Level of acceptability of EULAR recommendations for the management of knee osteoarthritis by practitioners in different European countries.

OBJECTIVE: To evaluate the level of acceptability of the EULAR recommendations for the management of knee osteoarthritis (KOA) in practice. METHODS: A questionnaire was sent to general practitioners, rheumatologists, rehabilitators, and orthopaedic surgeons in five European countries (France, Spain, Belgium, Switzerland, Italy). Practitioners were asked to give their opinion on the 10 EULAR recommendations and on 23 treatment modes for KOA. Practitioners' opinions were compared with those of the expert task force involved in the development of these recommendations. RESULTS: The overall response rate was 10.4% (4204 replies). Results were similar across countries and specialties. Of the 23 treatment modes proposed, only joint lavage and intra-articular (IA) corticosteroid injections were more strongly recommended by the expert task force than by the responders as a whole, while the opposite was true for spa therapy. Principal component analysis showed: (1) some practitioners preferred "hard line" treatments (surgery, IA injections, or non-steroidal anti-inflammatory drugs (NSAIDs)); (2) there was a difference between those prescribing pharmacological (paracetamol) or non-pharmacological measures with low iatrogenicity (exercises, sticks, education), and those prescribing less well validated treatments closer to "alternative" medicine; (3) each specialist tended to advocate modes that they were most familiar with: rheumatologists were more likely to recommend IA injections and NSAIDs; orthopaedic surgeons, surgical procedures; rehabilitators, education and all non-pharmacological modes; general practitioners, spa therapy and opioids. CONCLUSIONS: A multidisciplinary approach is optimal in the management of this chronic disease with its variable course.

EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT).

OBJECTIVES: To update the EULAR recommendations for management of knee osteoarthritis (OA) by an evidence based medicine and expert opinion approach. METHODS: The literature search and guidelines were restricted to treatments for knee OA pertaining to clinical and/or radiological OA of any compartment of the knee. Papers for combined treatment of knee and other types of OA were excluded. Medline and Embase were searched using a combination of subject headings and key words. Searches for those treatments previously investigated were conducted for January 1999 to February 2002 and for those treatments not previously investigated for 1966 to February 2002. The level of evidence found for each treatment was documented. Quality scores were determined for each paper, an effect size comparing the treatment with placebo was calculated, where possible, and a toxicity profile was determined for each treatment modality. RESULTS: 497 new publications were identified by the search. Of these, 103 were intervention trials and included in the overall analysis, and 33 treatment modalities were identified. Previously identified publications which were not exclusively knee OA in the initial analysis were rejected. In total, 545 publications were included. Based on the results of the literature search and expert opinion, 10 recommendations for the treatment of knee OA were devised using a five stage Delphi technique. Based on expert opinion, a further set of 10 items was identified by a five stage Delphi technique as important for future research. CONCLUSION: The updated recommendations support some of the previous propositions published in 2000 but also include modified statements and new propositions. Although a large number of treatment options for knee OA exist, the evidence based format of the EULAR Recommendations continues to identify key clinical questions that currently are unanswered.

Epidemiological profile of symptomatic osteoarthritis in older adults: a population based study in Dicomano, Italy.

OBJECTIVES: To assess the prevalence of hand, hip, and knee osteoarthritis (OA) in an older Italian community dwelling population and its association with disability. METHOD: A cross sectional survey of the whole community aged 65 years and over, was carried out in Dicomano, a small rural town in Tuscany, Italy. Subjects were screened by geriatricians for major chronic conditions, including hip, knee, and hand OA, using diagnostic algorithms based on the American College of Rheumatology (ACR) clinical criteria. A rheumatologist examined subjects who screened positive. Disability was assessed by a World Health Organisation questionnaire. RESULTS: 697 of 864 eligible subjects (81% of the eligible population) were screened. OA of the knee, hand, or hip was identified by clinical ACR criteria respectively in 159, 139, and 81 subjects, and was confirmed by the rheumatologist in 158/182 (87%), 75/101 (74%), and 63.2% of cases. The estimated prevalence was 29.8%, 14.9%, and 7.7%, respectively. Only hip OA was significantly associated with disability in basic activities of daily living. CONCLUSIONS: About one third of community dwelling older people are affected by symptomatic peripheral OA. Hip OA was strongly associated with disability.

