2016 updated EULAR evidence-based recommendations for the management of gout.

BACKGROUND: New drugs and new evidence concerning the use of established treatments have become available since the publication of the first European League Against Rheumatism (EULAR) recommendations for the management of gout, in 2006. This situation has prompted a systematic review and update of the 2006 recommendations. METHODS: The EULAR task force consisted of 15 rheumatologists, 1 radiologist, 2 general practitioners, 1 research fellow, 2 patients and 3 experts in epidemiology/methodology from 12 European countries. A systematic review of the literature concerning all aspects of gout treatments was performed. Subsequently, recommendations were formulated by use of a Delphi consensus approach. RESULTS: Three overarching principles and 11 key recommendations were generated. For the treatment of flare, colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), oral or intra-articular steroids or a combination are recommended. In patients with frequent flare and contraindications to colchicine, NSAIDs and corticosteroids, an interleukin-1 blocker should be considered. In addition to education and a non-pharmacological management approach, urate-lowering therapy (ULT) should be considered from the first presentation of the disease, and serum uric acid (SUA) levels should be maintained at<6 mg/dL (360 µmol/L) and <5 mg/dL (300 µmol/L) in those with severe gout. Allopurinol is recommended as first-line ULT and its dosage should be adjusted according to renal function. If the SUA target cannot be achieved with allopurinol, then febuxostat, a uricosuric or combining a xanthine oxidase inhibitor with a uricosuric should be considered. For patients with refractory gout, pegloticase is recommended. CONCLUSIONS: These recommendations aim to inform physicians and patients about the non-pharmacological and pharmacological treatments for gout and to provide the best strategies to achieve the predefined urate target to cure the disease.

OARSI recommendations for the management of hip and knee osteoarthritis: part III: Changes in evidence following systematic cumulative update of research published through January 2009.

OBJECTIVE: To update evidence for available therapies in the treatment of hip and knee osteoarthritis (OA) and to examine whether research evidence has changed from 31 January 2006 to 31 January 2009. METHODS: A systematic literature search was undertaken using MEDLINE, EMBASE, CINAHL, AMED, Science Citation Index and the Cochrane Library. The quality of studies was assessed. Effect sizes (ESs) and numbers needed to treat were calculated for efficacy. Relative risks, hazard ratios (HRs) or odds ratios were estimated for side effects. Publication bias and heterogeneity were examined. Sensitivity analysis was undertaken to compare the evidence pooled in different years and different qualities. Cumulative meta-analysis was used to examine the stability of evidence. RESULTS: Sixty-four systematic reviews, 266 randomised controlled trials (RCTs) and 21 new economic evaluations (EEs) were published between 2006 and 2009. Of 51 treatment modalities, new data on efficacy have been published for more than half (26/39, 67%) of those for which research evidence was available in 2006. Among non-pharmacological therapies, ES for pain relief was unchanged for self-management, education, exercise and acupuncture. However, with new evidence the ES for pain relief for weight reduction reached statistical significance, increasing from 0.13 [95% confidence interval (CI) -0.12, 0.36] in 2006 to 0.20 (95% CI 0.00, 0.39) in 2009. By contrast, the ES for electromagnetic therapy which was large in 2006 (ES=0.77, 95% CI 0.36, 1.17) was no longer significant (ES=0.16, 95% CI -0.08, 0.39). Among pharmacological therapies, the cumulative evidence for the benefits and harms of oral and topical non-steroidal anti-inflammatory drugs, diacerhein and intra-articular (IA) corticosteroid was not greatly changed. The ES for pain relief with acetaminophen diminished numerically, but not significantly, from 0.21 (0.02, 0.41) to 0.14 (0.05, 0.22) and was no longer significant when analysis was restricted to high quality trials (ES=0.10, 95% CI -0.0, 0.23). New evidence for increased risks of hospitalisation due to perforation, peptic ulceration and bleeding with acetaminophen >3g/day have been published (HR=1.20, 95% CI 1.03, 1.40). ES for pain relief from IA hyaluronic acid, glucosamine sulphate, chondroitin sulphate and avocado soybean unsponifiables also diminished and there was greater heterogeneity of outcomes and more evidence of publication bias. Among surgical treatments further negative RCTs of lavage/debridement were published and the pooled results demonstrated that benefits from this modality of therapy were no greater than those obtained from placebo. CONCLUSION: Publication of a large amount of new research evidence has resulted in changes in the calculated risk-benefit ratio for some treatments for OA. Regular updating of research evidence can help to guide best clinical practice.

Signalling cascades in mechanotransduction: cell-matrix interactions and mechanical loading.

