Abstract: 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.
Abstract: OBJECTIVE: To assess the factorial structure of the Disease Activity Score including a 28-joint count (DAS28) if applied in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA). METHODS: DAS28 values from 85 consecutive PsA outpatients and 2 RA patient cohorts comprising 85 patients each were compared. The first RA cohort (RA1) consisted of age- and sex-matched patients seen during the same period as the patients with PsA. The first 85 RA outpatients from September 2003 were included in the second cohort (RA2). Item weighting, factor loading, and internal consistency were assessed by factor analysis, principal component analysis, and calculation of Cronbach's alpha. RESULTS: The mean +/- SD DAS28 scores of patients in the PsA, RA1, and RA2 cohorts were 3.2 +/- 1.31, 3.21 +/- 1.45, and 3.79 +/- 1.44, respectively. A significant difference between the PsA and RA2 cohorts was found for DAS28 (P = 0.0063), swollen joint count (P = 0.007), and patient's global assessment (P < 0.001), but not for erythrocyte sedimentation rate. Internal consistency of the DAS28 in patients with PsA was considerably lower, item weighting showed remarkable differences, and factor analysis revealed that the DAS28 constitutes a bidimensional instrument in patients with PsA, whereas in both RA cohorts it appeared to be monodimensional. CONCLUSION: With respect to its statistical properties, the DAS28 proved to be considerably different in PsA compared with RA. Therefore its application for disease activity assessment in patients with PsA cannot be recommended without a formal validation procedure.
Abstract: OBJECTIVE: To confirm the reliability and applicability of the Polymyalgia Rheumatica Disease Activity Score (PMR-AS), and to establish a threshold for remission. METHODS: First, 78 patients with PMR (50 women/28 men, mean age 65.97 years) were enrolled in a cross-sectional evaluation. The PMR-AS, patient's satisfaction with disease status (PATSAT; range 1-5), erythrocyte sedimentation rate (ESR; first hour), and a visual analog scale of patients' general health assessment (VAS patient global; range 0-100) were recorded. Subsequently, another 39 PMR patients (24 women/15 men, mean age 68.12 years) were followed longitudinally. Relationships between the PMR-AS, PATSAT, ESR, and VAS patient global were analyzed by the Kruskal-Wallis test, Spearman's rank correlation, and kappa statistics. PMR-AS values in patients with a PATSAT score of 1 and a VAS patient global <10 formed the basis to establish a remission threshold. RESULTS: PMR-AS values were significantly related to PATSAT (P < 0.001), VAS patient global (P < 0.001), and ESR (P < 0.01). PATSAT and VAS patient global were reasonably different (kappa = 0.226). The median PMR-AS score in patients with PATSAT score 1 and VAS patient global <10 was 0.7 (range 0-3.3), and the respective 75th percentile was 1.3. To enhance applicability, a range from 0 to 1.5 was proposed to define remission in PMR. The median ESR in these patients was 10 mm/hour (range 3-28), indicating external validity. CONCLUSION: We demonstrated the reliability, validity, and applicability of the PMR-AS in daily routine. Moreover, we proposed a remission threshold (0-1.5) founded on patient-dependent parameters.
Abstract: 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.
Abstract: The objective of this work was to assess the therapeutic efficacy and tolerability of intravenously applied n-3-PUFA in patients with active rheumatoid arthritis (RA). Thirty-four patients with active RA [identified as having a DAS28 (disease activity score including a 28 joint count) > 4.0] were enrolled into this 5-wk open pilot study (one group design). From the time of screening (visit 0, or V0), background therapy had to remain unchanged. Patients received 2 mL/kg (= 0.1-0.2 g fish oil/kg) fish oil emulsion intravenously on 7 consecutive days (Visit 1-Visit 2, or V1-V2) in addition to their background therapy. A decrease of the DAS28 > 0.6 at day 8 (Visit 2) was the primary efficacy measure. Moreover, the DAS28 at day 35 (Visit 3, or V3), the modified Health Assessment Questionnaire, the American College of Rheumatology (ACR) response criteria (V2, V3) and the Short Form-36 (V3) were assessed. Thirty-three patients completed the trial. The mean DAS28 at V1 was 5.45;at V2, 4.51 (P < .001 V1-V2) and at V3, 4.73 (P < .001 V1-V3; V2-V3, not significantly different). Of the 34 patients, 56% achieved a reduction of the DAS28 > 0.6 at V2 (mean 1.52); 27% > 1.2. At V3, 41% of the patients showed a DAS28 reduction > 0.6 (mean 1.06), and 36% > 1.2. ACR 20 and 50% responses at V2 were seen in 29 and 12% of patients, respectively; at V3, the comparable values were 18 and 9%, respectively. Overall tolerability was excellent. Intravenous application of n-3-PUFA (as an add-on therapy) was considerably well tolerated and led to improvement of the disease activity status in a reasonable number of RA patients. Future trials are warranted to answer whether the intravenous application of n-3-PUFA constitutes a therapeutic option in RA patients.
Abstract: The objective of this study was to assess the efficacy and tolerability of a combination of leflunomide (LEF) and chloroquin (ChL) in patients with rheumatoid arthritis (RA). Fifteen female RA patients (46-80 years, mean disease duration 100.7 months, ten patients RF+) were enrolled into this open trial. Patients were either treatment failures or partial responders to LEF (n=6) or ChL (n=9). At week 8 and 16, DAS28 and morning stiffness (MST) were evaluated. Moreover, safety was assessed by reporting of side effects, laboratory examinations, and blood pressure measurement. Baseline mean disease activity Index including a 28-joint count (DAS28) amounted to 5.61 and decreased to 4.54 at week 8 (p=0.023) and to 3.79 (p=0.00031) at week 16. MST remained unchanged. DAS28 values significantly decreased statistically in originally ChL-treated patients with additional LEF but did not in LEF patients with additional ChL (DAS28: 1.48; 2.29 vs 0.60; 0.87). Adverse reactions were observed in four patients. Three patients had to be withdrawn from the study. Combination therapy with LEF and ChL was effective and reasonably tolerated. The far higher treatment response could be observed in originally ChL-treated patients after initiation of LEF.
Abstract: 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.
Abstract: OBJECTIVE: To obtain information on changes in patients' satisfaction (PATSAT) and physicians' global assessment (PhGASS) with regard to rheumatoid arthritis (RA) activity fluctuations. METHODS: Eighty-eight RA outpatients out of 207 investigated were assessed for 3 months on average after the initial evaluation. PATSAT (1 = excellent to 5 = unsatisfactory), PhGASS (visual analogue scale 1-100), and the 28-joint Disease Activity Score (DAS28) were assessed as at the first evaluation. The only prerequisite for enrolment was any therapeutic change at the first visit. Changes in PATSAT (SATCH) and PhGASS (PhGACH) were categorized and subsequently related to the DAS28 changes. Statistical evaluation was carried out by the Kruskal-Wallis test, the Mann-Whitney U-test, and by kappa statistics. RESULTS: To achieve a positive SATCH (n = 26/88 patients), a median DAS28 reduction of -1.06 (-25.0%) was necessary, whereas a considerably lower median increase of +0.16 (+10.5%) caused a negative SATCH. PhGASS (n = 38/88 patients) changed positively on a median DAS28 reduction of -0.82 (-16.0%), whereas it worsened at a mean DAS28 increase of +0.55 (+16.5%). Approximately 60% congruence between SATCH and PhGACH could be observed (kappa = 0.139). The DAS28 values preceding a positive SATCH and PhGACH were significantly higher (p < 0.001) than before a negative change. CONCLUSION: The patients' perspective with respect to improvement or worsening of RA is asymmetric. In contrast to the physicians' perspective, patients require greater improvement to be satisfied and less deterioration to be dissatisfied. These results may provide additional guidance in considerations about defining response and non-response in RA.