WHO Collaborating Centre consensus meeting on anti-cytokine therapy in rheumatoid arthritis.

Severe adult rheumatoid arthritis is a cause of progressive disability and increased mortality across Europe. A cure for the disease remains elusive, but control of symptoms and maintenance of individual independence is possible. Anti-cytokine therapies offer a new approach to disease management. They are effective after the failure of full doses of methotrexate, and are at least as effective as methotrexate in retarding the progression of radiological changes. Until more is known about the long-term safety and efficacy of these drugs they should be reserved for patients with severe disease who are progressing despite adequate doses of methotrexate or other disease-modifying anti-rheumatic drugs. They should be continued until therapeutic failure or intolerance. A comprehensive health economic evaluation is needed to optimally direct the use of these drugs. This should be undertaken when long-term safety and efficacy studies are completed.

EULAR recommendations for the management of knee osteoarthritis: report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT).

BACKGROUND: Osteoarthritis (OA) is the most common joint disease encountered throughout Europe. A task force for the EULAR Standing Committee for Clinical Trials met in 1998 to determine the methodological and logistical approach required for the development of evidence based guidelines for treatment of knee OA. The guidelines were restricted to cover all currently available treatments for knee OA diagnosed either clinically and/or radiographically affecting any compartment of the knee. METHODS: The first stage was the selection of treatment modalities to be considered. The second stage comprised a search of the electronic databases Medline and Embase using a combination of subject headings and keywords. All European language publications in the form of systematic reviews, meta-analyses, randomised controlled trials, controlled trials, and observational studies were included. During stage three all the relevant studies were quality scored. The summary statistics for validated outcome measures, when available, were recorded and, where practical, the numbers needed to treat and the effect size for each treatment were calculated. In the fourth stage key clinical propositions were determined by expert consensus employing a Delphi approach. The final stage ranked these propositions according to the available evidence. A second set of propositions relating to a future research agenda was determined by expert consensus using a Delphi approach. RESULTS: Over 2400 English language publications and 400 non-English language publications were identified. Seven hundred and forty four studies presented outcome data of the effects of specific treatments on knee OA. Quantitative analysis of treatment effect was possible in only 61 studies. Recommendations for the management of knee OA based on currently available data and expert opinion are presented. Proposals for a future research agenda are highlighted. CONCLUSIONS: These are the first clinical guidelines on knee OA to combine an evidence based approach and a consensus approach across a wide range of treatment modalities. It is apparent that certain clinical propositions are supported by substantial research based evidence, while others are not. There is thus an urgent need for future well designed trials to consider key clinical questions.

Epidemiology and genetics of hand osteoarthritis.

The aim of this session was to identify current issues and problems relating to risk factors for hand osteoarthritis (OA). The following important factors were discussed: Genetics, Age, Gender, Obesity, HRT (hormone replacement therapy), Physical activity/trauma.

Prevalence of symptomatic hand osteoarthritis in community-dwelling older persons: the ICARe Dicomano study. Insufficienza Cardiaca negli Anzizni Residenti a Dicomano.

