A Dutch consensus statement on the diagnosis and treatment of ANCA-associated vasculitis.

INTRODUCTION: Despite the availability of several guidelines on the diagnosis and treatment of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), clinical routine practice will only improve when an implementation strategy is in place to support clinical decision making and adequate implementation of guidelines. We describe here an initiative to establish national and multidisciplinary consensus on broad aspects of the diagnosis and treatment of AAV relevant to daily clinical practice in the Netherlands. METHODS: A multidisciplinary working group of physicians in the Netherlands with expertise on AAV addressed the broad spectrum of diagnosis, terminology, and immunosuppressive and non-immunosuppressive treatment, including an algorithm for AAV patients. Based on recommendations from (inter)national guidelines, national consensus was established using a Delphi-based method during a conference in conjunction with a nationally distributed online consensus survey. Cut-off for consensus was 70% (dis)agreement. RESULTS: Ninety-eight professionals were involved in the Delphi procedure to assess consensus on 50 statements regarding diagnosis, treatment, and organisation of care for AAV patients. Consensus was achieved for 37/50 statements (74%) in different domains of diagnosis and treatment of AAV including consensus on the treatment algorithm for AAV. CONCLUSION: We present a national, multidisciplinary consensus on a diagnostic strategy and treatment algorithm for AAV patients as part of the implementation of (inter)national guideline-derived recommendations in the Netherlands. Future studies will focus on evaluating local implementation of treatment protocols for AAV, and assessments of current and future clinical practice variation in the care for AAV patients in the Netherlands.

Changes in Farr radioimmunoassay and EliA fluorescence immunoassay anti-dsDNA in relation to exacerbation of SLE.

Measuring anti-dsDNA levels could support treatment adjustment during follow-up of patients with systemic lupus erythematosus (SLE). We investigated whether patients with exacerbations of SLE showed changes in anti-double-stranded DNA (anti-dsDNA) levels prior to the exacerbation using the Farr and EliA assay and examined which assay showed highest specificity and predictive value for exacerbations. Changes in anti-dsDNA of ≥ 25% prior to exacerbation were considered of clinical significance. Exacerbations were retrospectively abstracted from medical records. Eighteen of 48 patients showed one or more exacerbations. We found 22 exacerbations with complete lab work-up, all accompanied by ≥ 25% change in anti-dsDNA in one or both assays. Only 10 exacerbations showed concordant changes in anti-dsDNA in both assays. Changes in anti-dsDNA had a low predictive value for exacerbations of SLE, but the specificity of anti-dsDNA changes for patients with exacerbations was higher for EliA than Farr. We conclude that despite the limited relation between anti-dsDNA changes and exacerbations of SLE, anti-dsDNA testing could still support clinical decision making when used in the correct setting. We conclude that EliA is preferable over Farr for assaying anti-dsDNA during follow-up of patients with SLE because of higher specificity, less "hands-on" time and absence of radioactivity.

Leflunomide in the treatment of rheumatoid arthritis. An analysis of predictors for treatment continuation.

AIMS: To determine factors predictive for leflunomide drug survival in an outpatient population with rheumatoid arthritis in a setting of care-as-usual. METHODS: A standard dataset was collected from medical records of consecutive outpatients on leflunomide treatment for rheumatoid arthritis between January 2000 and June 2003. The dataset consisted of patient, disease and treatment characteristics at the start of leflunomide treatment, and data on leflunomide use. RESULTS: Leflunomide was started in 279 patients and 173 patients (62.0%) withdrew from treatment during follow-up. From univariate analysis, concomitant systemic corticosteroid use [hazard ratio (HR) (95% confidence interval) 1.35 (1.00, 1.83)] and an erythrocyte sedimentation rate <35 mm h(-1)[HR 1.38 (1.01, 1.88)] at start of leflunomide were found to be predictive for better leflunomide survival. Furthermore, the attending rheumatologist was correlated with leflunomide drug survival. Hazard ratios varied, depending on the individual rheumatologist, from 0.60 to 2.66. Multivariate analysis suggested attending rheumatologist (HR varying from 0.54 to 2.30 depending on the individual rheumatologist), concomitant systemic corticosteroid use [HR 1.58 (1.14 2.21)] and erythrocyte sedimentation rate <35 mm h(-1)[HR 1.42 (1.03, 1.96)] at start of leflunomide to be associated with leflunomide survival. CONCLUSIONS: Concomitant systemic corticosteroid use, erythrocyte sedimentation rate at the start of treatment and attending rheumatologist were found to be predictive for leflunomide survival. Information on these predictors at the start of leflunomide therapy may offer information on which patients are at an increased risk of withdrawal from leflunomide. Whether this information leads to optimization of leflunomide treatment outcomes remains to be studied.