Abstract: Polymyalgia rheumatica (PMR) is a common disorder in the elderly population. The diagnosis is based upon recognition of a clinical syndrome, consisting of pain and stiffness in the shoulder and pelvic girdle, muscle tenderness of the upper and lower limbs and nonspecific somatic complaints. In addition, in most cases the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) concentration are highly elevated. Although PMR and giant cell arteritis (GCA) are commonly regarded as two clinical variations of the same disease, their clinical picture is quite different. Whilst in PMR the musculoskeletal symptoms predominate, the major features of GCA are arterial inflammation and its consequences, which suggests clinical and pathological discrepancies between the two syndromes and important differences with respect to morbidity and mortality. The prognosis of correctly diagnosed PMR is excellent. It is well known that corticosteroid therapy in PMR usually leads to rapid and dramatic improvement of patients' complaints and returns them to previous functional status. However, prolonged corticosteroid treatment, sometimes for several years, may be necessary to maintain clinical improvement. Despite all the knowledge about the beneficial effects of corticosteroid treatment, data concerning the optimal dosage regimen are lacking. Long-term corticosteroid use can be associated with various adverse events, of which induction of osteoporosis, diabetes mellitus and infection among the worst. A Corticosteroid Side Effect Questionnaire has been shown to dose-dependently detect adverse effects perceived by patients. The European League Against Rheumatism (EULAR) response criteria for PMR comprise a core set of markers for monitoring therapeutic responses in PMR, namely ESR or CRP, the visual analogue scale of patient's pain and physician's global assessment, as well as morning stiffness and the ability to elevate the upper limbs. The PMR-disease activity score has been developed on the basis of EULAR response criteria as a means of expressing disease activity as an absolute number. A score <7 indicates low disease activity, scores 7-17 suggest medium activity, and a score >17 is indicative of high disease activity. The PMR-disease activity score has been proven to be highly correlated with patient's global assessment, patient satisfaction and ESR. It provides an easily applicable and valid tool for disease activity monitoring in patients with PMR. Improved knowledge of disease activity processes, exact monitoring of disease activity and treatment responses, and increased risk-estimation of treatment schedules should ultimately improve the care of patients with PMR.
Abstract: BACKGROUND: This systematic meta-analysis on randomized controlled trials with diacerein was performed to provide an evidence-based assessment of its symptomatic efficacy in the treatment of osteoarthritis. METHODS: Electronic databases were searched for randomized controlled trials with diacerein. A manual review of the literature, abstracts, and posters was also conducted. Unpublished final reports were obtained from the manufacturer. Only studies performed in knee and/or hip osteoarthritis were chosen for review. Study inclusion, quality scoring, and data extraction were performed by 2 reviewers independently. Objectives for analysis comprised pain, function, escape medication use, global efficacy, and safety ratings by patients and investigators. Specific study periods, such as the active treatment period and the treatment-free follow-up period (when present), were analyzed. Statistical analyses were based on the intention-to-treat principle as far as possible, and acknowledged tests were used for data analysis. RESULTS: A total of 23 studies were identified, 19 of which were included. Diacerein was significantly superior to placebo during the active treatment phase (Glass score, 1.50 [95% confidence interval, 0.80-2.20]). Both diacerein and nonsteroidal anti-inflammatory drugs (NSAIDs) were similarly efficacious during the treatment period; however, diacerein, but not NSAIDs, showed a carryover effect, persisting up to 3 months after treatment, with a significant analgesic-sparing effect during the follow-up period (Glass score, 2.06 [95% confidence interval, 0.66-3.46]). Tolerability assessment revealed no differences between diacerein and NSAIDs, although the latter showed more severe events. CONCLUSION: This systematic meta-analysis provides evidence for the symptomatic efficacy of diacerein in the treatment of knee and hip osteoarthritis, with reasonable tolerability.
Abstract: 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.
Abstract: BACKGROUND: Methotrexate is transported into the cell by the reduced folate carrier (RFC) and out of the cell by members of the multidrug resistance protein family (MRP). Transport proteins may affect the therapeutic efficacy of this drug in patients with rheumatoid arthritis. OBJECTIVE: To investigate the potential benefit of the presence of RFC and the absence of functional MRP for the efficacy of methotrexate treatment. METHODS: The study involved 163 patients (116 female, 47 male; mean age 59.5 years) on methotrexate (mean weekly dose 12.2 mg). RFC was determined using reverse transcriptase polymerase chain reaction, and MRP function by flow cytometry, using a calcein acetoxymethylesther/probenecid assay. Clinical response to methotrexate was evaluated by the EULAR response criteria and the ACR 20% improvement criteria. The clinical data were obtained at the beginning of methotrexate treatment and at the time of blood sampling during ongoing therapy. Patients were divided into four groups according to the presence (+) or absence (-) of RFC and functional (f) MRP. RESULTS: fMRP+/RFC+ and fMRP-/RFC- patients more often had good EULAR response rates (60%, p = 0.014, and 53%, p = 0.035, respectively) in comparison with the fMRP-/RFC+ group (29%); fMRP+/RFC- patients had a low frequency of good disease activity responses. CONCLUSIONS: Absence of fMRP plus presence of RFC did not prove to be related to beneficial effects of methotrexate, but the lack or the presence of both fMRP and RFC led to a significantly better therapeutic outcome. Determination of these markers may predict responsiveness to methotrexate.
Abstract: BACKGROUND: Monitoring disease activity in rheumatoid arthritis (RA) patients by composite indexes is regarded as obligatory when following the recent recommendations for therapy. Whether these recommendations and the patient's perspective are in congruence is a crucial question with respect to the patient's compliance. The aim of the study was to obtain information on the patient's perspective with respect to the disease activity indexes used most often. METHODS: Two hundred and seven RA patients (157 female, 50 male; mean age 59.03 yr, 17-86 yr) were enrolled in this cross-sectional evaluation. The patients' satisfaction [PATSAT (Austrian school mark system) 1 = excellent to 5 = unsatisfactory] and the patients' attitude to therapy (PATATT 1 = reduction, 2 = no change, 3 = increase) were assessed and related to the 28-joint Disease Activity Score (DAS28), the Simplified Disease Activity Index (SDAI) and the Modified Health Assessment Questionnaire (M-HAQ). Statistical evaluation was carried out by applying the Mann-Whitney U test, calculating chi2 and ANOVA. RESULTS: According to the DAS28 and the M-HAQ, patients were at a moderately active disease stage and had low functional deficiency. PATSAT was significantly correlated to the disease activity indexes (all PS < or = 0.002). The mean DAS28 (2.56) at PATSAT 1 was within the remission range, whereas at PATSAT 5 a mean of 5.52 indicated highly active disease. PATATT was found to be related to PATSAT, but did not completely parallel it. Reduction of therapy was intended at a mean DAS28 of 2.87, whereas a request for an increase did not occur before a mean DAS28 of 4.92. CONCLUSION: The patients' therapeutic attitudes are somewhat in line with their satisfaction, which mirrors disease activity to a great extent, though not with the common therapeutic recommendations. The DAS28 proved to be superior to both other indexes taking account of the patient's perspective. These results may provide guidance in patient care and education as well as therapeutic strategies.