OBJECTIVE: To assess whether the American College of Rheumatology (ACR) classification criteria for hand osteoarthritis (OA) may be used successfully to detect hand OA in population-based studies and to estimate the prevalence of hand OA in an elderly italian population. DESIGN: This study was part of a cross-sectional population-based survey on heart failure in the elderly (ICARe Dicomano study). All community-dwelling citizens aged >65 were considered eligible and screened by expert geriatricians for the presence of major chronic conditions, including hip, knee and hand OA, using custom-made algorithms based on standard criteria. Those subjects who screened positively were subsequently assessed by a rheumatologist. RESULTS: Six hundred and ninety-seven subjects (80% of the eligible population) underwent a general examination by a geriatrician. One hundred and thirty-nine of these met the ACR criteria for hand OA at screening: 22 subjects with isolated first carpometacarpal (CMC) joint OA and 117 with generalized nodal OA. 74.2% of the diagnoses were confirmed in the 101 participants re-examined in a second phase by a rheumatologist (19 subjects presented with isolated thumb-base OA and 56 with nodal OA). The estimated prevalence in the cohort was 14.9%. CONCLUSIONS: The ACR clinical criteria for hand OA may be used in population studies, especially when the burden of this disease is evaluated.

Antisense targeting of the urokinase receptor blocks urokinase-dependent proliferation, chemoinvasion, and chemotaxis of human synovial cells and chondrocytes in vitro.

Proliferation and invasion of synovial pannus in rheumatoid arthritis and cartilage remodeling in osteoarthritis are key events in development of disability of arthritic joints. The mechanisms that trigger these events are still poorly understood. The production of urokinase-type plasminogen activator (u-PA) by synovial cells and chondrocytes and the subsequent interaction of u-PA with its membrane receptor (u-PAR) is under the control of a variety of growth factors and cytokines released within the inflamed joints. Here we show that u-PA, on interaction with the specific receptor, regulates movement and invasion as well as proliferation of human synovial cells and chondrocytes. Targeting the urokinase receptor with an antisense oligonucleotide blocks the u-PA-dependent synoviocyte and chondrocyte proliferation and chemoinvasion, suggesting a possible use for this new class of drugs in the progression of the disease in rheumatoid arthritis and osteoarthritis.

Efficacy and tolerability of ketoprofen 200 mg controlled-release cps vs indomethacin 50 mg cps in patients with symptomatic hip osteoarthritis. A multicentre study.

BACKGROUND: An open-label, randomised, multicentre study was carried out to compare the efficacy and tolerability of indomethacin capsules and ketoprofen controlled-release capsules in the symptomatic treatment of coxarthrosis. MATERIALS AND METHODS: 113 out-patients were enrolled: 57 were assigned to receive indomethacin 50 mg twice daily and 56 ketoprofen 200 mg once daily for 4 weeks. RESULTS: Indomethacin and ketoprofen proved equally effective in relieving osteoarticular pain and stiffness and in improving the quality of life of patients. There was essentially no difference as to gastrointestinal adverse events which occurred in 25% of patients on indomethacin and in 27% of those on ketoprofen. Indomethacin caused more non-gastrointestinal untoward effects, especially CNS effects (headache and dizziness: 11%) which were not observed with ketoprofen. Indomethacin was discontinued because of adverse events in a larger proportion of patients (20%) than ketoprofen (11%).

Ipriflavone prevents radial bone loss in postmenopausal women with low bone mass over 2 years.

Two hundred and fifty-five postmenopausal women with distal forearm bone mineral density (BMD) 1 SD below the mean value for normal age-matched postmenopausal subjects were randomly allocated to a 2-year treatment with oral ipriflavone (200 mg t.i.d) or a matched placebo, according to a double-masked, parallel group design. All patients also received a 1 g/day calcium supplement. Distal radius BMD and bone metabolism markers were measured at baseline, and every 6 months. Blood haematology and chemistry and physical parameters were monitored at the same time. One hundred and ninety-six patients completed 2 years of treatment. BMD changes from baseline were analysed according to valid completers (VC) and intention to treat (ITT) analyses. In both cases radial BMD was maintained in patients treated with ipriflavone while in decrease in those receiving the placebo, the between-treatment difference being significant at year 1 and year 2. Urinary hydroxyproline/creatinine levels were decreased in the ipriflavone-treated group and increased in the placebo group, with a significant between-treatment difference. Adverse reactions, mainly gastrointestinal, occurred to a similar extent in the two treatment groups.