Mechanical loading of articular cartilage stimulates the metabolism of resident chondrocytes and induces the synthesis of molecules to maintain the integrity of the cartilage. Mechanical signals modulate biochemical activity and changes in cell behavior through mechanotransduction. Compression of cartilage results in complex changes within the tissue including matrix and cell deformation, hydrostatic and osmotic pressure, fluid flow, altered matrix water content, ion concentration and fixed charge density. These changes are detected by mechanoreceptors on the cell surface, which include mechanosensitive ion channels and integrins that on activation initiate intracellular signalling cascades leading to tissue remodelling. Excessive mechanical loading also influences chondrocyte metabolism but unlike physiological stimulation leads to a quantitative imbalance between anabolic and catabolic activity resulting in depletion of matrix components. In this article we focus on the role of mechanical signalling in the maintenance of articular cartilage, and discuss how alterations in normal signalling can lead to pathology.

Mechanical regulation of proteoglycan synthesis in normal and osteoarthritic human articular chondrocytes--roles for alpha5 and alphaVbeta5 integrins.

The importance of biomechanical forces in regulating normal chondrocyte metabolism is well established and the mechanisms whereby mechanical forces are transduced into biochemical responses by chondrocytes are beginning to be understood. Previous studies have indicated that cyclical mechanical stimulation induces increased aggrecan gene expression in normal but not osteoarthritic chondrocytes in monolayer. It remains unclear, however, whether these effects on gene expression are associated with changes in proteoglycan production and whether any changes in proteoglycan expression is dependent on integrins or integrin associated proteins. Normal and osteoarthritic articular chondrocytes in monolayer were exposed to 0.33 Hz mechanical stimulation for 20 min in the absence or presence of function modifying anti-integrin antibodies. Following stimulation GAG and proteoglycan (PG) synthesis was assessed by DMMB assay and western blotting. Mechanical stimulation of normal chondrocytes resulted in increased GAG synthesis that was blocked by the presence of antibodies to alpha5 and alphaVbeta5 integrins and CD47. Electrophoretic patterns of PGs released from normal chondrocytes following mechanical stimulation showed an increase in newly-synthesized aggrecan that was not fragmented or degraded. Chondrocytes from osteoarthritic cartilage showed lower levels of GAG production when compared to normal chondrocytes and synthesis was not influenced by mechanical stimulation. These studies show that chondrocytes derived from normal and OA cartilage have different matrix production responses to mechanical stimulation and suggest previously unrecognised roles for alphaVbeta5 integrin in regulation of chondrocyte responses to biomechanical stimulation.

Cod liver oil (n-3 fatty acids) as an non-steroidal anti-inflammatory drug sparing agent in rheumatoid arthritis.

OBJECTIVES: Dose-dependant gastrointestinal and cardiovascular side-effects limit the use of NSAIDs in the management of RA. The n-3 essential fatty acids (EFAs) have previously demonstrated some anti-inflammatory and NSAID-sparing properties. The objective of this study was to determine whether cod liver oil supplementation helps reduce daily NSAID requirement of patients with RA. METHODS: Dual-centre, double-blind placebo-controlled randomized study of 9 months' duration. Ninety-seven patients with RA were randomized to take either 10 g of cod liver oil containing 2.2 g of n-3 EFAs or air-filled identical placebo capsules. Documentation of NSAID daily requirement, clinical and laboratory parameters of RA disease activity and safety checks were done at 0, 4, 12, 24 and 36 weeks. At 12 weeks, patients were instructed to gradually reduce, and if possible, stop their NSAID intake. Relative reduction of daily NSAID requirement by >30% after 9 months was the primary outcome measure. RESULTS: Fifty-eight patients (60%) completed the study. Out of 49 patients 19 (39%) in the cod liver oil group and out of 48 patients 5 (10%) in the placebo group were able to reduce their daily NSAID requirement by >30% (P = 0.002, chi-squared test). No differences between the groups were observed in the clinical parameters of RA disease activity or in the side-effects observed. CONCLUSIONS: This study suggests that cod liver oil supplements containing n-3 fatty acids can be used as NSAID-sparing agents in RA patients.

OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines.