Abstract: OBJECTIVE: To assess the reliability and congruency of the Simplified Disease Activity Index (SDAI) compared with the Disease Activity Score including 28 joints (DAS28) in daily practice. METHODS: In 399 consecutive rheumatoid arthritis patients (307 women, 92 men), the SDAI and the DAS28 were calculated. Additionally, 115 of them were observed for 1 year and changes of both values were recorded. Joint assessments were performed by 4 experienced physicians. DAS28 and SDAI values and the respective changes were compared by correlation and regression analyses. Reliability assessment and factor analyses were performed. Disease activity categorizing was compared by the Wilcoxon's rank sum test. RESULTS: The median +/- SD scores were 3.42 +/- 1.45 for the DAS28 and 11.50 +/- 11.50 for the SDAI. Spearman's rho was 0.897 (P < 0.0001). Score changes were also significantly correlated. Reliability testing and factor analysis revealed that both scores can be regarded as monocomponent. Categorizing patients according to the European League Against Rheumatism response criteria (EULARC) or the SDAI revealed statistically significant differences between the 2 scales (P < 0.0001). CONCLUSION: SDAI values are considerably shifted to the left compared with DAS28 levels. Internal consistency and reliability of both scores are comparable. For the differences in disease activity categorizing due to the SDAI compared with the EULARC, a major limitation of the application of this newly developed disease activity score is given, unless these incongruencies can be cleared.
Abstract: OBJECTIVE: To compare the performance of the several different diagnostic criteria sets currently in use for polymyalgia rheumatica (PMR). METHODS: 213 patients attending eight rheumatological centres in eight different European countries were studied. All had recently been referred and were considered by the senior investigator at each centre, selected because of their experience in treatment of PMR, to have this condition. By use of a standard international proforma, the requisite diagnostic points in each criteria set were sought. Sensitivity for each criterion from each set was then calculated, as well as the sensitivity of each criteria set as a whole. RESULTS: Of four criteria sets compared, the Bird (1979) criteria performed best with a sensitivity of 99.5%, and the Hunder (1982) criteria second best, with sensitivity of 93.3%. These both performed significantly better than the two other criteria sets, though each of these was admittedly developed for rather specialised reasons. CONCLUSIONS: Although this study compares homogeneity, we suggest the Bird 1979 or Hunder 1982 criteria should be used whenever possible. Studies that have used alternative criteria may have less sensitivity in diagnosis.
Abstract: Rheumatoid arthritis potentially causes joint destruction, organ failures, and accompanying disorders. Therefore initiating therapeutic measures as early as possible is crucial, whereby symptomatic treatment only is definitely insufficient. Among the traditional disease-modifying antirheumatic drugs (DMARD) Methotrexate is regarded the gold standard. Increasing knowledge of cell-interactions, particularly of the cytokine-cascade, resulted in new therapeutic options. Direct impact via "biologicals" on key inflammatory mediators, primarily TNF-alpha, offers the possibility of effectively modulating or even arresting disease progression. Nowadays, those substances are applied in non-responders to traditional DMARD. Despite their benefits, cons like an increased risk for infections, for exacerbating latent tuberculosis and possibly for malignancies must be considered. Thus, a thorough patient check-up before initiating these therapies is mandatory. Pharmacoeconomic aspects influence the discussion about these "new therapies". The high costs of biologicals, however, should be related to the possible reduction of the diseases psychological, social and economic burdens.
Abstract: OBJECTIVE: The aim of this trial was to compare acemetacin (ACE) with celecoxib (CEL) in terms of tolerability and efficacy in the treatment of osteoarthritis of the knee joint. METHODS: A total of 105 patients (26-64 years old) suffering from primary osteoarthritis (OA) of the knee were enrolled in this international, multicenter, randomized, double blind controlled trial. Fifty three patients were given ACE and 52 CEL. They were treated with either 90 mg bid of slow release ACE or 200 mg bid of CEL for 6 weeks. Additional gastroprotective therapy was not provided. Tolerability was assessed by physical examination, laboratory tests, vital signs and reports of side effects, as well as by patient and physician global assessments. Efficacy parameters comprised pain assessment by visual analogue scale (VAS) and ordinal scale, WOMAC, SF-36 and patient and physician global impressions of efficacy. In addition, acetaminophen consumption was recorded. RESULTS: In 21 ACE (39.6%) and 19 CEL patients (36.5%), the number of side effects totaled 56 (ACE n=29; CEL n=27) (ns). Mean pain reduction at week 6 was highly significant ( P<0.0001) in both groups and amounted to 38.7 mm (+/-20.3) in the ACE group and to 35.1 mm (+/-18.7) in the CEL group (ns). Very similar results were seen with respect to the other efficacy parameters. CONCLUSION: ACE is not inferior to CEL for the short-term treatment of knee OA in terms of tolerability and efficacy.
Abstract: OBJECTIVE: To compare the DAS28 (Disease Activity Score including a 28-joint count) values of rheumatoid arthritis (RA) and fibromyalgia (FM) patients, and to establish whether high pain levels and impaired mood influence DAS28 values. METHODS: DAS28 values were calculated in 62 consecutive patients with RA and in 26 patients suffering from FM. Values for DAS28 scores as well as for the single items of the patient cohorts were compared using Student's t-tests. To evaluate the item weighting and internal consistency of the total score factor analysis was performed and Cronbach's alpha calculated. RESULTS: RA patients showed a mean DAS28 score of 4.23 (+/-1.2; range 0.77-7.46) and in FM patients the mean DAS28 came to 4.04 (+/-1.13; range 1.19-6.28). DAS28 values of RA and FM patients were not significantly different statistically. Comparing the single components of the score, however, highly significant differences (P<0.0005) occurred between RA and FM patients. Cronbach's alpha for the DAS28 in RA patients amounted to 0.7329, indicating high internal consistency, whereas in FM patients it was 0.4832. CONCLUSION: The DAS28, as expected, proved to be inappropriate to express disease activity in FM patients. DAS28 values for expressing disease activity in RA patients may be flawed by coexisting FM and should therefore be regarded with caution as high pain levels more than impaired mood may lead to higher total scores.
