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author:("havelka, K")
1.  2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis 
Annals of the Rheumatic Diseases  2011;70(6):896-904.
This first update of the ASAS/EULAR recommendations on the management of ankylosing spondylitis (AS) is based on the original paper, a systematic review of existing recommendations and the literature since 2005 and the discussion and agreement among 21 international experts, 2 patients and 2 physiotherapists in a meeting in February 2010. Each original bullet point was discussed in detail and reworded if necessary. Decisions on new recommendations were made — if necessary after voting. The strength of the recommendations (SOR) was scored on an 11-point numerical rating scale after the meeting by email. These recommendations apply to patients of all ages that fulfill the modified NY criteria for AS, independent of extra-articular manifestations, and they take into account all drug and non-drug interventions related to AS. Four overarching principles were introduced, implying that one bullet has been moved to this section. There are now 11 bullet points including 2 new ones, one related to extra-articular manifestations and one to changes in the disease course. With a mean score of 9.1 (range 8-10) the SOR was generally very good.
doi:10.1136/ard.2011.151027
PMCID: PMC3086052  PMID: 21540199
2.  Resistin in rheumatoid arthritis synovial tissue, synovial fluid and serum 
Annals of the Rheumatic Diseases  2006;66(4):458-463.
Background
Resistin is a newly identified adipocytokine which has demonstrated links between obesity and insulin resistance in rodents. In humans, proinflammatory properties of resistin are superior to its insulin resistance‐inducing effects.
Objectives
To assess resistin expression in synovial tissues, serum and synovial fluid from patients with rheumatoid arthritis, osteoarthritis and spondylarthropathies (SpA), and to study its relationship with inflammatory status and rheumatoid arthritis disease activity.
Methods
Resistin expression and localisation in synovial tissue was determined by immunohistochemistry and confocal microscopy. Serum and synovial fluid resistin, leptin, interleukin (IL)1β, IL6, IL8, tumour necrosis factor α, and monocyte chemoattractant protein‐1 levels were measured. The clinical activity of patients with rheumatoid arthritis was assessed according to the 28 joint count Disease Activity Score (DAS28).
Results
Resistin was detected in the synovium in both rheumatoid arthritis and osteoarthritis. Staining in the sublining layer was more intensive in patients with rheumatoid arthritis compared with those with osteoarthritis. In rheumatoid arthritis, macrophages (CD68), B lymphocytes (CD20) and plasma cells (CD138) but not T lymphocytes (CD3) showed colocalisation with resistin. Synovial fluid resistin was higher in patients with rheumatoid arthritis than in those with SpA or osteoarthritis (both p<0.001). In patients with rheumatoid arthritis and SpA, serum resistin levels were higher than those with osteoarthritis (p<0.01). Increased serum resistin in patients with rheumatoid arthritis correlated with both CRP (r = 0.53, p<0.02), and DAS28 (r = 0.44, p<0.05), but not with selected (adipo) cytokines.
Conclusion
The upregulated resistin at local sites of inflammation and the link between serum resistin, inflammation and disease activity suggest a role for resistin in the pathogenesis of rheumatoid arthritis.
doi:10.1136/ard.2006.054734
PMCID: PMC1856051  PMID: 17040961
3.  EULAR evidence based recommendations for the management of hand osteoarthritis: Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT) 
Annals of the Rheumatic Diseases  2006;66(3):377-388.
Objectives
To develop evidence based recommendations for the management of hand osteoarthritis (OA).
Methods
The multidisciplinary guideline development group comprised 16 rheumatologists, one physiatrist, one orthopaedic surgeon, two allied health professionals, and one evidence based medicine expert, representing 15 different European countries. Each participant contributed up to 10 propositions describing key clinical points for management of hand OA. Final recommendations were agreed using a Delphi consensus approach. A systematic search of Medline, Embase, CINAHL, Science Citation Index, AMED, Cochrane Library, HTA, and NICE reports was used to identify the best available research evidence to support each proposition. Where possible, the effect size and number needed to treat were calculated for efficacy. Relative risk or odds ratio was estimated for safety, and incremental cost effectiveness ratio was used for cost effectiveness. The strength of recommendation was provided according to research evidence, clinical expertise, and perceived patient preference.