PURPOSE: To develop concise, patient-focussed, up to date, evidence-based, expert consensus recommendations for the management of hip and knee osteoarthritis (OA), which are adaptable and designed to assist physicians and allied health care professionals in general and specialist practise throughout the world. METHODS: Sixteen experts from four medical disciplines (primary care, rheumatology, orthopaedics and evidence-based medicine), two continents and six countries (USA, UK, France, Netherlands, Sweden and Canada) formed the guidelines development team. A systematic review of existing guidelines for the management of hip and knee OA published between 1945 and January 2006 was undertaken using the validated appraisal of guidelines research and evaluation (AGREE) instrument. A core set of management modalities was generated based on the agreement between guidelines. Evidence before 2002 was based on a systematic review conducted by European League Against Rheumatism and evidence after 2002 was updated using MEDLINE, EMBASE, CINAHL, AMED, the Cochrane Library and HTA reports. The quality of evidence was evaluated, and where possible, effect size (ES), number needed to treat, relative risk or odds ratio and cost per quality-adjusted life years gained were estimated. Consensus recommendations were produced following a Delphi exercise and the strength of recommendation (SOR) for propositions relating to each modality was determined using a visual analogue scale. RESULTS: Twenty-three treatment guidelines for the management of hip and knee OA were identified from the literature search, including six opinion-based, five evidence-based and 12 based on both expert opinion and research evidence. Twenty out of 51 treatment modalities addressed by these guidelines were universally recommended. ES for pain relief varied from treatment to treatment. Overall there was no statistically significant difference between non-pharmacological therapies [0.25, 95% confidence interval (CI) 0.16, 0.34] and pharmacological therapies (ES=0.39, 95% CI 0.31, 0.47). Following feedback from Osteoarthritis Research International members on the draft guidelines and six Delphi rounds consensus was reached on 25 carefully worded recommendations. Optimal management of patients with OA hip or knee requires a combination of non-pharmacological and pharmacological modalities of therapy. Recommendations cover the use of 12 non-pharmacological modalities: education and self-management, regular telephone contact, referral to a physical therapist, aerobic, muscle strengthening and water-based exercises, weight reduction, walking aids, knee braces, footwear and insoles, thermal modalities, transcutaneous electrical nerve stimulation and acupuncture. Eight recommendations cover pharmacological modalities of treatment including acetaminophen, cyclooxygenase-2 (COX-2) non-selective and selective oral non-steroidal anti-inflammatory drugs (NSAIDs), topical NSAIDs and capsaicin, intra-articular injections of corticosteroids and hyaluronates, glucosamine and/or chondroitin sulphate for symptom relief; glucosamine sulphate, chondroitin sulphate and diacerein for possible structure-modifying effects and the use of opioid analgesics for the treatment of refractory pain. There are recommendations covering five surgical modalities: total joint replacements, unicompartmental knee replacement, osteotomy and joint preserving surgical procedures; joint lavage and arthroscopic debridement in knee OA, and joint fusion as a salvage procedure when joint replacement had failed. Strengths of recommendation and 95% CIs are provided. CONCLUSION: Twenty-five carefully worded recommendations have been generated based on a critical appraisal of existing guidelines, a systematic review of research evidence and the consensus opinions of an international, multidisciplinary group of experts. The recommendations may be adapted for use in different countries or regions according to the availability of treatment modalities and SOR for each modality of therapy. These recommendations will be revised regularly following systematic review of new research evidence as this becomes available.

Gout in the UK and Germany: prevalence, comorbidities and management in general practice 2000-2005.

OBJECTIVE: To investigate and compare the prevalence, comorbidities and management of gout in practice in the UK and Germany. METHODS: A retrospective analysis of patients with gout, identified through the records of 2.5 million patients in UK general practices and 2.4 million patients attending GPs or internists in Germany, using the IMS Disease Analyzer. RESULTS: The prevalence of gout was 1.4% in the UK and Germany. Obesity was the most common comorbidity in the UK (27.7%), but in Germany the most common comorbidity was diabetes (25.9%). The prevalence of comorbidities tended to increase with serum uric acid (sUA) levels. There was a positive correlation between sUA level and the frequency of gout flares. Compared with those in whom sUA was <360 micromol/l (<6 mg/dl), odds ratios for a gout flare were 1.33 and 1.37 at sUA 360-420 micromol/l (6-7 mg/dl), and 2.15 and 2.48 at sUA >530 micromol/l ( >9 mg/dl) in the UK and Germany, respectively (p<0.01). CONCLUSIONS: The prevalence of gout in practice in the UK and Germany in the years 2000-5 was 1.4%, consistent with previous UK data for 1990-9. Chronic comorbidities were common among patients with gout and included conditions associated with an increased risk for cardiovascular disease, such as obesity, diabetes and hypertension. The importance of regular monitoring of sUA in order to tailor gout treatment was highlighted by data from this study showing that patients with sUA levels >or=360 micromol/l (>or=6 mg/dl) had an increased risk of gout flares.

OARSI recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of existing treatment guidelines and systematic review of current research evidence.