Abstract: OBJECTIVES: The Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands (SACRAH) is a self-administered questionnaire assessing functional status, stiffness and pain in patients suffering from hand osteoarthritis (HOA) as well as rheumatoid arthritis (RA) of the hand. It consists of 23 questions in three domains, to be answered on 100 mm visual analogue scales (VAS). Our goal was to shorten the original SACRAH by elimination of redundant questions in order to make it easier to use for patients and physicians. METHODS: Following an arbitrary procedure employing high intervariable correlations, redundant questions were eventually eliminated. To validate the shortened version, 60 patients with HOA, recruited at four rheumatological centres in Austria, completed the original SACRAH as well as the shortened version. Fifty-five patients suffering from RA of the hands treated at the Second Department of Medicine, Humanis Klinikum Stockerau, also completed both questionnaires. RESULTS: A total of 11 questions (nine from the function domain and two from the pain domain) were eliminated, leading to the modified score consisting of 12 questions. Comparing the results of SACRAH and M-SACRAH, as well as the domain scores in individual patients, correlation coefficients were r = 0.978 for HOA patients (P < 0.0001) and r = 0.986 for RA patients (P < 0.0001). CONCLUSION: M-SACRAH, the shortened and simplified version of the original SACRAH questionnaire, proved to be as reliable and as representative as SACRAH for hand status in individual HOA and RA patients.
Abstract: OBJECTIVE: To develop a composite score for measurement of disease activity in polymyalgia rheumatica (PMR) and assess its internal and external validity. METHODS: A PMR activity score (AS) was designed and assessed for internal and external validity in two patient cohorts: 57 international patients evaluated primarily for development of the PMR-AS at baseline, weeks 4 and 24; and for validation, 24 Austrian patients assessed at baseline, week 4, and at a mean (SD) point of week 33.6 (24.5). The PMR-AS was calculated as: CRP (mg/dl)+VAS p (0-10)+VAS ph (0-10)+(MST (min)x0.1)+EUL (3-0); Cronbach's alpha was calculated. Factor analysis by linear regression was applied, and responses calculated on the basis of the PMR response criteria and the PMR-AS applied. PMR-AS values at different times were compared by paired t tests. RESULTS: Cronbach's alpha for the composite score was 0.91 and 0.88 in the two cohorts. Factor analysis showed that each single item contributed significantly to the total score and the relative weight of each item in both cohorts was equally distributed. Mean PMR-AS at baseline was 27.54 and 28.72, respectively, at week 4, 5.99 and 8.99, and at the final visit 5.35 and 5.92 (NS). PMR-AS values at baseline and at later visits were significantly different (p<0.0001). PMR-AS values <7 indicated low disease activity, 7-17 medium disease activity, and >17 high PMR activity. In a third control cohort the PMR-AS correlated highly with patient's global assessment, patient satisfaction, and ESR (p<0.001). CONCLUSION: The PMR-AS provides an easily applicable and valid tool for monitoring disease activity, and in combination with the PMR response criteria provides a better description of response.
Abstract: OBJECTIVE: The enzyme folylpolyglutamyl synthetase (FPGS) is involved in the resistance to methotrexate in tumor cell lines. The aim of the present study was to determine the impact of FPGS mRNA expression on resistance to methotrexate therapy in patients with rheumatoid arthritis (RA). METHODS: We determined the expression of FPGS mRNA using the Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) in 141 patients with RA. All patients received methotrexate therapy. The primary outcome measures were disease activity as determined by a disease activity score (DAS) and response to therapy. RESULTS: Seventy-eight of 141 patients (55%) showed expression of FPGS mRNA. FPGS mRNA expression was not associated with age, sex, disease duration, white blood cell count, erythrocyte sedimentation rate, C-reactive protein (CRP), number of swollen joints, number of painful joints, and combined therapy with other disease-modifying antirheumatic drugs (DMARDs) or additional corticosteroids. The response rate to methotrexate therapy was 44% for the total study population. Patients without FPGS mRNA expression showed a significantly higher response rate than patients with FPGS mRNA expression (57% versus 33%; p = 0.005). Multivariate logistic regression analysis revealed that female sex (p = 0.009) and FPGS mRNA expression (p = 0.004) were independent predictive factors for failure to achieve a response to methotrexate therapy. CONCLUSION: FPGS mRNA expression is an independent predictive factor associated with poor response to methotrexate therapy in RA patients.
Abstract: OBJECTIVES: To establish a questionnaire to quantify the extent of the function and activities of the hand in patients with degenerative or inflammatory disease of the hand and finger joints. METHODS: One hundred and seventy-two patients with osteoarthritis (OA, n = 69) or rheumatoid arthritis (RA, n = 103) completed a new questionnaire, the SACRAH, that included 23 visual analogue scales covering the extent of hand function, stiffness and level of pain. SACRAH scores may range from 0 to 100. RESULTS: Comparing all studied patients, there was no significant difference in SACRAH scores between OA and RA patients (34 vs 32, not significant). Scores for both patient groups differed significantly from those for 30 healthy controls. Among patients taking NSAIDs only, individuals suffering from OA (n = 50) scored significantly lower than RA patients (n = 42) (36 vs 48, P < 0.004). Sixty-one RA patients taking DMARDs scored lower than the RA patient group treated with NSAIDs only (20 vs 48, P < 0.0001). Thirty-two RA patients were evaluated longitudinally at their first visit and 3 months after the initiation of DMARDs. Following therapy, SACRAH scores were significantly reduced from 50 to 11 (P < 0.0001). CONCLUSIONS: The questionnaire enables the quantification of compromised hand function, stiffness and pain in OA and RA patients, and is sensitive to therapy-related changes in RA patients.
Abstract: OBJECTIVE: To develop response criteria for polymyalgia rheumatica (PMR) for monitoring treatment and comparing alternative treatments regimens. METHODS: 76 patients, mean (SD) age 68.7 (7.7) years, were enrolled. Corticosteroids, and non-steroidal anti-inflammatory drugs (NSAIDs) were the only drugs allowed during the observation period. Erythrocyte sedimentation rate (ESR), C reactive protein (CRP), alpha(2) globulin, serum iron, pain, physician's global assessment (PGA), morning stiffness (MST), muscle tenderness (MT), myalgia, and the elevation of upper limbs (EUL) were determined regularly. The daily corticosteroid and NSAID doses as the corticosteroid response time were recorded. To ensure evaluation of an adequate number of patients (n = 57) week 24 was chosen for final analysis. RESULTS: ESR, CRP, alpha(2) globulin, pain, PGA, MST, myalgia, MT, and EUL showed significant improvement (p<0.0001) at week 24 compared with week 0. Multiple regression analysis showed that changes of ESR (p = 0.08), CRP (p = 0.41), alpha(2) globulin (p = 0.13), MST (p = 0.1), and MT (p = 0.07) were independent of pain, but myalgia (p<0.001) and EUL (p = 0.003) were pain dependent. Consequently, a core set of PMR response criteria, comprising ESR or CRP, pain, PGA, MST, and EUL was established. Assessment of treatment responses with this core set resulted in 90%, 70%, 50%, and 20% improvement in 31/57 (54%), 46/57 (81%), 51/57 (89%), and 54/57 (95%) of the patients, respectively. CONCLUSION: These PMR response criteria are a promising tool for better monitoring of disease activity and treatment in PMR. It is proposed that these criteria should be used in clinical trials in the near future to explore alternative treatment options for PMR.
Abstract: 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.