Spa treatment for primary fibromyalgia syndrome: a combination of thalassotherapy, exercise and patient education improves symptoms and quality of life.

OBJECTIVES: To study the effect of a combination of thalassotherapy, exercise and patient education in people with fibromyalgia. METHODS: Patients with fibromyalgia, selected from a rheumatology out-patient department and from members of the Dutch fibromyalgia patient association, were pre-randomized to receive either 2(1/2) weeks of treatment in a Tunisian spa resort, including thalassotherapy, supervised exercise and group education (active treatment) or treatment as usual (control treatment). Primary outcome measure was health-related quality of life, measured with the RAND-36 questionnaire. Secondary measures included the Fibromyalgia Impact Questionnaire, the McGill Pain Questionnaire, the Beck Depression Inventory, tender point score and a 6-min treadmill walk test. RESULTS: Fifty-eight participants receiving the active treatment reported significant improvement on RAND-36 physical and mental component summary scales. For physical health, differences from the 76 controls were statistically significant after 3 months, but not after 6 and 12 months. A similar pattern of temporary improvement was seen in the self-reported secondary measures. Tender point scores and treadmill walk tests improved more after active treatment, but did not reach significant between-group differences, except for walk tests after 12 months. CONCLUSIONS: A combination of thalassotherapy, exercise and patient education may temporarily improve fibromyalgia symptoms and health-related quality of life.

Differences in understanding and application of 1987 ACR criteria for rheumatoid arthritis and 1991 ESSG criteria for spondylarthropathy. A pilot survey.

OBJECTIVES: To determine areas of agreement and disagreement among experts in the interpretation of the published criteria for RA (ACR) and spondylarthropathies ( ESSG). METHODS: Thirty-two experts (16 from France and 16 from 10 other countries) replied anonymously to a mailed questionnaire. RESULTS: Tenosynovitis and 'sausage-like' painless swelling of the toes were considered as criteria for RA by 18 and 14 experts, respectively. The definition of symmetry differed widely among experts (symmetry of only one group of joints was sufficient for 13). Twenty-five experts considered erosions of other joints than the wrists and fingers as a criterion for RA, 17 thought that fulfilment of criteria could be achieved cumulatively, and 19 would appreciate clarifications of the current criteria. Among possible clarifications for RA, it was frequently recommended that morning stiffness and nodules be eliminated and that new marker antibodies, X-rays of the feet, and exclusion criteria be added. Twenty-three of the 29 experts who gave an opinion (79%) agreed with the notion of SP in the absence of axial signs and sacroiliitis, 26/31 (84%) indicated that a patient can have both RA and SP, and 19/30 (63%) thought that RA and SP could be regarded as syndromes more than diseases. Only 5/32 experts relied more on the criteria than on their clinical judgement in diagnosing RA. CONCLUSIONS: There would seem to be a needfor the optimisation of RA and ESSG criteria, particularly within the context of early arthritis.

The rheumatoid arthritis articular damage score: first steps in developing a clinical index of long term damage in RA.

OBJECTIVE: To design and validate a clinical method for scoring irreversible long term articular damage in rheumatoid arthritis (RA). METHODS: The rheumatoid arthritis articular damage score (RAAD score) is based on examination of 35 large and small joints. Concise definitions were formulated to score each joint on a three point scale (0, no irreversible damage; 1, partially damaged; 2, severe damage, ankylosis, or prosthesis). The RAAD score was determined for 121 patients with RA with a large range of disease duration. Interobserver agreement was studied in 39 patients scored by three observers. Data on disease duration, Health Assessment Questionnaire, disease activity score, and Larsen score were collected for 121, 78, 47, and 45 patients, respectively. RESULTS: The RAAD score correlated well with the Larsen score (r(s)=0.81) and disease duration (r(s)=0.68) and (as intended) not with disease activity (r(s)=0.10). Good interobserver agreement was found for total scores and individual joints. The wide range of RAAD scores for patients with the same disease duration suggested good discriminating power, especially after >10 years. CONCLUSION: The RAAD score is a quick and feasible method for measuring the long term articular damage in large RA populations. It has good reliability and construct validity and deserves further study to assess its discriminant validity.