PURPOSE: As a prelude to developing updated, evidence-based, international consensus recommendations for the management of hip and knee osteoarthritis (OA), the Osteoarthritis Research Society International (OARSI) Treatment Guidelines Committee undertook a critical appraisal of published guidelines and a systematic review (SR) of more recent evidence for relevant therapies. METHODS: Sixteen experts from four medical disciplines (primary care two, rheumatology 11, orthopaedics one and evidence-based medicine two), two continents and six countries (USA, UK, France, Netherlands, Sweden and Canada) formed the guidelines development team. Three additional experts were invited to take part in the critical appraisal of existing guidelines in languages other than English. MEDLINE, EMBASE, Science Citation Index, CINAHL, AMED, Cochrane Library, seven Guidelines Websites and Google were searched systematically to identify guidelines for the management of hip and/or knee OA. Guidelines which met the inclusion/exclusion criteria were assigned to four groups of four appraisers. The quality of the guidelines was assessed using the AGREE (Appraisal of Guidelines for Research and Evaluation) instrument and standardised percent scores (0-100%) for scope, stakeholder involvement, rigour, clarity, applicability and editorial independence, as well as overall quality, were calculated. Treatment modalities addressed and recommended by the guidelines were summarised. Agreement (%) was estimated and the best level of evidence to support each recommendation was extracted. Evidence for each treatment modality was updated from the date of the last SR in January 2002 to January 2006. The quality of evidence was evaluated using the Oxman and Guyatt, and Jadad scales for SRs and randomised controlled trials (RCTs), respectively. Where possible, effect size (ES), number needed to treat, relative risk (RR) or odds ratio and cost per quality-adjusted life year gained (QALY) were estimated. RESULTS: Twenty-three of 1462 guidelines or consensus statements retrieved from the literature search met the inclusion/exclusion criteria. Six were predominantly based on expert opinion, five were primarily evidence based and 12 were based on both. Overall quality scores were 28%, 41% and 51% for opinion-based, evidence-based and hybrid guidelines, respectively (P=0.001). Scores for aspects of quality varied from 18% for applicability to 67% for scope. Thirteen guidelines had been developed for specific care settings including five for primary care (e.g., Prodigy Guidance), three for rheumatology (e.g., European League against Rheumatism recommendations), three for physiotherapy (e.g., Dutch clinical practice guidelines for physical therapy) and two for orthopaedics (e.g., National Institutes of Health consensus guidelines), whereas 10 did not specify the target users (e.g., Ontario guidelines for optimal therapy). Whilst 14 guidelines did not separate hip and knee, eight were specific for knee but only one for hip. Fifty-one different treatment modalities were addressed by these guidelines, but only 20 were universally recommended. Evidence to support these modalities ranged from Ia (meta-analysis/SR of RCTs) to IV (expert opinion). The efficacy of some modalities of therapy was confirmed by the results of RCTs published between January 2002 and 2006. These included exercise (strengthening ES 0.32, 95% confidence interval (CI) 0.23, 0.42, aerobic ES 0.52, 95% CI 0.34, 0.70 and water-based ES 0.25, 95% CI 0.02, 0.47) and nonsteroidal anti-inflammatory drugs (NSAIDs) (ES 0.32, 95% CI 0.24, 0.39). Examples of other treatment modalities where recent trials failed to confirm efficacy included ultrasound (ES 0.06, 95% CI -0.39, 0.52), massage (ES 0.10, 95% CI -0.23, 0.43) and heat/ice therapy (ES 0.69, 95% CI -0.07, 1.45). The updated evidence on adverse effects also varied from treatment to treatment. For example, while the evidence for gastrointestinal (GI) toxicity of non-selective NSAIDs (RR=5.36, 95% CI 1.79, 16.10) and for increased risk of myocardial infarction associated with rofecoxib (RR=2.24, 95% CI 1.24, 4.02) were reinforced, evidence for other potential drug related adverse events such as GI toxicity with acetaminophen or myocardial infarction with celecoxib remained inconclusive. CONCLUSION: Twenty-three guidelines have been developed for the treatment of hip and/or knee OA, based on opinion alone, research evidence or both. Twenty of 51 modalities of therapy are universally recommended by these guidelines. Although this suggests that a core set of recommendations for treatment exists, critical appraisal shows that the overall quality of existing guidelines is sub-optimal, and consensus recommendations are not always supported by the best available evidence. Guidelines of optimal quality are most likely to be achieved by combining research evidence with expert consensus and by paying due attention to issues such as editorial independence, stakeholder involvement and applicability. This review of existing guidelines provides support for the development of new guidelines cognisant of the limitations in existing guidelines. Recommendations should be revised regularly following SR of new research evidence as this becomes available.

Evidence for JNK-dependent up-regulation of proteoglycan synthesis and for activation of JNK1 following cyclical mechanical stimulation in a human chondrocyte culture model.