Results
Eleven key propositions involving 17 treatment modalities were generated through three Delphi rounds. Treatment topics included general considerations (for example, clinical features, risk factors, comorbidities), non‐pharmacological (for example, education plus exercise, local heat, and splint), pharmacological (for example, paracetamol, NSAIDs, NSAIDs plus gastroprotective agents, COX‐2 inhibitors, systemic slow acting disease modifying drugs, intra‐articular corticosteroids), and surgery. Of 17 treatment modalities, only six were supported by research evidence (education plus exercise, NSAIDs, COX‐2 inhibitors, topical NSAIDs, topical capsaicin, and chondroitin sulphate). Others were supported either by evidence extrapolated from studies of OA affecting other joint sites or by expert opinion. Strength of recommendation varied according to level of evidence, benefits and harms/costs of the treatment, and clinical expertise.
Conclusion
Eleven key recommendations for treatment of hand OA were developed using a combination of research based evidence and expert consensus. The evidence was evaluated and the strength of recommendation was provided.
doi:10.1136/ard.2006.062091
PMCID: PMC1856004  PMID: 17046965
EULAR; recommendations; hand osteoarthritis; treatment
4.  Consensus statement on the use of rituximab in patients with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2006;66(2):143-150.
A large number of experts experienced in the treatment of rheumatoid arthritis were involved in formulating a consensus statement on the use of B cell‐targeted treatment with rituximab in patients with rheumatoid arthritis. The statement was supported by data from randomised controlled clinical trials and the substantial literature on oncology. The statement underwent three rounds of discussions until its ultimate formulation. It should guide clinicians in the use of this newly approved biological agent in treating patients with rheumatoid arthritis.
doi:10.1136/ard.2006.061002
PMCID: PMC1798500  PMID: 17068064
5.  S100A4 is expressed at site of invasion in rheumatoid arthritis synovium and modulates production of matrix metalloproteinases 
Annals of the Rheumatic Diseases  2006;65(12):1645-1648.
The metastasis‐associated protein S100A4 promotes the progression of cancer by regulating the remodelling of the extracellular matrix. The expression of S100A4 in vivo is shown and the functional role of S100A4 in the pathogenesis of osteoarthritis and rheumatoid arthritisis is explored. The expression of S100A4 in rheumatoid arthritis, osteoarthritis and normal synovial tissues was determined by immunohistochemistry. The expression of matrix metalloproteinase (MMP) mRNA was measured in rheumatoid arthritis and osteoarthritis synovial fibroblasts treated and untreated with S100A4 oligomer by real‐time polymerase chain reaction. Levels of released MMPs were confirmed by ELISA in cell culture supernatants. S100A4 protein was expressed in rheumatoid arthritis and osteoarthritis synovial tissues, in contrast with normal synovium. S100A4 up regulated MMP‐3 mRNA in rheumatoid arthritis synovial fluid, with a peak after 6 h. This resulted in release of MMP‐3 protein. MMP‐1, MMP‐9 and MMP‐13 mRNA were also up regulated in synovial fluid, but with different kinetics. MMP‐14 mRNA showed no change. Thus, S100A4 protein is expressed in synovial tissues of patients with rheumatoid arthritis and osteoarthritis in contrast with healthy people. It induces the expression and release of MMP‐3 and other MMPs from synovial fluid. The data suggest that S100A4‐producing cells could be involved in the pathogenesis of osteoarthritis and rheumatoid arthritis, including pannus formation and joint destruction.
doi:10.1136/ard.2005.047704
PMCID: PMC1798462  PMID: 17105852
6.  Etanercept and sulfasalazine, alone and combined, in patients with active rheumatoid arthritis despite receiving sulfasalazine: a double‐blind comparison 
Annals of the Rheumatic Diseases  2006;65(10):1357-1362.
Objective
To compare the efficacy and safety of etanercept and sulfasalazine, alone and in combination, in patients with active rheumatoid arthritis despite sulfasalazine treatment.
Methods
A double‐blind, randomised study in adult patients with active rheumatoid arthritis despite stable sulfasalazine (2–3 g/day) treatment. The primary end point was a 20% response by the American College of Rheumatology (ACR) criteria at 24 weeks.