Lessons from an international survey of paper cases of 10 real patients from an early arthritis clinic. CRI (Club Rhumatismes et Inflammation) Group.

OBJECTIVE: To determine how experts would classify 10 early-arthritis cases (7 atypical) and to study discrepancies in diagnoses relative to ACR criteria for rheumatoid arthritis (RA) or ESSG criteria for spondyloarthropathy (SpA). METHODS: Ten real cases (5 met ACR criteria for RA, 6 ESSG criteria for SpA, 3 both and 2 neither) followed for 28.5 +/- 4.8 months were sent as paper cases to 20 international and 12 French experts. Each expert selected a diagnosis among 8 possible choices and rated it on a 0-10 confidence scale. For each case, 3 analog scales (0-100 mm) were used to indicate the probability of RA, SpA or undifferentiated arthritis (UA). RESULTS: Experts often disagreed about diagnoses (up to 5 different diagnoses for a given case, with a mean of 3.9 per case). Similarly, expert opinions on probabilities for RA and SpA differed widely, with great overlap between confidence for RA, SpA and UA. Fulfilment of ACR or ESSG criteria was poorly related to the experts' diagnosis and evaluation of probabilities for RA and SpA. However, UA was a relatively infrequent choice (19%). CONCLUSIONS: There was no general consensus about the nosology of early RA and SpA. Classification of atypical early arthritis was not resolved by currently available criteria for RA and SpA. This may have implications for therapy in early disease.

No increased risk of malignancies and mortality in cyclosporin A-treated patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the cyclosporin A (CSA)-attributed risk of developing malignancies in general and malignant lymphoproliferative diseases (LPDs) and skin cancers in particular, as well as the CSA-attributed incidence of mortality in patients with rheumatoid arthritis (RA). METHODS: In a retrospective, controlled cohort study, the incidence of malignancies and mortality was evaluated in 208 CSA-treated patients with RA compared with 415 matched control patients with RA between 1984 and 1995. Patients were followed up for a median of 5.0 years (range 1.4-12.0). RESULTS: Forty-eight cases of malignancy (8 in the CSA group and 40 in the control group; relative risk [RR] 0.40, 95% confidence interval [95% CI] 0.19-0.84) were identified, of which 8 were malignant LPDs (2 CSA versus 6 control; RR 0.67, 95% CI 0.14-3.27) and 14 were skin cancers (2 CSA versus 12 control; RR 0.33, 95% CI 0.08-1.47). Seventy-three patients died (16 CSA versus 57 control; RR 0.56, 95% CI 0.33-0.95) due primarily to cardiovascular diseases (4 CSA versus 22 control; RR 0.36, 95% CI 0.13-1.04) or a malignancy (3 CSA versus 8 control; RR 0.67, 95% CI 0.18-2.43). Proportional hazards regression analysis with correction for potential confounding factors did not significantly change the results. CONCLUSION: The study findings suggest that CSA treatment in RA patients does not increase the risk of malignancies in general or the risk of malignant LPDs or skin cancers in particular. Moreover, the incidence of mortality in CSA-treated RA patients was comparable to that in matched control RA patients.

Laboratory screening for side effects of disease modifying antirheumatic drugs in daily rheumatological practice.

To observe the actual laboratory screening for side effects of disease modifying antirheumatic drugs (DMARDs) in daily rheumatological practice, a retrospective multi-center cohort study was performed on the laboratory tests in DMARD treated rheumatoid arthritis (RA) patients. RA patients were investigated by chart review if they started with a DMARD (cohort 1) or were treated with a DMARD for at least one year (cohort 2). Hematological, hepatic, and renal tests were collected. In cohort 1 and 2, 513 and 1209 patients were included, respectively. A fairly outlined screening profile was observed for each DMARD studied. Except for antimalarials, the testing frequency decreased with time in cohort 1. For all DMARDs the testing frequency in cohort 1 was higher than in cohort 2. In general, rheumatologists requested laboratory tests less frequently than is internationally recommended. This discrepancy raises questions about the relation between the efficacy and costs of laboratory screening for side effects of DMARDs in patients with RA.