OBJECTIVE: To examine the expression of mitogen-activated protein kinases (MAPKs) in human chondrocytes, to investigate whether selective activation of MAPKs is involved in up-regulation of proteoglycan (PG) synthesis following cyclical mechanical stimulation (MS), and to examine whether MS is associated with integrin-dependent or independent activation of MAPKs. METHODS: The C-28/I2 and C-20/A4 human chondrocyte cell lines were mechanically stimulated in monolayer cell culture. PG synthesis was assessed by [(35)S]-sulphate incorporation in the presence and absence of the p38 inhibitor SB203580, and the extracellular-regulated kinase (ERK1/2) inhibitor PD98059. Kinase expression and activation were assessed by Western blotting using phosphorylation status-dependent and independent antibodies, and by kinase assays. The Jun N-terminal kinase (JNK) inhibitor SP600125 and the anti-beta(1) integrin (CD29) function-blocking antibody were used to assess JNK activation and integrin dependence, respectively. RESULTS: Increased PG synthesis following 3 h of cyclic MS was abolished by pretreatment with 10 microM SB203580, but was not affected by 50 microM PD98059. The kinases p38, ERK1/ERK2 and JNKs were expressed in both stimulated and unstimulated cells. Phosphorylated p38 was detected at various time points following 0.5, 1, 2 and 3 h MS in C-28/I2, but not detected in C-20/A4 cell lines. Phosphorylation of ERK1 and ERK2 was not significantly affected by MS. Phosphorylation of the 54 and 46 kDa JNKs increased following 0.5, 1, 2 and 3 h of MS, and following CO(2) deprivation. MS-induced JNK phosphorylation was inhibited by SB203580 at concentrations > or =5 microM and activation of JNK1 following MS was blocked by SP600125 and partially inhibited by anti-CD29. CONCLUSIONS: The data suggest JNK, rather than p38 or ERK dependent increases in PG synthesis, and selective, partially integrin-dependent, activation of JNK kinases in human chondrocyte cell lines following cyclical MS. JNK activation is also very sensitive to changes in CO(2)/pH in this chondrocyte culture model.

EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT).

OBJECTIVE: To develop evidence based recommendations for the management of gout. METHODS: The multidisciplinary guideline development group comprised 19 rheumatologists and one evidence based medicine expert representing 13 European countries. Key propositions on management were generated using a Delphi consensus approach. Research evidence was searched systematically for each proposition. Where possible, effect size (ES), number needed to treat, relative risk, odds ratio, and incremental cost-effectiveness ratio were calculated. The quality of evidence was categorised according to the level of evidence. The strength of recommendation (SOR) was assessed using the EULAR visual analogue and ordinal scales. RESULTS: 12 key propositions were generated after three Delphi rounds. Propositions included both non-pharmacological and pharmacological treatments and addressed symptomatic control of acute gout, urate lowering therapy (ULT), and prophylaxis of acute attacks. The importance of patient education, modification of adverse lifestyle (weight loss if obese; reduced alcohol consumption; low animal purine diet) and treatment of associated comorbidity and risk factors were emphasised. Recommended drugs for acute attacks were oral non-steroidal anti-inflammatory drugs (NSAIDs), oral colchicine (ES = 0.87 (95% confidence interval, 0.25 to 1.50)), or joint aspiration and injection of corticosteroid. ULT is indicated in patients with recurrent acute attacks, arthropathy, tophi, or radiographic changes of gout. Allopurinol was confirmed as effective long term ULT (ES = 1.39 (0.78 to 2.01)). If allopurinol toxicity occurs, options include other xanthine oxidase inhibitors, allopurinol desensitisation, or a uricosuric. The uricosuric benzbromarone is more effective than allopurinol (ES = 1.50 (0.76 to 2.24)) and can be used in patients with mild to moderate renal insufficiency but may be hepatotoxic. When gout is associated with the use of diuretics, the diuretic should be stopped if possible. For prophylaxis against acute attacks, either colchicine 0.5-1 mg daily or an NSAID (with gastroprotection if indicated) are recommended. CONCLUSIONS: 12 key recommendations for management of gout were developed, using a combination of research based evidence and expert consensus. The evidence was evaluated and the SOR provided for each proposition.

EULAR evidence based recommendations for gout. Part I: Diagnosis. Report of a task force of the Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT).

OBJECTIVE: To develop evidence based recommendations for the diagnosis of gout. METHODS: The multidisciplinary guideline development group comprised 19 rheumatologists and one evidence based medicine expert, representing 13 European countries. Ten key propositions regarding diagnosis were generated using a Delphi consensus approach. Research evidence was searched systematically for each proposition. Wherever possible the sensitivity, specificity, likelihood ratio (LR), and incremental cost-effectiveness ratio were calculated for diagnostic tests. Relative risk and odds ratios were estimated for risk factors and co-morbidities associated with gout. The quality of evidence was categorised according to the evidence hierarchy. The strength of recommendation (SOR) was assessed using the EULAR visual analogue and ordinal scales. RESULTS: 10 key propositions were generated though three Delphi rounds including diagnostic topics in clinical manifestations, urate crystal identification, biochemical tests, radiographs, and risk factors/co-morbidities. Urate crystal identification varies according to symptoms and observer skill but is very likely to be positive in symptomatic gout (LR = 567 (95% confidence interval (CI), 35.5 to 9053)). Classic podagra and presence of tophi have the highest clinical diagnostic value for gout (LR = 30.64 (95% CI, 20.51 to 45.77), and LR = 39.95 (21.06 to 75.79), respectively). Hyperuricaemia is a major risk factor for gout and may be a useful diagnostic marker when defined by the normal range of the local population (LR = 9.74 (7.45 to 12.72)), although some gouty patients may have normal serum uric acid concentrations at the time of investigation. Radiographs have little role in diagnosis, though in late or severe gout radiographic changes of asymmetrical swelling (LR = 4.13 (2.97 to 5.74)) and subcortical cysts without erosion (LR = 6.39 (3.00 to 13.57)) may be useful to differentiate chronic gout from other joint conditions. In addition, risk factors (sex, diuretics, purine-rich foods, alcohol, lead) and co-morbidities (cardiovascular diseases, hypertension, diabetes, obesity, and chronic renal failure) are associated with gout. SOR for each proposition varied according to both the research evidence and expert opinion. CONCLUSIONS: 10 key recommendations for diagnosis of gout were developed using a combination of research based evidence and expert consensus. The evidence for diagnostic tests, risk factors, and co-morbidities was evaluated and the strength of recommendation was provided.