Results
At baseline, the three treatment groups (sulfasalazine, n = 50; etanercept, n = 103; etanercept and sulfasalazine, n = 101) were comparable for demographic variables and disease activity. Lack of efficacy was the primary reason for discontinuation (sulfasalazine, n = 12; etanercept, n = 1; etanercept and sulfasalazine, n = 4; p<0.001). Significantly more patients receiving etanercept, alone or in combination (74% for each), achieved ACR 20 responses at 24 weeks than those receiving sulfasalazine (28%; p<0.01). Similarly, more patients in the etanercept groups achieved ACR 50 and ACR 70 responses than those in the sulfasalazine group (p<0.01). In the groups receiving etanercept, significant differences in the ACR core components were observed by week 2 compared with those receiving sulfasalazine alone (p<0.01). The incidences of several common adverse events (headache, nausea, asthenia) were lower with etanercept alone than with the combination (p<0.05), but infections and injection site reactions were higher with etanercept alone (p<0.05). The safety profiles of both etanercept treatment groups were comparable with previous experience of etanercept.
Conclusions
For all efficacy variables assessed, etanercept alone or in combination with sulfasalazine resulted in substantial and similar improvement in disease activity from baseline to week 24 compared with sulfasalazine alone in patients with active rheumatoid arthritis despite their sulfasalazine treatment. All three treatments were generally well tolerated.
doi:10.1136/ard.2005.049650
PMCID: PMC1798315  PMID: 16606651
7.  ASAS/EULAR recommendations for the management of ankylosing spondylitis 
Annals of the Rheumatic Diseases  2005;65(4):442-452.
Objective
To develop evidence based recommendations for the management of ankylosing spondylitis (AS) as a combined effort of the ‘ASsessment in AS' international working group and the European League Against Rheumatism.
Methods
Each of the 22 participants was asked to contribute up to 15 propositions describing key clinical aspects of AS management. A Delphi process was used to select 10 final propositions. A systematic literature search was then performed to obtain scientific evidence for each proposition. Outcome data for efficacy, adverse effects, and cost effectiveness were abstracted. The effect size, relative risk, number needed to treat, and incremental cost effectiveness ratio were calculated. On the basis of the search results, 10 major recommendations for the management of AS were constructed. The strength of recommendation was assessed based on the strength of the literature evidence, risk‐benefit trade‐off, and clinical expertise.
Results
The final recommendations considered the use of non‐steroidal anti‐inflammatory drugs (NSAIDs) (conventional NSAIDs, coxibs, and co‐prescription of gastroprotective agents), disease modifying antirheumatic drugs, treatments with biological agents, simple analgesics, local and systemic steroids, non‐pharmacological treatment (including education, exercise, and physiotherapy), and surgical interventions. Three general recommendations were also included. Research evidence (categories I–IV) supported 11 interventions in the treatment of AS. Strength of recommendation varied, depending on the category of evidence and expert opinion.
Conclusion
Ten key recommendations for the treatment of AS were developed and assessed using a combination of research based evidence and expert consensus. Regular updating will be carried out to keep abreast of new developments in the management of AS.
doi:10.1136/ard.2005.041137
PMCID: PMC1798102  PMID: 16126791
ankylosing spondylitis; management; recommendations; evidence based medicine; spondyloarthropathies; ASAS; EULAR
8.  Single, intra-articular treatment with 6 ml hylan G-F 20 in patients with symptomatic primary osteoarthritis of the knee: a randomised, multicentre, double-blind, placebo controlled trial 
Annals of the Rheumatic Diseases  2009;69(1):113-119.
Objectives:
The primary objective was to compare a single, 6 ml, intra-articular injection of hylan G-F 20 with placebo in patients with symptomatic knee osteoarthritis. The safety of a repeat injection of hylan G-F 20 was also assessed.