Abstract: The ongoing evaluation of the cytokine-cascade and the steadily growing knowledge about cytokine mediated processes seem to open striking therapeutical options in the fields of sepsis, autoimmune and chronic inflammatory joint or bowel diseases via modulation or inhibition of the cytokine-cascade. There is no doubt about the efficacy of the various anticytokine-treatments in the therapy of chronic inflammatory rheumatic diseases. A large number of preclinical and clinical studies forms the scientific basis for these almost widely established therapies. These so-called "biologicals" are fully accepted as disease modifying antirheumatic drugs, equal to or even more potent than the classical substances. On the one hand, these agents are acting as tumor necrosis factor-alpha-blockers, like a chimeric (human/mouse) monoclonal anti-tumor-necrosis-factor-alpha-antibody (Infliximab), a recombinant soluble tumor necrosis factor-receptor p75 fusion protein (Etanercept), and a fully humanized anti-tumor-necrosis-factor-alpha-antibody (Adalimumab); on the other hand a recombinant human interleukin-1 receptor antagonist (Anakinra) is used in clinical practice. Generally these drugs are very well tolerated; the most common adverse events are higher infection rates (including tuberculosis) and injection-site reactions for the subcutaneously administered agents. Of course one should be aware of the possibly elevated risk for malignancies although there is no evidence for that so far, but the observation time since launching of these drugs is considerably short. To conclude, involved physicians should use these new "tools" very carefully and critically, because long-term tolerance and safety is a matter of ongoing investigation and last but not least because of the growing importance of cost effectiveness when using such expensive medications. Above all initiation and monitoring of those therapies should be restricted to rheumatologists
Abstract: A pan-European study involving 23407 patients with pain due to various inflammatory or degenerative rheumatic diseases was undertaken in Austria, Belgium, Germany and Greece, to evaluate overall pain relief and satisfaction with aceclofenac therapy. Aceclofenac was considered by patients to be a highly efficacious treatment with excellent and fast analgesic activity that was maintained throughout the study period. At the conclusion of the study, assessment of patient status, a parameter encompassing both efficacy against inflammatory pain and tolerability, by both patient and physician, was either much improved or improved in 84% of cases. These evaluations were similar irrespective of the country or whether the indication was acute (e.g. post-pain) or chronic pain (e.g. osteoarthritis). Patient satisfaction with, and compliance of, aceclofenac therapy was similarly impressive; 90% of patients were satisfied and over 90% of patients were treatment compliant. In combination with the recently published SAMM study results, the findings of the European Observational Cohort study validate aceclofenac, in everyday clinical practice, as an effective, well-tolerated and well-accepted therapy for both acute and chronic inflammatory and degenerative disease. The availability of a powerful anti-inflammatory agent with a low incidence of side-effects is of considerable value to both the patient and physician in the management of inflammatory pain. This objective has been fulfilled with aceclofenac therapy.
Abstract: OBJECTIVE: To examine the efficacy of chondroitin sulfate (CS) in the treatment of osteoarthritis (OA) on the basis of a metaanalysis of controlled clinical trials. METHODS: After personal, Medline, and Embase searches, a decision tree analysis of the available publications was performed, with respect to types of joint involvement studied, study designs, numbers of patients enrolled, and variables analyzed. The Lequesne index and pain rating on visual analog scale (VAS) were considered the main variables. Of a total of 16 publications found, 7 trials of 372 patients taking CS could be enrolled into the metaanalysis. Although all selected studies claimed to be randomized, double blind designs in parallel groups, it should be noted that CS was given along with analgesics or nonsteroidal antiiflammatory drugs, making required dosage of comedication an important factor. RESULTS: Following patients to 120 or more days, CS was shown to be significantly superior to placebo with respect to the Lequesne index and pain VAS. Pooled data confirmed these results and showed at least 50% improvement in the study variables in the CS group compared to placebo. CONCLUSION: CS may be useful in OA, but further investigations in larger cohorts of patients for longer time periods are needed to prove its usefulness as a symptom modifying drug in OA.
Abstract: 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.
Abstract: Due to intensive research in the field of cytokines during the last decade the knowledge of cytokine mediated processes has increased intensively. Modulation or even inhibition of the inflammatory cascade gave hope to effective therapeutic possibilities in sepsis or autoimmune diseases, particularly in rheumatoid arthritis (RA). Interestingly the application of biological immunomodulating substances could not increase the prognosis in sepsis, sometimes even deterioration occurred. However, in inflammatory bowel diseases and RA substantial efficacy could be revealed. Since blockade of II-1 or II-2 led to some beneficial results, but also sometimes to significant toxicity, TNF-alpha blockade gave hope to constitute a promising therapeutical target. Since the efficacy of a monoclonal anti-TNF-alpha antibody and a recombinant soluble TNF receptor p75 fusion protein had been demonstrated in animal studies and in vitro, these results could be confirmed in controlled multicenter trials, showing significant improvement of patients according to Paulus and/or ACR criteria. However, a final assessment of therapeutical TNF-alpha blockade in RA cannot be given yet, since the tolerability in long-term application, particularly with respect to the risk of infections and the induction of malignancies and antibodies (e.g. drug induced lupus erythematosus) has to be observed carefully for longer times. Also the cost effectiveness of this new therapeutic approach needs further investigations.
Abstract: Rheumatoid arthritis (RA) is a disease that seriously affects patients' quality of life and may lead to disability or even premature death, despite the availability of effective treatments. Evidence suggests that delay of treatment may be the main contributing factor for poor outcome. Delay is caused primarily by the erroneous belief that the course of RA may be controlled in many cases by mild measures such as nonsteroidal antiinflammatory drugs, physiotherapy, and rest. While this may be true in a certain percentage of patients, many patients with RA progress to severe disability. To prevent progression of disease, early treatment of RA, particularly in patients at high risk, seems mandatory. Therefore, early arthritis clinics (EAC) have been established in a number of countries. We discuss the rationale for early intervention and our experiences in Austrian EAC.
Abstract: OBJECTIVE: To assess differences in soluble tumor necrosis factor receptor 55 (sTNF-R55), sTNF-R75, and soluble interleukin 2 receptor (sIL-2R) in synovial fluid (SF) of patients with psoriatic arthritis (PsA), a seronegative inflammatory joint disease, in comparison with those of patients with rheumatoid arthiritis (RA) and osteoarthritis (OA). METHODS: sIL-R were measured in SF with commercial sandwich ELISA and the results correlated with serological and clinical disease activity variables. RESULTS: In PsA SF the level of sTNF-R55 was 11.8 +/- 0.8 ng/ml and that of sTNF-R75 13.0 +/- 1.3 ng/ml. sIL-2R concentration in PsA SF was 800 +/- 84 U/ml. Compared to PsA SF, cytokine receptor levels in OA SF were significantly lower: 8.7 +/- 0.8 ng/ml for sTNF-R55 (p < 0.02); 7.1 +/- 0.9 ng/ml for sTNF-R75 (p < 0.0003); and 505 +/- 53 U/ml for sIL-2R (p < 0.009). In contrast RA SF cytokine receptor levels were even higher than those of PsA SF (sTNF-R55: 18.1 +/- 2.0 ng/ml, p < 0.04; sTNF-R75: 29.5 +/- 2.9 ng/ml, p < 0.0002; and for sIL-2R: 1957 +/- 290 U/ml, p < 0.03). CONCLUSION: In PsA SF sTNF-R55, sTNF-R75, and sIL-2R are upregulated compared to OA SF but are lower than in RA SF. Our results for TNF-R agree with recent findings in PsA, since TNF-alpha, an important stimulator for TNF-R, is also significantly lower in PsA than in RA. The upregulation of the cytokine receptors in PsA reconfirms its inflammatory nature, but indicates the more benign course of disease compared with RA.
