. Objectives To establish whether proprioception and varus-valgus laxity moderate the association between muscle strength and activity limitations in patients with early symptomatic knee OA. Methods A cross-sectional study was conducted in a sample of 151 participants with early symptomatic knee OA from the Cohort Hip and Cohort Knee (CHECK) study. Regression analyses were performed to establish the associations between muscle strength, proprioception (knee joint motion detection threshold in the anterior-posterior direction), varus-valgus laxity and activity limitations (self-reported and performance based). Interaction terms were used to establish whether proprioception and laxity moderated the association between muscle strength and activity limitations. Results Proprioception moderated the association between muscle strength and activity limitations: the negative association between muscle strength and activity limitations was stronger in participants with poor proprioception than in participants with accurate proprioception (performance based activity limitations, p=0.02; self-reported activity limitations, p=0.08). Varus-valgus laxity did not moderate the association between muscle strength and activity limitations: the interaction between muscle strength and varus-valgus laxity was not significantly associated with activity limitations. Conclusions The results of the present study support the theory that in the absence of adequate motor control through poor proprioceptive input, lower muscle strength affects a patient’s level of activities to a greater degree than in the presence of adequate motor control. References Michaud CM, McKenna MT, Begg S, Tomijima N, Majmudar M, Bulzacchelli MT et al. The burden of disease and injury in the United States 1996. Popul Health Metr 2006; 4:11. van der Esch M, Steultjens M, Knol DL, Dinant H, Dekker J. Joint laxity and the relationship between muscle strength and functional ability in patients with osteoarthritis of the knee. Arthritis Rheum 2006; 55(6):953-959. van der Esch M, Steultjens M, Harlaar J, Knol D, Lems W, Dekker J. Joint proprioception, muscle strength, and functional ability in patients with osteoarthritis of the knee. Arthritis Rheum 2007; 57(5):787-793. Disclosure of Interest None Declared

Background Although biomechanical factors of the knee joint like muscle strength, proprioceptive accuracy and laxity play an important role in knee osteoarthritis (OA), only limited evidence exists on associations with specific tissue abnormalities. Furthermore, findings from physical examination have never been studied in relation to tissue abnormalities of the knee joint. Objectives To explore associations between tissue abnormalities assessed by conventional radiography and high resolution MRI, biomechanical factors and physical examination findings in patients with knee OA. Methods Explorative cross-sectional study in 105 patients with knee OA. Knees were imaged using radiography and 3.0 Tesla MRI. Multivariable regression analyses were used to explore associations between tissue abnormalities, visualised by radiography or MRI, biomechanical factors (quadriceps and hamstrings muscle strength, proprioceptive accuracy and varus-valgus laxity) and physical examination findings (bony tenderness, crepitus, bony enlargement and palpable warmth). Results MRI based synovitis, MRI based cartilage loss and radiographic based joint space narrowing were found to be associated with quadriceps weakness. Radiographic features (joint space narrowing and osteophyte formation) were related to varus-valgus laxity. Multiple tissue abnormalities, but only those detected by MRI, were associated with physical examination findings (crepitus and palpable warmth). Neither MRI features nor radiographic features were found to be associated with hamstrings muscle strength, proprioceptive accuracy, bony tenderness and bony enlargement. Conclusions In conclusion, a discordance between tissue abnormalities, biomechanical factors and physical examination findings in knee OA was observed, for both conventional radiography and high resolution MRI. Relevant new findings include a highly significant association between MRI based synovitis and quadriceps weakness and a superiority of MRI over conventional radiography in association with physical examination findings. Disclosure of Interest None Declared

Background Exercise therapy is a cornerstone treatment in knee OA, but effects on pain and activity limitations are only moderate at best. Objectives To test our hypothesis that an exercise program, initially focusing on knee joint stabilization and subsequently on muscle strength and performance of daily activities is more effective in reducing activity limitations in patients with knee osteoarthritis (OA) and instability of the knee joint, compared to an exercise program focusing on muscle strength and performance of daily activities only. Methods A single-blind, randomized, controlled trial involving 159 knee OA patients with self-reported and/or biomechanically assessed knee instability, randomly assigned to two treatment groups. Both groups received a supervised exercise program for 12 weeks, consisting of muscle strengthening exercises and training of daily activities, but only in the experimental group exercises initial knee stabilization training was provided. Outcome measures included activity limitations (WOMAC physical function, primary outcome), pain, global perceived effect and knee stability. Results Both treatment groups demonstrated large (~20-40%) and clinically relevant reductions in activity limitations, pain and knee instability, which were sustained six months post treatment. No differences in effectiveness between experimental and control treatment were found on WOMAC physical function (B (95% CI) = -0.01 (-2.58-2.57)) or secondary outcome measures, except for a higher global perceived effect in the experimental group (p=.04). Subgroupanalyses revealed a significant interaction between baseline upper leg muscles strength and group effect on WOMAC, physical function (p=.02). Conclusions Both exercise programs were highly effective in reducing activity limitations and pain and restoring knee stability. Addition of specific knee joint stabilization training does not seem to be necesarry in the targeted group of knee OA patients suffering from knee instability, although subgroupanalyses suggest that those persons that have stronger upper leg muscles at baseline may benefit more from an exercise program that additionally focuses on knee joint stabilization. Disclosure of Interest None Declared

INTRODUCTION: We aimed to explore the associations between knee osteoarthritis (OA)-related tissue abnormalities assessed by conventional radiography (CR) and by high-resolution 3.0 Tesla magnetic resonance imaging (MRI), as well as biomechanical factors and findings from physical examination in patients with knee OA.METHODS: This was an explorative cross-sectional study of 105 patients with knee OA. Index knees were imaged using CR and MRI. Multiple features from CR and MRI (cartilage, osteophytes, bone marrow lesions, effusion and synovitis) were related to biomechanical factors (quadriceps and hamstrings muscle strength, proprioceptive accuracy and varus-valgus laxity) and physical examination findings (bony tenderness, crepitus, bony enlargement and palpable warmth), using multivariable regression analyses.RESULTS: Quadriceps weakness was associated with cartilage integrity, effusion, synovitis (all detected by MRI) and CR-detected joint space narrowing. Knee joint laxity was associated with MRI-detected cartilage integrity, CR-detected joint space narrowing and osteophyte formation. Multiple tissue abnormalities including cartilage integrity, osteophytes and effusion, but only those detected by MRI, were found to be associated with physical examination findings such as crepitus.CONCLUSION: We observed clinically relevant findings, including a significant association between quadriceps weakness and both effusion and synovitis, detected by MRI. Inflammation was detected in over one-third of the participants, emphasizing the inflammatory component of OA and a possible important role for anti-inflammatory therapies in knee OA. In general, OA-related tissue abnormalities of the knee, even those detected by MRI, were found to be discordant with biomechanical and physical examination features.