Methods:
Patients with primary osteoarthritis knee pain were randomly assigned to arthrocentesis plus a 6 ml intra-articular injection of either hylan G-F 20 or placebo in a prospective, double-blind (one injector/one blinded observer) study. Results were evaluated at 4, 8, 12, 18 and 26 weeks post-injection. The primary outcome criterion was change from baseline over 26 weeks in Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index A pain. Secondary outcome measures included WOMAC A1 and C, patient global assessment (PGA) and clinical observer global assessment (COGA) and Outcome Measures in Rheumatology, Osteoarthritis Research Society International responder rates. A 4-week, open, repeat treatment phase evaluated safety only.
Results:
A total of 253 patients (Kellgren–Lawrence grade II or III) was randomly assigned. Patients receiving hylan G-F 20 experienced statistically significantly greater improvements in WOMAC A pain scores (−0.15, SE 0.076, p = 0.047), and several of the secondary outcome measures (WOMAC A1, PGA and COGA), than patients receiving placebo. There was no difference between the safety results of the two groups. No increased risk of local adverse events was observed in the open, repeat treatment phase.
Conclusions:
This placebo-controlled study demonstrated that, in patients with knee osteoarthritis, a single 6 ml intra-articular injection of hylan G-F 20 is safe and effective in providing statistically significant, clinically relevant pain relief over 26 weeks, with a modest difference versus placebo.
Trial registration number:
NCT00131352.
doi:10.1136/ard.2008.094623
PMCID: PMC2789938  PMID: 19304567
9.  Dissemination and evaluation of the ASAS/EULAR recommendations for the management of ankylosing spondylitis: results of a study among 1507 rheumatologists 
Annals of the Rheumatic Diseases  2008;67(6):782-788.
Background:
Ten ASAS/EULAR recommendations for the management of ankylosing spondylitis (AS) were published in 2006.
Objectives:
(a) To disseminate and (b) to evaluate conceptual agreement with, and (c) application of, these recommendations as well as (d) potential barriers to the application.
Methods:
A questionnaire was sent to rheumatologists in 10 countries. It included (a) the text of the recommendations; (b) rheumatologists’ demographic variables; (c) two numerical rating scales from 1 to 10 for each recommendation: conceptual agreement with, and application of, the recommendation (10 indicates maximal agreement and maximal application); and (d) a list of potential barriers to the application of the recommendation. Statistical analysis included descriptive and multivariate analyses.
Results:
7206 questionnaires were sent out; 1507 (21%) were returned. Of the 1507 answering rheumatologists, 62% were men, mean (SD) age 49 (9) years, and 34% had an academic position. Conceptual agreement with the recommendations was high (mean (SD) for all recommendations 8.9 (0.9)). Self-reported application was also high (8.2 (1.0)). The difference between agreement and application varied across recommendations and countries. The most pronounced discrepancies were reported for use of anti-tumour necrosis factor drugs in a few countries, with funding as the most commonly reported barrier for application of this recommendation.
Conclusion:
This large project has helped the dissemination of the ASAS/EULAR recommendations for the management of AS and shows that conceptual agreement with the recommendations is very high. The project also highlights inequalities in access to healthcare for European citizens with AS.
doi:10.1136/ard.2007.080077
PMCID: PMC2565578  PMID: 18055468
10.  Efficacy, safety and patient-reported outcomes of combination etanercept and sulfasalazine versus etanercept alone in patients with rheumatoid arthritis: a double-blind randomised 2-year study 
Annals of the Rheumatic Diseases  2008;68(7):1146-1152.
Objective:
To determine the efficacy and safety of etanercept and etanercept plus sulfasalazine versus sulfasalazine in patients with rheumatoid arthritis (RA) despite sulfasalazine therapy.
Methods:
Patients were randomly assigned to etanercept (25 mg twice weekly; sulfasalazine was discontinued at baseline), etanercept plus sulfasalazine (unchanged regimen of 2–3 g/day) or sulfasalazine in a double-blind, randomised, 2-year study in adult patients with active RA despite sulfasalazine therapy. Efficacy was assessed using the American College of Rheumatology criteria, disease activity scores (DAS) and patient-reported outcomes (PRO).