A multicentre, randomised, double blind, placebo controlled phase II study of subcutaneous interferon beta-1a in the treatment of patients with active rheumatoid arthritis.

OBJECTIVE: To assess the efficacy of interferon beta (IFN beta) in combination with methotrexate in treatment of patients with rheumatoid arthritis. METHODS: 209 patients with active rheumatoid arthritis, who had been on methotrexate for at least six months and at a stable dose for four weeks before study entry, were randomised in double blind fashion to receive placebo (0.05 ml or 0.5 ml), IFN beta 2.2 microg (0.05 ml), or IFN beta 44 microg (0.5 ml), given subcutaneously three times weekly for 24 weeks. The primary efficacy measure was a change in radiological scores at week 24. The secondary endpoint was the proportion of patients who met the ACR 20% improvement criteria at the end of the study. Synovial biopsy specimens were obtained before and after treatment from a subset of patients. Immunohistochemistry was used to detect the presence of inflammatory cells and the results were measured by digital image analysis. Collagen crosslinks were measured in urine at different times throughout the study. RESULTS: Analysis of radiological scores and clinical variable showed no changes in any of the groups, and there were no differences between the groups. On microscopic analysis of synovial tissue there was no significant change in the scores for infiltration by inflammatory cells after IFN beta treatment. Urinary levels of collagen crosslinks were unchanged between the treatment groups. CONCLUSIONS: At the doses tested, treatment with IFN beta three times weekly in combination with methotrexate did not have a clinical or radiological effect in patients with rheumatoid arthritis.

The need for clinical guidance in the use of calcium and vitamin D in the management of osteoporosis: a consensus report.

A European Union (EU) directive on vitamins and minerals used as ingredients of food supplements with a nutritional or physiological effect (2002/46/EC) was introduced in 2003. Its implications for the use of oral supplements of calcium and vitamin D in the prevention and treatment of osteoporosis were discussed at a meeting organized with the help of the World Health Organization (WHO) Collaborating Center for Public Health Aspects of Rheumatic Diseases (Liège, Belgium) and the support of the WHO Collaborating Center for Osteoporosis Prevention (Geneva, Switzerland). The following issues were addressed: Is osteoporosis a physiological or a medical condition? What is the evidence for the efficacy of calcium and vitamin D in the management of postmenopausal osteoporosis? What are the risks of self-management by patients in osteoporosis? From their discussions, the panel concluded that: (1) osteoporosis is a disease that requires continuing medical attention to ensure optimal therapeutic benefits; (2) when given in appropriate doses, calcium and vitamin D have been shown to be pharmacologically active (particularly in patients with dietary deficiencies), safe, and effective for the prevention and treatment of osteoporotic fractures; (3) calcium and vitamin D are an essential, but not sufficient, component of an integrated management strategy for the prevention and treatment of osteoporosis in patients with dietary insufficiencies, although maximal benefit in terms of fracture prevention requires the addition of antiresorptive therapy; (4) calcium and vitamin D are a cost-effective medication in the prevention and treatment of osteoporosis; (5) it is apparent that awareness of the efficacy of calcium and vitamin D in osteoporosis is still low and further work needs to be done to increase awareness among physicians, patients, and women at risk; and (6) in order that calcium and vitamin D continues to be manufactured to Good Manufacturing Practice standards and physicians and other health care professionals continue to provide guidance for the optimal use of these agents, they should continue to be classified as medicinal products.

The effect of DXA scanning on clinical decision making by general practitioners: a randomized, prospective trial of direct access versus referral to a hospital consultant.