Silicone breast prostheses and rheumatic symptoms: a retrospective follow up study.

OBJECTIVES: To determine whether women with silicone breast prostheses have more rheumatic complaints than controls. METHODS: The study included 287 women who had silicone breast prostheses implanted between 1978-90. For every patient a female control of the same age was selected who had had an aesthetic operation in the same year. A questionnaire was sent to this retrospective cohort of women with silicone breast prostheses and controls. RESULTS: Questionnaires were returned by 235 cases (82%) and 210 controls (73%). Patients reported more symptoms arising after surgery than controls (0.6 v 0.3 complaints per subject, p < 0.001). The average interval between surgery and onset of complaints was 5.1 years for patients and 5.9 for controls. Complaints presented by patients were: painful joints (p < 0.005), burning eyes (p < 0.01), and skin abnormalities (p < 0.005). Differences in the use of antirheumatic drugs or medical consultations related to rheumatic symptoms did not reach statistical significance. Further information obtained from the patients and controls reporting rheumatic symptoms did not reveal the presence of a specific syndrome in connection with silicone materials. CONCLUSION: Women with silicone breast prostheses report more rheumatic complaints after silicone implantation than controls, but there is no evidence of increased prevalence of common rheumatic diseases.

Data-source effects on the sensitivities and specificities of clinical features in the diagnosis of rheumatoid arthritis: the relevance of multiple sources of knowledge for a decision-support system.

An experimental computer system was developed to support diagnosis of rheumatic disorders by computing diagnostic probabilities using modified likelihood ratios. The authors examined whether the performance of the model was affected by the settings in which the data used to derive the likelihood ratios were collected. The sensitivities and specificities of various clinical features for diagnosing rheumatoid arthritis (RA) were obtained from: 1) a study of 1,570 consecutive outpatients at a rheumatology clinic; 2) a review of the literature; 3) estimates by rheumatologists; and 4) a population study. Considerable variations in sensitivity and specificity but satisfactory agreement in likelihood ratios were found across the four data sets. The likelihood ratios were then used to compute the probabilities of RA in a test series of 570 of the rheumatology clinic outpatients. The model's diagnoses with likelihood ratios from the other sources were adequate. When the likelihood ratios from these sources were combined, discrimination came close to what could be achieved by using the likelihood ratios based on the data from the clinic. The method applied in the study, which makes use of variation of input data instead of variation of test series, and the results are relevant to assessing the external validity and transferability of Bayesian decision-support systems.

Validation of the AI/RHEUM knowledge base with data from consecutive rheumatological outpatients.

The diagnostic accuracy of AI/RHEUM, an experimental expert system for support in the diagnosis of rheumatic diseases, was assessed using a collection of data in a cohort of 1,570 consecutive outpatients of a Dutch rheumatological clinic. Computer diagnoses based on these data and diagnostic predictions made by rheumatologists were compared with reference diagnoses that had been obtained by consensus of rheumatologists after 6-12 months follow-up. Performance of the tested version of the AI/RHEUM knowledge base is presented by various methods. Sensitivity varied between 29% and 100% for different rheumatological diseases. Average sensitivity and specificity for all 26 diagnoses present in the knowledge base were 67% and 98%, respectively. Performance according to the level of confidence indicated that 78% of the "definite", 65% of the "probable", and 33% of the "possible" conclusions made by AI/RHEUM were in agreement with the reference diagnoses. These results approximated the predictions made by rheumatologists after a single, initial examination. The system was less accurate than it had appeared in previous evaluation studies with complex clinical cases. The AI/RHEUM knowledge base needed refining to diagnose early rheumatic complaints. This study further illustrates the need for objective and informative parameters for expressing accuracy of diagnostic support systems.

Comparison of the sensitivity and specificity of the 1958 and 1987 criteria for rheumatoid arthritis.