Effect of chronic treatment with ipriflavone in postmenopausal women with low bone mass.

We present the results of two multicenter, double-blind, placebo-controlled, 2-year studies to evaluate the efficacy and tolerability of ipriflavone in postmenopausal women (PMW) with low bone mass. 453 PMW (aged 50-65 years) with a vertebral (VMD) or radial (RMD) mineral density value 1 SD lower compared with age-matched controls, were randomly selected to receive oral ipriflavone (200 mg T.I.D. at meals) or matching placebo, plus 1 g oral calcium daily. Vertebral (study A, by dual X-ray absorptiometry-DXA) and radial (study B, by dual photon absorptiometry-DPA) bone density, serum bone Gla-protein (BGP), and urinary hydroxyproline/creatinine (HOP/Cr) were measured every 6 months. In both studies, the Valid Completers (VC) analysis showed a maintenance of bone mass in ipriflavone-treated women, whereas in the placebo group, bone mineral density (BMD) was significantly decreased. The final outcome was a bone-sparing effect of 1.6% in study A, and of 3.5% in study B after 2 years. The Intention to Treat (ITT) analysis confirmed the decrease in the placebo group, with no changes in ipriflavone-treated women. A significant (P < 0.05) between-treatment difference was found in both studies. Biochemical markers of bone turnover decreased in patients treated with ipriflavone, thus suggesting a reduction of bone turnover rate. Twenty-six women treated with ipriflavone and 28 receiving the placebo dropped out because of side effects, mainly gastrointestinal. The compliance to the oral long-term treatment was good. The results of these studies show that ipriflavone is able to prevent both axial and peripheral bone loss in PMW with low bone mass, and is well tolerated.

Spondyloarthritis in patients with ulcerative colitis.

BACKGROUND: Extraintestinal manifestations can complicate the course of ulcerative colitis and can influence the prognosis. AIMS: Sixty-eight patients of the metropolitan area of Florence with ulcerative colitis in clinical and endoscopic remission were evaluated to establish the presence of spondyloarthritis. PATIENTS AND METHODS: Each patient was studied through clinical and radiological evaluations to assess the presence of joint involvement. RESULTS: We found signs of spondyloarthritis in 19 patients (27.9%). Four of them had a classic ankylosing spondylitis (5.8%) and in 3 of them the aplotype HLA B27 was present. Sacroileitis was found in 9 (13.2%) patients (monolateral in 5 cases and bilateral in 4). Six patients (8.8%) showed an unclassifiable form of arthritis, fulfilling the Amor criteria. In 13 of 19 patients with spondyloarthritis, we found a pancolic extension of disease (68.4%). CONCLUSIONS: The results obtained from our series of ulcerative colitis patients reveal a lower proportion of cases of spondyloarthritis than that found in other Italian studies. We are planning further investigations on a larger population to better assess the prevalence of spondyloarthritis in ulcerative colitis patients.

Plasminogen activator and receptor in osteoarthritis.

Evidence indicates that breakdown of articular cartilage resulting in the loss of normal joint function is the distinctive feature of osteoarthritis. Degradation of cartilage extracellular matrix components involves the action of at least 2 classes of proteinases: serine proteinases and metalloproteinases. Receptors have been described on a wide range of cell lines for many such proteinases [urokinase-type plasminogen activator (u-PA), plasminogen/plasmin, collagenase], which subsequently activate each other on the solid phase of the cell surface, leading to cartilage destruction. We review the leading role of u-PA and its receptor (u-PAR) in cartilage degradation.

A multi-centre, double-blind comparative study of the efficacy and safety of aceclofenac and diclofenac in the treatment of rheumatoid arthritis.