The objective of the study was to assess the impact of direct access DXA scanning (DADS) upon GPs' management decisions in patients considered to be at risk of osteoporosis. It was designed as a randomized, prospective, parallel group trial, set within the primary care environment and a university teaching hospital. The participants were 330 patients aged 31 to 89 years from 18 general practices in Edinburgh. Patients were randomized to either DADS or to the current system of specialist referral (controls). The primary outcome measure was frequency of change of management after DXA scanning. Secondary outcome measures were: change in health status, adherence to therapy, clinical events and resource use at one-year follow-up. The primary outcome was that 60% each of DADS patients (98/165) and controls (99/165) had changes in management following DXA scanning. In 30% of patients (12/41) in whom GPs had proposed changing management even in the absence of a scan, different therapy was chosen after the scan (no difference between DADS and control groups). There was an improvement in health utility (p =0.014 for both groups combined), differing slightly between the two groups even after age correction (p =0.014). 68% of the DADS group and 70% of controls were adherent to therapy after one year. In terms of clinical events, at one year there was one major adverse event (control group patient), 5 new fractures in the DADS group and 3 in controls - there were no hip fractures in this study. With regard to resource use, there were 24 referrals to hospital specialist after DXA scanning among the DADS group, vs 12 among controls (p < 0.05). The total number of visits to health professionals was 525 in DADS and 585 in controls (p=ns); mean waiting time from randomization to receipt of report/clinic letter was 4 weeks for DADS vs 13 weeks for controls( p < 0.0001). In conclusion, DXA scanning resulted in management change in at least 60% of cases. Direct access does not result in a clinical outcome significantly different from a consultant led service, and is more economically efficient than the current model of hospital referral.

Activation of Integrin-RACK1/PKCalpha signalling in human articular chondrocyte mechanotransduction.

OBJECTIVE: The objective of this study was to examine PKC isozyme expression in human articular chondrocytes and assess roles for RACK1, a receptor for activated C kinase in the mechanotransduction process. METHODS: Primary cultures of human articular chondrocytes and a human chondrocyte cell line were studied for expression of PKC isozymes and RACK1 by western blotting. Following mechanical stimulation of chondrocytes in vitro in the absence or presence of anti-integrin antibodies and RGD containing oligopeptides, subcellular localization of PKCalpha and association of RACK1 with PKCalpha and beta1 integrin was assessed. RESULTS: Human articular chondrocytes express PKC isozymes alpha, gamma, delta, iota, and lambda. Following mechanical stimulation at 0.33Hz chondrocytes show a rapid, beta1 integrin dependent, translocation of PKCalpha to the cell membrane and increased association of RACK1 with PKCalpha and beta1 integrin. CONCLUSIONS: RACK1 mediated translocation of activated PKCalpha to the cell membrane and modulation of integrin-associated signaling are likely to be important in regulation of downstream signaling cascades controlling chondrocyte responses to mechanical stimuli.

Differential responses of chondrocytes from normal and osteoarthritic human articular cartilage to mechanical stimulation.

Mechanical stimulation is critically important for the maintenance of normal articular cartilage integrity. Molecular events regulating responses of chondrocytes to mechanical forces are beginning to be defined. Chondrocytes from normal human knee joint articular cartilage show increased levels of aggrecan mRNA following 0.33 Hz mechanical stimulation whilst at the same time relative levels of MMP3 mRNA are decreased. This anabolic response, associated with membrane hyperpolarisation, is activated via an integrin-dependent interleukin (IL)-4 autocrine/paracrine loop. Work in our laboratory suggests that this chondroprotective response may be aberrant in osteoarthritis (OA). Chondrocytes from OA cartilage show no changes in aggrecan or MMP3 mRNA following 0.33 Hz mechanical stimulation. alpha5beta1 integrin is the mechanoreceptor in both normal and OA chondrocytes but downstream signalling pathways differ. OA chondrocytes show membrane depolarisation following 0.33 Hz mechanical stimulation consequent to activation of an IL1beta autocrine/paracrine loop. IL4 signalling in OA chondrocytes is preferentially through the type I (IL4alpha/cgamma) receptor rather than via the type II (IL4alpha/IL13R) receptor. Altered mechanotransduction and signalling in OA may contribute to changes in chondrocyte behaviour leading to increased cartilage breakdown and disease progression.

Integrin-interleukin-4 mechanotransduction pathways in human chondrocytes.

Mechanical stimuli are known to have major influences on chondrocyte function. The molecular events that regulate chondrocyte responses to mechanical stimulation are beginning to be understood. In vitro analyses have allowed identification of mechanotransduction pathways that control molecular and biochemical responses of human articular chondrocytes to cyclical mechanical stimulation. These studies have shown that human articular chondrocytes use alpha5beta1 integrin as a mechanoreceptor. After stimulation of this integrin by mechanical stimulation, there is activation of a signal cascade, involving stretch-activated ion channels, the actin cytoskeleton and tyrosine phosphorylation of the focal adhesion complex molecules pp125 focal adhesion kinase and paxillin, and beta-catenin. Subsequently, there is secretion of interleukin-4, which acts in an autocrine manner via Type II receptors, to induce membrane hyperpolarization, increase levels of aggrecan messenger ribonucleic acid, and decrease levels of matrix metalloproteinase 3 messenger ribonucleic acid. Chondrocytes from osteoarthritic cartilage also use alpha5beta1 integrin as a mechanoreceptor, but downstream signaling cascades and cell responses including changes in aggrecan messenger ribonucleic acid are different. Abnormalities of chondroprotective mechanotransduction pathways in osteoarthritis may contribute to disease progression.