Abstract: OBJECTIVE: The aim of this study was to investigate the concentrations of T cell derived cytokines in the synovial fluids (SFs) of patients with psoriatic arthritis (PsA) in comparison with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: Th1 type cytokines (interleukin 2 (IL2), tumour necrosis factor beta (TNF beta), and interferon gamma (INF gamma) and Th2 type cytokines (IL4, IL10) were measured by means of enzyme linked immunosorbent assays. RESULTS: IL2 was usually not detectable in any of the disease groups. TNF beta was found in 3 of 31 PsA SFs (mean (SEM) 11.1 (2.3) pg/ml) and in a significantly lower concentration than in 20 of the 40 RA SFs (42.2 (15.6) pg/ml; p < 0.002). INF gamma was measurable in 2 of 10 PsA and 6 of 16 RA SFs (p > 0.05). IL4 was present at low concentrations in 4 of 22 PsA SFs (0.41 (0.8) pg/ml), and in 15 of 20 RA SFs (0.63 (0.09) pg/ml; p < 0.01). IL10 was found in 4 of 27 PsA SFs (12.3 (0.9) pg/ml) and in 27 of 32 RA SFs (37.3 (4.9) pg/ml; p < 0.0001). In all OA SFs cytokine concentrations were below the limit of detection. CONCLUSION: The pattern of T cell derived cytokines in PsA SFs was similar to that of RA SFs. However, both the frequency and the concentrations of cytokines were lower in PsA SFs than in RA SFs, while OA SFs generally lacked any detectable T cell cytokines altogether. The presence of Th1 and Th2 cell derived cytokines in PsA SFs suggests the presence of activated T cells in the inflamed joint tissues and their participation in the immunoinflammatory events.
Abstract: OBJECTIVE: To evaluate the efficacy, pharmacokinetics, immunogenicity, and safety of multiple infusions of a chimeric monoclonal anti-tumor necrosis factor alpha antibody (cA2) (infliximab; Remicade, Centocor, Malvern, PA) given alone or in combination with low-dose methotrexate (MTX) in rheumatoid arthritis (RA) patients. METHODS: In a 26-week, double-blind, placebo-controlled, multicenter trial, 101 patients with active RA exhibiting an incomplete response or flare of disease activity while receiving low-dose MTX were randomized to 1 of 7 groups of 14-15 patients each. The patients received either intravenous cA2 at 1, 3, or 10 mg/kg, with or without MTX 7.5 mg/week, or intravenous placebo plus MTX 7.5 mg/week at weeks 0, 2, 6, 10, and 14 and were followed up through week 26. RESULTS: Approximately 60% of patients receiving cA2 at 3 or 10 mg/kg with or without MTX achieved the 20% Paulus criteria for response to treatment, for a median duration of 10.4 to >18.1 weeks (P < 0.001 versus placebo). Patients receiving cA2 at 1 mg/kg without MTX became unresponsive to repeated infusions of cA2 (median duration 2.6 weeks; P=0.126 versus placebo). However, coadministration of cA2 at 1 mg/kg with MTX appeared to be synergistic, prolonging the duration of the 20% response in >60% of patients to a median of 16.5 weeks (P < 0.001 versus placebo; P=0.006 versus no MTX) and the 50% response to 12.2 weeks (P < 0.001 versus placebo; P=0.002 versus no MTX). Patients receiving placebo infusions plus suboptimal low-dose MTX continued to have active disease, with a Paulus response lasting a median of 0 weeks. A 70-90% reduction in the swollen joint count, tender joint count, and C-reactive protein level was maintained for the entire 26 weeks in patients receiving 10 mg/kg of cA2 with MTX. In general, treatment was well tolerated and stable blood levels of cA2 were achieved in all groups, except for the group receiving 1 mg/kg of cA2 alone, at which dosage antibodies to cA2 were observed in approximately 50% of the patients. CONCLUSION: Multiple infusions of cA2 were effective and well tolerated, with the best results occurring at 3 and 10 mg/kg either alone or in combination with MTX in approximately 60% of patients with active RA despite therapy with low-dose MTX. When cA2 at 1 mg/kg was given with low-dose MTX, synergy was observed. The results of the trial provide a strategy for further evaluation of the efficacy and safety of longer-term treatment with cA2.
Abstract: OBJECTIVE: To investigate the potential role of cytokines in psoriatic arthritis (PsA) by assessing the profiles of the proinflammatory cytokines in synovial fluid (SF) of PsA in comparison with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: Levels of tumor necrosis factor-alpha (TNF-alpha), interleukin 1 (IL-1), IL-6, and IL-8 were measured in SF using ELISA. RESULTS: Levels of TNF-alpha, IL-1beta, and IL-8 were significantly higher in PsA SF than in OA SF, although lower than in RA SF. No difference was detected in the IL-6 levels between PsA and RA SF, both of which were much higher than in OA SF. CONCLUSION: The pattern of expression of proinflammatory cytokines seen in PsA is similar to that in RA. Since PsA is also a destructive arthropathy, cytokines, in particular TNF-alpha and IL-1, may be principle factors in joint destruction.
Abstract: Since the early eighties methotrexate (MTX) has become of increasing importance in long-term therapy of rheumatoid arthritis (RA) as a disease modifying drug (DMARD). Nowadays it is probably the most frequently prescribed DMARD for RA and can be regarded as the gold standard in long-term therapy. MTX can be administered orally or parenterally, the bioavailability shows high individual differences, but is about 70% after oral administration on average. Its protein-binding amounts to 50%, the main pathway of elimination is renal tubular secretion, to a smaller extent also biliary excretion. MTX polyglutamates are stored intracellularly. Its mode of action in RA is not completely elucidadet yet, besides inhibition of dihydrofolatereductase and consequently inhibition of thymidilate synthesis, some antiinflammatory effects, such as stimulation of Adenosine release from neutrophils, may contribute to the therapeutical effects. MTX' efficacy could be proven by several controlled trials, some of them lasting for more than five years. During long-term therapy with MTX a folate deficiency may occur, which can lead to some side effects. Most important but rarely occurring is pneumonitis, moreover hepatotoxicity and hematological features have to be intensively considered. The risk of the development of osteopenia or an increased incidence of malignancies during MTX therapy is currently investigated. In case of clinical and laboratory controls at regular intervals and patient education MTX therapy can be regarded as effective, well tolerable and considerably safe for patients with rheumatoid arthritis.