Results:
Demographic variables and baseline disease characteristics were comparable among treatment groups; mean DAS 5.1, 5.2 and 5.1 for etanercept (n  =  103), etanercept plus sulfasalazine (n  =  101) and sulfasalazine (n  =  50), respectively. Withdrawal due to lack of efficacy was highest with sulfasalazine (26 (52%) vs 6 (6%) for either etanercept group, p<0.001). Patients receiving etanercept or etanercept plus sulfasalazine had a more rapid initial response, which was sustained at 2 years, than those receiving sulfasalazine: mean DAS 2.8, 2.5 versus 4.5, respectively (p<0.05); ACR 20 response was achieved by 67%, 77% versus 34% of patients, respectively (p<0.01) Overall, PRO followed a similar pattern; a clinically significant improvement in health assessment questionnaire was achieved by 76%, 78% versus 40% of patients, respectively (p<0.01). Commonly reported adverse events occurring in the etanercept groups were injection site reactions and pharyngitis/laryngitis (p<0.01).
Conclusion:
Etanercept and etanercept plus sulfasalazine are efficacious for the long-term management of patients with RA. The addition of etanercept or substitution with etanercept should be considered as treatment options for patients not adequately responding to sulfasalazine.
doi:10.1136/ard.2007.087106
PMCID: PMC2689524  PMID: 18794178
11.  Increased pentosidine, an advanced glycation end product, in serum and synovial fluid from patients with knee osteoarthritis and its relation with cartilage oligomeric matrix protein 
Annals of the Rheumatic Diseases  2005;64(6):886-890.
Background: Pentosidine, an advanced glycation end product, increasingly accumulates in articular cartilage with age, and contributes to the pathogenesis of osteoarthritis (OA). Increased pentosidine concentrations are associated with inflammatory disorders—for example, rheumatoid arthritis.
Objective: To compare pentosidine serum concentrations in patients with knee OA and in healthy volunteers and to determine a relationship between pentosidine and cartilage oligomeric matrix protein (COMP)—a marker of articular cartilage destruction.
Methods: Paired serum and synovial fluid samples were obtained by arthrocentesis from 38 patients with knee OA and from 38 healthy volunteers. Pentosidine concentration was measured by reverse phase high performance liquid chromatography with fluorescent detection and COMP was determined by sandwich ELISA.
Results: Significantly increased serum pentosidine (p<0.01) and COMP (p<0.05) levels were detected in the patients with OA compared with the control group. Serum pentosidine correlated significantly with synovial fluid pentosidine (p<0.001). Pentosidine in synovial fluid (p<0.05) and in serum (p<0.05) correlated significantly with synovial fluid COMP. Pentosidine and COMP concentrations did not correlate significantly with the radiological stage of the disease.
Conclusion: Increased pentosidine serum concentration in patients with OA and its correlation with the cartilage destruction marker COMP in synovial fluid suggests that pentosidine may be important in OA pathology and is a new potential OA marker.
doi:10.1136/ard.2004.029140
PMCID: PMC1755507  PMID: 15897309
12.  EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT) 
Annals of the Rheumatic Diseases  2004;64(5):669-681.
Objective: To develop evidence based recommendations for the management of hip osteoarthritis (OA).
Methods: The multidisciplinary guideline development group comprised 18 rheumatologists, 4 orthopaedic surgeons, and 1 epidemiologist, representing 14 European countries. Each participant contributed up to 10 propositions describing key clinical aspects of hip OA management. Ten final recommendations were agreed using a Delphi consensus approach. Medline, Embase, CINAHL, Cochrane Library, and HTA reports were searched systematically to obtain research evidence for each proposition. Where possible, outcome data for efficacy, adverse effects, and cost effectiveness were abstracted. Effect size, rate ratio, number needed to treat, and incremental cost effectiveness ratio were calculated. The quality of evidence was categorised according to the evidence hierarchy. The strength of recommendation was assessed using the traditional A–D grading scale and a visual analogue scale.
Results: Ten key treatment propositions were generated through three Delphi rounds. They included 21 interventions, such as paracetamol, NSAIDs, symptomatic slow acting disease modifying drugs, opioids, intra-articular steroids, non-pharmacological treatment, total hip replacement, osteotomy, and two general propositions. 461 studies were identified from the literature search for the proposed interventions of efficacy, side effects, and cost effectiveness. Research evidence supported 15 interventions in the treatment of hip OA. Evidence specific for the hip was strikingly lacking. Strength of recommendation varied according to category of research evidence and expert opinion.