Mechanotransduction via integrins and interleukin-4 results in altered aggrecan and matrix metalloproteinase 3 gene expression in normal, but not osteoarthritic, human articular chondrocytes.

OBJECTIVE: To determine molecular events in the regulation of messenger RNA (mRNA) of cartilage matrix molecules and proteases by mechanical stimulation of chondrocytes from normal human articular cartilage and to ascertain whether similar regulatory systems are present in chondrocytes from osteoarthritic (OA) cartilage. METHODS: Chondrocytes extracted from macroscopically and microscopically normal and OA cartilage were mechanically stimulated in the presence or absence of GRGDSP or GRADSP oligopeptides, neutralizing interleukin-4 (IL-4) antibodies, gadolinium, or apamin. The relative levels of mRNA for aggrecan, tenascin, matrix metalloproteinase 1 (MMP-1), MMP-3, and tissue inhibitor of metalloproteinases 1 (TIMP-1) were determined by semiquantitative reverse transcription-polymerase chain reaction at several time points up to 24 hours poststimulation, using GAPDH as a control. RESULTS: Normal chondrocytes showed an increase in aggrecan mRNA and a decrease in MMP-3 mRNA within 1 hour following stimulation, with a return to baseline levels within 24 hours. These changes were blocked by GRGDSP, IL-4 antibodies, and gadolinium, but were unaffected by apamin. In contrast, chondrocytes isolated from OA cartilage showed no change in aggrecan or MMP-3 mRNA levels following mechanical stimulation. The mRNA levels of tenascin, MMP-1, and TIMP-1 were unaltered in mechanically stimulated normal and OA chondrocytes. CONCLUSION: Mechanical stimulation of human articular chondrocytes in vitro results in increased levels of aggrecan mRNA and decreased levels of MMP-3 mRNA. The transduction process involves integrins, stretch-activated ion channels, and IL-4. This chondroprotective response is absent in chondrocytes from OA cartilage. Abnormalities of mechanotransduction leading to aberrant chondrocyte activity in diseased articular cartilage may be important in the progression of OA.

Integrin and mechanosensitive ion channel-dependent tyrosine phosphorylation of focal adhesion proteins and beta-catenin in human articular chondrocytes after mechanical stimulation.

Mechanical forces influence chondrocyte metabolism and function. We have previously shown that 0.33 Hz cyclical pressure-induced strain (PIS) results in membrane hyperpolarization of normal human articular chondrocytes (HAC) by activation of Ca(2+)-dependent K+ small conductance potassium activated calcium (SK) channels. The mechanotransduction pathway involves alpha 5 beta 1-integrin, stretch-activated ion channels (SAC) actin cytoskeleton and tyrosine protein kinases, with subsequent release of the chondroprotective cytokine interleukin-4 (IL-4). The objective of this study was to examine in detail tyrosine phosphorylation events in the mechanotransduction pathway. The results show tyrosine phosphorylation of three major proteins, p125, p90, and p70 within 1 minute of onset of mechanical stimulation. Immunoblotting and immunoprecipitation show these to be focal adhesion kinase (pp125FAK), beta-catenin, and paxillin, respectively. Tyrosine phosphorylation of all three proteins is inhibited by RGD containing oligopeptides and gadolinium, which is known to block SAC. beta-catenin coimmunoprecipitates with FAK and is colocalized with alpha 5-integrin and pp125FAK. These results indicate a previously unrecognized role for an integrin-beta-catenin signaling pathway in human articular chondrocyte (HAC) responses to mechanical stimulation.

Altered electrophysiological responses to mechanical stimulation and abnormal signalling through alpha5beta1 integrin in chondrocytes from osteoarthritic cartilage.

OBJECTIVE: To establish whether chondrocytes from normal and osteoarthritic human articular cartilage recognize and respond to pressure induced mechanical strain in a similar manner. DESIGN: Chondrocytes, extracted from macroscopically normal and osteoarthritic human articular cartilage obtained from knee joints at autopsy, were grown in monolayer culture and subjected to cyclical pressure-induced strain (PIS) in the absence or presence of anti-integrin antibodies, agents known to block ion channels and inhibitors of key molecules involved in the integrin-associated signalling pathways. The response of the cells to mechanical stimulation was assessed by measuring changes in membrane potential. RESULTS: Unlike chondrocytes from normal articular cartilage, which showed a membrane hyperpolarization response to PIS, chondrocytes from osteoarthritic cartilage responded by membrane depolarization. The mechanotransduction pathway involves alpha5beta1 integrins, stretch-activated ion channels, tyrosine kinases and phospholipase C but the actin cytoskeleton and protein kinase C, which are important in the membrane hyperpolarization response in normal chondrocytes, are not necessary for membrane depolarization in osteoarthritic chondrocytes in response to PIS. CONCLUSION: Chondrocytes derived from osteoarthritic cartilage show a different signalling pathway via alpha5beta1 integrin in response to mechanical stimulation which may be of importance in the production of phenotypic changes recognized to be present in diseased cartilage.