Abstract: 61 patients, suffering from osteoarthritis of the hip, knee and/or finger joints, were included into this open, multicenter, phase IV trial. Patients were treated with chondroitinsulfate (CS) at the recommended dose for 3 months. Concomitant NSAID-therapy, which was necessary for disease control at the beginning of the observation period could be reduced by 72% throughout the 3 months of CS-therapy. The decrease of pain was revealed to be statistically significant; serious side effects were not to be observed during the study. At the beginning of the observation period patients suffered from overall severe pain, and therefore the decrease of pain down to a level, which could not have been achieved by NSAID therapy alone to a greater extent, is of special interest. The results of this trial represent the first office based Austrian data on CS-therapy. In conclusion it could be demonstrated that a significant reduction of the daily NSAID consumption was possible by concomitant CS-therapy, without the risk of deterioration of the patients' symptoms. The 97% compliance does not give evidence for drop-out bias. Moreover, the results of this trial are comparable to other international double-blind, in part placebo-controlled studies, concerning CS-therapy, indicating beneficial results in the treatment of osteoarthritis.
Abstract: Rheumatoid arthritis (RA) is the most frequent inflammatory joint disease, and it affects about 1% of the population. The onset of arthritis is rarely acute; it is subacute and usually progresses slowly. The clinical picture of RA is variable: mild to very aggressive and destructive courses, sometimes accompanied by organ involvement, leading to severe functional impairment and early disability can be observed. RA is diagnosed according to the ACR criteria published in 1958 and modified in 1988. The appearance of a palpable joint swelling or effusion is obligatory for the clinical diagnosis of arthritis. In RA, typically involvement of the joint of the hands and feet can be seen. Laboratory parameters play an important role as both diagnostic and prognostic tools. Besides clinical features and laboratory parameters, imaging techniques provide another cornerstone in the diagnosis of RA. Until now plain X-rays, which primarily visualize osseous changes, are the most important technique in daily practice, whereas magnetic resonance imaging and ultrasound may provide information about soft tissue changes in an earlier stage of disease. The main differential diagnoses of RA to be considered are the seronegative spondylarthropathies (psoriatic arthritis, arthritides accompanying inflammatory bowel diseases, Reiter's syndrome, and spondylitis ankylosans with peripheral arthritis), Parvovirus-induced arthritis, crystal-induced arthritides and septic arthritis. Early diagnosis and therapeutic intervention seem to be of great prognostic importance. In several independently performed investigations a higher mortality was found in RA patients than in the normal population. Drug therapy of RA consists of nonsteroidal antirheumatic drugs (NSAIDs), corticosteroids and disease-modifying drugs (DMARDs). When the functional and radiological parameters were assessed, the DMARDs were found to have a disease modifying and in rare cases a remission-inducing property. Moreover, tolerance these to drugs is limited. Newer therapeutic trials have employed substances like Tenidap, Leflunomid, bacterial extracts, antibiotics and biological subcomes (e.g., monoclonal antibodies against cytokines, fusion proteins for soluble cytokinereceptors). Some promising results of these investigations need confirmation in larger patient populations, but some new perspectives for a more efficacious treatment of RA can be expected.
Abstract: OBJECTIVE: Serum hyaluronan (HA) was determined in 37 patients suffering from psoriatic arthritis (PSA), 39 patients with rheumatoid arthritis (RA), 31 with osteoarthritic joint disease (OA) and 26 healthy controls (C) in order to examine earlier reports that HA levels are increased in the serum of RA and to assess whether this finding is also relevant for PSA, another inflammatory joint disease, since HA in serum is considered a sign of inflammation in general. METHOD: HA in the serum samples was measured with an enzyme linked microplate assay. RESULTS: Sera from PSA, RA and OA patients showed a significantly higher HA concentration than those of healthy controls (56.0 +/- 16.0 micrograms/l). The serum HA concentration in PSA patients amounted to 107.8 +/- 57.2 micrograms/l, which was not significantly different from OA patients (104.9 +/- 16 micrograms/l). A significant difference, however, could be observed between the HA concentrations of the PSA subgroups: the mean HA level of patients suffering from symmetrical polyarthritis was 134 +/- 79.6 micrograms/l, which turned out to be significantly higher than in patients suffering from symmetrical oligoarthritis (89.9 +/- 42.8 micrograms/l; P < 0.04), but was insignificantly increased in comparison to patients with ankylosing spondylitis as the predominant feature (109 +/- 27.8 micrograms/l; P = 0.49). The mean HA concentration for RA sera was 197.1 +/- 122.9 micrograms/l, which was statistically significantly increased compared to PSA (P < 0.001) and OA (P < 0.001) sera. The sera of seropositive RA patients showed significantly higher HA levels than PSA patients with symmetrical polyarthritis (P < 0.04). CONCLUSION: The data obtained support recent studies which have shown HA levels to be higher in RA patients than in OA patients. Seronegative and seropositive RA patients showed the same HA concentrations, while patients suffering from "seronegative" PSA were found to have lower HA concentrations. Therefore, HA serum levels may reflect cartilage degradation in general or the degree of articular inflammatory processes, indicating different pathogenetic pathways.
Abstract: OBJECTIVE. The purpose of our study was to evaluate the potential of contrast-enhanced MR imaging to detect and to characterize craniocervical rheumatoid arthritis in a large population group, to compare MR imaging with clinical and conventional radiographic findings, and to examine the relationship between the histopathologic and MR imaging findings in seven patients. SUBJECTS AND METHODS. We performed contrast-enhanced MR imaging using T2-weighted gradient-echo sequences and T1-weighted spin-echo sequences in 136 patients with rheumatoid arthritis. Sequential T1-weighted images were obtained before, 3 min after, and 15 min after injection of contrast material. Plain films were acquired in all patients. Serologic status and neurologic status were determined in each patient within 2 days of MR imaging. Patients were categorized into one of four groups, depending upon whether they had joint effusion, hypervascular pannus, hypovascular pannus, or fibrous pannus according to signal patterns on contrast-enhanced MR images. Signal intensity was measured to assess the enhancement of synovial hypertrophy, joint capsule, joint effusion, and the various stages of pannus tissue. Histologic specimens were obtained from seven patients and were correlated with MR imaging findings. RESULTS. Acute and chronic synovitis were differentiated with contrast-enhanced MR imaging as follows: joint effusion (n = 29), hypervascular pannus (n = 54), hypovascular pannus tissue (n = 8), and fibrous pannus (n = 22). Signal intensity differed significantly among the four groups on contrast-enhanced T1-weighted images. In 59 patients with effusion or hypervascular pannus tissue, atlantoaxial subluxation was diagnosed with plain films. Patients with negative findings on radiographic studies (n = 20) had joint effusion, hypervascular pannus tissue, hypovascular pannus formation, or fibrous pannus tissue on MR imaging studies. Cord compression was found in 10% of all cases and isolated sac compression in 16%. Neurologic findings showed no correlation with MR imaging features. CONCLUSION. Contrast-enhanced T1-weighted spin-echo MR imaging can discriminate between joint effusion and various forms of pannus in patients with rheumatoid arthritis of the craniocervical region. MR imaging also can detect joint effusion and pannus tissue in patients with negative radiographic findings. No relationship between MR imaging findings and clinical symptoms were found. Tissue enhancement and histopathologic findings correlated in a limited number of autopsies.