Conclusion: Ten key recommendations for the treatment of hip OA were developed based on research evidence and expert consensus. The effectiveness and cost effectiveness of these recommendations were evaluated and the strength of recommendation was scored.
doi:10.1136/ard.2004.028886
PMCID: PMC1755499  PMID: 15471891
13.  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 (IFNß) 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), IFNß 2.2 µg (0.05 ml), or IFNß 44 µg (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 IFNß treatment. Urinary levels of collagen crosslinks were unchanged between the treatment groups.
Conclusions: At the doses tested, treatment with IFNß three times weekly in combination with methotrexate did not have a clinical or radiological effect in patients with rheumatoid arthritis.
doi:10.1136/ard.2003.020347
PMCID: PMC1755211  PMID: 15242865
14.  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) 
Annals of the Rheumatic Diseases  2003;62(12):1145-1155.
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.
doi:10.1136/ard.2003.011742
PMCID: PMC1754382  PMID: 14644851
15.  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) 
Annals of the Rheumatic Diseases  2000;59(12):936-944.
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.


doi:10.1136/ard.59.12.936
PMCID: PMC1753053  PMID: 11087696
17.  Hydroxychloroquine sulphate in the treatment of rheumatoid arthritis: a double blind comparison of two dose regimens. 
Annals of the Rheumatic Diseases  1989;48(7):542-546.
A controlled, double blind, parallel group, long term study of hydroxychloroquine sulphate in the treatment of rheumatoid arthritis, comparing daily doses of 200 mg and 400 mg, is described. The trial involved 54 patients with moderate disease activity who had not previously received antimalarial drugs. Forty three patients completed the one year treatment. The groups receiving different doses were homogeneous and did not differ in any of the 25 monitored indicators. Both dose regimens were effective, and a significant reduction of disease activity was observed after one year's treatment. Of the nine laboratory and 11 clinical indices of efficacy monitored, no statistically significant differences were reported, but in the group of patients treated with the 400 mg daily dose the number of side effects was three times greater. As there have been no reports of retinopathy with hydroxychloroquine at daily doses of 200 mg the effectiveness of this dose is of practical importance.
PMCID: PMC1003813  PMID: 2673079
18.  Effect of yttrium 90 on experimental allergic arthritis in rabbits. 
Seventeen rabbits were immunized with complete Freund's adjuvant and bovine serum albumin by the method of Dumonde and Glynn (1962), as modified by Cooke and Jasin (1972). Fifteen weeks after allergic arthritis developed in the knee joint, 8 animals were given an injection of 20 muCi yttrium 90 (90Y) into the left joint cavity; 7 were injected with 400 muCi. The animals were sacrificed at 2, 4, 8, 12, and 16 weeks and at 6 and 12 months after the injection. The right knee joint served as control for assessment of untreated allergic arthritis. Morphological control of the severity of the arthritis was provided by sacrificing 2 uninjected animals 13 weeks after immunization.
Images
PMCID: PMC1006509  PMID: 1275583
19.  Histological study of effects of colloidal 90 yttrium on knee joint tissues of rabbits. 
The administration of 0-2-0-4 mCi 90 yttrium (90Y) into a normal rabbit knee joint fails to induce medical synovectomy and results in the proliferation of the synovialis. The synovial mesothelium shows early radiation damage but subsequently follows a restitution of the whole. Later (within 4 to 16 weeks) an extensive fibrosis of the stratum synovialis develops, as well as an occlusion and sclerosis of smaller synovial vessels and capillaries. These changes explain the beneficial therapeutic effect of 90Y in a chronic inflammatory joint effusion. After irradiation that joint cartilage shows an increased cellular proliferation of the superficial tangential cells and in the vicinity of the cruciate ligaments small foci of degenerated cartilage are present. The overall pattern of a joint treated with intra-articular 90Y corresponds to the histological pattern encountered regularly in joints of older people. Changes of the cartilage after the 90Y radiation could represent a factor predisposing the treated joint to a subsequent development of osteoarthrosis.
Images
PMCID: PMC1006347  PMID: 1124956

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