The 2 variations of the new criteria for rheumatoid arthritis (RA) proposed by a subcommittee of the American College of Rheumatology (ACR) in 1987 were evaluated and compared with the earlier (1958) criteria in 2 patients data collections from a Dutch rheumatological outpatient clinic. One group comprised 1,570 newly referred, consecutive patients, including 93 patients with RA. The other consisted of 1,338 patients with a clinical diagnosis of RA, whose charts were reviewed retrospectively. The sensitivities of the 2 variations of the 1987 criteria in the prospective and retrospective subgroups varied from 66 to 89%; those of the 1958 set, from 71 to 86%. Specificity was 98% for both criteria sets. Comparison in subgroups with different disease durations showed reduction in sensitivity for early RA for either variation of the new criteria. However, the differences between the results of the 1958 and 1987 criteria sets are small enough to conclude that they perform equally well.

Assessment of inflammatory joint activity in rheumatoid arthritis and changes in atmospheric conditions.

Seventy-nine patients suffering from rheumatoid factor positive rheumatoid arthritis (RA) were included in this study. In each patient disease activity was assessed three times at two-week intervals during a four-week period. All factors that might possibly influence RA, except atmospheric conditions (AC) were held constant as far as possible. Current AC parameters were obtained from the local observatory of the Royal Dutch Meteorological Institute. There were no relevant correlations between AC and RA variables. Also relations between changes in AC variables preceding the disease activity assessment or between changes in AC variables and RA variables were not seen. By means of factor analysis, uncorrelated factors pertaining to RA or to weather were extracted. No clear association between any of the AC variables and any of the RA variables was noted. Our results do not support the widely accepted, but insufficiently documented, influence of weather on RA.

Comparison of rheumatological diagnoses by a Bayesian program and by physicians.

A Bayesian decision support system was developed for the diagnosis of rheumatic disorders. Knowledge in this system is represented as evidential weights of findings. Simple weights were calculated as the logarithm of likelihood ratios on the basis of 1,000 consecutive patients from a rheumatological clinic. The effect of various methods to improve performance of the system by modification of the weights was studied. Three methods had a mathematical basis; a fourth consisted of weights adapted by a human expert, which allowed inclusion of diagnostic rules such as defined in widely accepted criteria sets. The system's performance was measured in a test population of 570 different cases from the same clinic and compared with predictions of diagnostic outcome made by rheumatologists. The weights from a human expert gave optimal results (sensitivity 65% and specificity 96%), that were close to the physicians' predictions (sensitivity 64% and specificity 98%). The methods to measure the performance of the various models used in this study emphasize sensitivity, specificity and the use of receiver operating characteristics.

Perivascular infiltration in normal skin of patients with rheumatoid arthritis: association with rheumatoid factors and HLA-DR antigens.

The relation between immunohistological findings in biopsy specimens of apparently normal skin, HLA antigens, and rheumatoid factors (RF) was studied in 120 patients with rheumatoid arthritis (RA), selected for treatment with D-penicillamine. Perivascular infiltration (PVI) of more than three mononuclear cells was present in 77 (68%) of 114 patients, accompanied usually by the presence of IgM or C3, or both, in immunofluorescence studies. The number of perivascular cells was associated significantly with the titre of circulating RF. A weak relation of both perivascular cellular infiltration and RF with HLA-DR3 and DR4 did not reach statistical significance. It is concluded that the histological presence of perivascular inflammation is associated mainly with deposition of RF. It is suggested that the first is merely an epiphenomenon of the latter. PVI was not prognostic for the occurrence of the clinical syndrome of rheumatoid vasculitis. For practical purposes skin biopsies do not appear to be useful in the evaluation of individual patients with RA.

Radiosynoviorthesis of the knee: a doubleblind trial of 1 versus 5 mCi Gold-198.

Since the minimal effective dosage for radiosynovectomy is not known, we have performed a doubleblind controlled trial of 1 mCi vs. 5 mCi 198Au in 60 knees of 46 patients with persistent rheumatoid synovitis. The therapeutic effect was assessed with a clinical score, 99mTc pertechnetate uptake measurements and plain X-rays. With regard to clinical parameters no statistical differences between the two groups were found, but results indicate a trend towards a better outcome in patients treated with 5 mCi. 99mTc uptake improved significantly in patients treated with the higher dose and not in the low dose group. Weighing ease of treatment and risk of side effects against the small difference in effectiveness, we conclude that the use of less than 5 mCi of 198Au may be justified. During the study the injection technique was changed, enabling a comparison of two methods. Leakage to lymph nodes and liver decreased when the needle was flushed with normal saline after administration of the radiocolloid.