Abstract: OBJECTIVE. To compare folic acid (FA) levels in patients being treated with methotrexate (MTX) with those of untreated patients in order to investigate potential folate depletion by MTX and its possible relationship to the drug's efficacy. METHODS. In 33 patients on low-dose MTX therapy and in 24 controls, FA and cyanocobalamin (B12) levels were determined in serum and red blood cells (RBC). In addition, MTX levels in the RBC and serum were measured, and clinical and laboratory measures of disease activity were evaluated. RESULTS. MTX treated patients had lower FA levels than controls (median 4.36 vs 7.37 ng/ml, p < 0.001). A significant correlation between serum FA and MTX/RBC (p < 0.01) and between the weekly dose and MTX/RBC (p < 0.01) was seen. There was apparently no correlation between FA and the cumulative total MTX. MTX patients had lower B12/RBC levels than the controls (p < 0.001); the serum levels of B12 were not different. Clinical features, ESR and CRP did not correlate with FA, B12 or MTX levels. CONCLUSIONS. The degree of folate depletion during MTX therapy depends primarily upon the weekly administered dose. Folate depletion may be related to B12 deficiency in RBC. Since FA levels were not related to parameters of disease activity it is conceivable that MTX does not exert its action in RA primarily by inhibiting dihydrofolatereductase. Therefore, additional folate compounds, if necessary, should not lead to a reduction in the efficacy of MTX.
Abstract: In the treatment of acute soft tissue injuries, topical nonsteroidal anti-inflammatory drugs are both highly effective and well tolerated. Target is a monopreparation that meets the demands made on a modern topical agent. The active substance, felbinac, readily, penetrates into the tissue affected and accumulates locally, selectively inhibiting inflammation and alleviating pain. This synoptic report on the clinical trials confirm the significant clinical superiority of felbinac over placebo. As compared with piroxicam, felbinac, is more successful in eliminating symptoms. The rapid alleviation of pain by the topical felbinac results in an improvement in the restriction of mobility and rapid restitution of function. The cooling, nongreasy gel base further favors the high level of acceptance of this well-tolerated preparation.
Abstract: Collagenase activity has been studied intensively in SF from OA and RA patients. Less is known about collagenolytic activity in PsA SF. Therefore we examined collagenolytic activity in crude and trypsin treated SF as well as the alpha 1-antitrypsin and alpha 2-macroglobulin concentrations in 50 patients suffering from OA (n = 13), RA (n = 17), and PsA (n = 20). Free collagenolytic activity was low in the crude OA SF (1.80 +/- 1.35 micrograms released collagen/min/ml SF) and almost equally low in RA SF (2.35 +/- 1.80 micrograms released collagen/min/ml SF; P > 0.3). The PsA SF, however, exhibited a significantly higher free collagenolytic activity (5.63 +/- 5.69 micrograms released collagen/min/ml SF; P < 0.05 in comparison to OA and RA SF). The treatment of the SF with trypsin further activated collagenolytic activity in each group (OA 2.17 +/- 1.35 micrograms released collagen/min/ml SF; RA 6.48 +/- 6.73 micrograms released collagen/min/ml SF; PsA 11.24 +/- 5.02 micrograms released collagen/min/ml SF) and yielded significant differences between OA and RA, OA and PsA, and RA and PsA SF (P < 0.05). Concomitantly with the collagenolytic activity, the alpha 1-antitrypsin and alpha 2-macroglobulin concentrations of the SF were measured. In SF from patients with PsA (172.9 +/- 69.4 mg/100 ml) and RA (190.6 +/- 64.7 mg/100 ml) the alpha 1-antitrypsin was significantly higher than in those from OA SF (106.1 +/- 39.2 mg/100 ml).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Tumour necrosis factor alpha (TNF alpha) is a critical inflammatory mediator in rheumatoid arthritis, and may therefore be a useful target for specific immunotherapy. In support of this hypothesis, we previously observed beneficial responses in patients with active rheumatoid arthritis after open-label administration of a chimeric monoclonal antibody to TNF alpha (cA2). We now report the results of a four-centre, randomised double-blind trial of a single infusion of 1 or 10 mg/kg cA2 compared with placebo in 73 patients with active rheumatoid arthritis. The primary endpoint of the study was the achievement at week 4 of a Paulus 20% response, an amalgam of six clinical, observational, and laboratory variables. Intention-to-treat analysis of data from individual patients showed only 2 of 24 placebo recipients responding at this time, compared with 11 of 25 patients treated with low-dose cA2 (p = 0.0083) and 19 of 24 patients treated with high-dose cA2 (p < 0.0001). Over half of the high-dose cA2 patients responded by the more stringent 50% Paulus criteria at this time (p = 0.0005). The magnitude of these responses was impressive, with maximum mean improvements in individual disease-activity assessments, such as tender or swollen-joint counts and in serum C-reactive protein, exceeding 60% for patients on high-dose treatment. There were two severe adverse events. 1 patient on 1 mg/kg cA2 developed pneumonia ("possibly" treatment-related) and 1 on 10 mg/kg had a fracture ("probably not" treatment-related). The results provide the first good evidence that specific cytokine blockade can be effective in human inflammatory disease and define a new direction for the treatment of rheumatoid arthritis.
Abstract: In 29 patients, 21 suffering from psoriatic arthritis and eight patients suffering from rheumatoid arthritis, methotrexate serum-levels were determined by means of radioimmunoassay. The aim of the investigation was to recognize an eventual dependence of the serum level of methotrexate on the total cumulative dose and to test the possibility of a concomitant therapy control. Beside the determinations of the serum levels of methotrexate, clinical examinations and laboratory tests were done at regular intervals. The values obtained showed no significant increase during the course of therapy compared to the values at the beginning of the treatment. Likewise no correlation to the total cumulative dose, the clinical picture or to the occurrence of side-effects could be found. Nor could any relationship between the changing of laboratory parameters and the methotrexate serum-levels be observed. No differences appeared in the methotrexate serum-levels during therapy of either rheumatoid or psoriatic arthritis patients. In conclusion it seems impossible to monitor a low-dose methotrexate therapy by continuous determinations of the serum levels of the drug.
Abstract: To verify the possibility of a concomitant therapy control in 31 patients (18 psoriatic arthritis [PA], 13 rheumatoid arthritis [RA]) the blood cell concentration of Methotrexate (MTX) was continuously measured over a period of 6 months. The determinations were carried out by using a RIA of the CIS Corp. At any time MTX was determined laboratory and clinical examinations were done and the P-III-P serum-level was measured by using a RIA of the Behringwerke. The cellular MTX showed to be statistically significantly elevated compared to baseline, whereas within ranges of total cumulative dosages only insignificant fluctuations could be noticed. Like in the treatment of Psoriasis a strict correlation between the weekly administered dose and the cellular MTX could be established, the total cumulative dose, however, had no influence on the cellular MTX-level. In the treatment of RA slightly higher weekly dosages were necessary, which caused significantly higher cellular MTX concentrations in RA patients. Some correlations between clinical as well as serological parameters of disease activity could be noticed, nevertheless they do not allow distinct interpretations. In both diseases a significant relationship between the cellular MTX-level and the P-III-P serum-level could be realized. A storage of MTX in blood cells, especially in erythrocytes, seems to be evident. To reach therapeutical benefit in RA slightly higher mean dosages may be necessary. A therapy monitoring by the means of continuous determinations of cellular MTX seems to be impossible. In contrast an approach to the early detection of liver fibrosis can be given by the correlation between cellular MTX and the P-III-P serum levels.