A long term multi-centre, double-blind, parallel group study was undertaken to investigate the efficacy and safety of aceclofenac (170 patients, 100 mg b.i.d. and placebo once daily) in comparison to diclofenac (173 patients, 50 mg t.i.d.) given for 6 months to patients of both sexes with active rheumatoid arthritis. Efficacy was evaluated in 131 aceclofenac and 130 diclofenac patients at 15 days, 1, 2, 4 and 6 months. Although both treatment groups showed significant improvement in all evaluations of pain and inflammation (assessed by a Visual Analogue Scale and the Ritchie Index) and a progressive reduction in morning stiffness, there were no significant differences between the groups. There was, however, a trend towards greater improvement in hand grip strength with aceclofenac (22% improvement) than diclofenac (17% improvement). Adverse events in both groups were minor, predominantly gastro-intestinal, and fewer patients tended to experience gastro-intestinal events on aceclofenac (13%) than on diclofenac (17%). The overall assessment of tolerance, however, did not differ significantly between groups. In summary, this study supports a therapeutic role for aceclofenac in the treatment of rheumatoid arthritis, and suggests it is an effective and safe NSAID for the treatment of this disease.

Control of the chondrocyte fibrinolytic balance by the drug piroxicam: relevance to the osteoarthritic process.

OBJECTIVE: Since the plasminogen activator [PA/plasminogen activator inhibitor (PAI) system is believed to be involved in a breakdown of articular cartilage in osteoarthritis (OA), we studied the modulation of single components of the fibrinolytic system (urokinase-type plasminogen activator, u-PA; plasminogen activator inhibitor-1, PAI-1; the surface receptor for u-PA, u-PAR) in human chondrocytes in the presence of piroxicam. METHODS: The drug was added to the chondrocyte culture medium either directly or by supplementing chondrocyte cultures with synovial fluid (SF) from patients with OA treated with piroxicam. We have shown u-PAR M(r) 55000 Da on human chondrocytes in suspension culture by cross linking chondrocyte lysates with 125I-labelled amino-terminal fragment (ATF) of human u-PA, which frames the sequence that specifically interacts with u-PAR. RESULTS: Such receptors decrease upon incubation of chondrocytes with piroxicam or with SF from patients treated with piroxicam. The culture medium of treated chondrocytes showed decreased fibrinolytic activity when compared with untreated controls, while PAI activity was increased in both SF chondrocyte culture medium following piroxicam treatment. At the same time, internalization of u-PA/u-PAR complexes increased after incubation of chondrocytes with piroxicam or PAI-1 rich SF. CONCLUSION: Our results indicate that the drug induces the surface clearance u-PAR by internalization of u-PA/PAI-/u-PAR complexes. Thus piroxicam reduces both the soluble fibrinolytic activity of human chondrocytes (increase of PAI activity and decrease of released u-PA) and the cell associated u-PA activity (clearance of u-PAR by internalization). The drug dependent changes in the fibrinolytic system suggest that piroxicam may be useful in preventing or limiting perilacunar cartilage damage in OA.

The effects of methotrexate on normal and osteoarthritic lapine articular cartilage.

OBJECTIVE: The effects of methotrexate (MTX) on articular cartilage and its influence on the development of osteoarthritis (OA) lesions were tested in a lapine partial medial meniscectomy model. METHOD: Animals were divided into groups consisting of unoperated and operated rabbits that either received or did not receive MTX treatment. After 8 weeks knee articular condylar cartilage was examined for gross and histologic anatomy, active and total neutral metalloproteinases, tissue inhibitor of metalloproteinase (TIMP), DNA, uronic acid and hydroxyproline content. RESULTS: Carbon black retention and histologic scores revealed moderately severe changes in the OA animals with a tendency to less severe changes in OA animals receiving MTX. Unoperated animals receiving MTX had abnormal cartilage that displayed pitting and elevations in histologic score. Active and total neutral metalloproteinase and TIMP were elevated in both untreated and treated OA animals when compared to either unoperated or unoperated and treated animals. CONCLUSION: Articular cartilage with lesser amounts of neutral metalloproteinase and high amounts of TIMP levels often seen with other therapeutic modalities for OA, were not observed with MTX therapy. Our data suggest that MTX may have limited value in the treatment of OA.