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.

Sustained beneficial effects of a protocolized treat-to-target strategy in very early rheumatoid arthritis: three-year results of the Dutch Rheumatoid Arthritis Monitoring remission induction cohort.

OBJECTIVE: Treat-to-target (T2T) leads to improved clinical outcomes in early rheumatoid arthritis (RA). The question is whether these results sustain in the long term. Our objective was to investigate the 3-year results of a protocolized T2T strategy in daily clinical practice. METHODS: In the Dutch Rheumatoid Arthritis Monitoring remission induction cohort, patients newly diagnosed with RA were treated according to a T2T strategy aimed at remission (Disease Activity Score in 28 joints [DAS28] <2.6). Patients were treated with methotrexate, followed by the addition of sulfasalazine, and exchange of sulfasalazine with anti-tumor necrosis factor α agents in case of failure. Primary outcomes were disease activity, Health Assessment Questionnaire (HAQ) score, Short Form 36 physical component summary (PCS) and mental component summary (MCS) scores, and the Sharp/van der Heijde score (SHS) after 3 years. Secondary outcomes were sustained DAS28 remission (≥6 months) and remission according to the provisional American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) definition. RESULTS: After 3 years (n = 342), 61.7% of patients were in DAS28 remission and 25.3% met the provisional ACR/EULAR definition of remission. Sustained remission was experienced by 70.5%, which in the majority was achieved with conventional disease-modifying antirheumatic drugs only. The median scores were 0.4 (interquartile range [IQR] 0.0-1.0) for the HAQ, 45.0 (IQR 38.4-53.2) for the PCS, 53.1 (IQR 43.2-60.8) for the MCS, and 6.0 (IQR 3.0-13.0) for the total SHS. CONCLUSION: In very early RA, T2T leads to high (sustained) remission rates, improved physical function and health-related quality of life, and limited radiographic damage after 3 years in daily clinical practice.

Multiple computer-based methods of measuring joint space width can discriminate between treatment arms in the COBRA trial -- Update of an ongoing OMERACT project.

Previously reported data on 5 computer-based programs for measurement of joint space width focusing on discriminating ability and reproducibility are updated, showing new data. Four of 5 different programs for measuring joint space width were more discriminating than observer scoring for change in narrowing in the 12 months interval. Three of 4 programs were more discriminating than observer scoring for the 0-18 month interval. The program that failed to discriminate in the 0-12 month interval was not the same program that failed in the 0-18 month interval. The committee agreed at an interim meeting in November 2007 that an important goal for computer-based measurement programs is a 90% success rate in making measurements of joint pairs in followup studies. This means that the same joint must be measured in images of both timepoints in order to assess change over time in serial radiographs. None of the programs met this 90% threshold, but 3 programs achieved 85%-90% success rate. Intraclass correlation coefficients for assessing change in joint space width in individual joints were 0.98 or 0.99 for 4 programs. The smallest detectable change was < 0.2 mm for 4 of the 5 programs, representing 29%-36% of the change within the 99th percentile of measurements.

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.

[Guideline 'NSAID use and the prevention of gastric damage']. / Richtlijn 'NSAID-gebruik en preventie van maagschade'.

Supported by the Dutch Institute for Health Care Improvement (CBO), a committee consisting of rheumatologists, general practitioners, gastroenterohepatologists, hospital pharmacists and a health-economist have developed a national evidence-based guideline for the prevention of gastric damage by non-steroidal anti-inflammatory drugs (NSAIDs). The goal of the guideline is to reduce the number of gastric ulcers with perforation or bleeding as a consequence of NSAID use. It is estimated that 165 patients died as a result of these complications in the year 2000. The guideline comprises chapters on the risk factors for ulceration during NSAID use, the effectiveness and relative toxicity of different NSAIDs for the stomach, the effectiveness of various treatments meant to reduce the risk of gastro-duodenal damage, and the management of dyspeptic symptoms during NSAID use. A strategy is recommended in which prescription of NSAIDs is always preceded by an assessment of the degree to which the risk of gastric damage is increased: the most important risk factors that need to be identified are previous peptic ulcer disease, age over 70 years, and an untreated Helicobacter pylori infection associated with peptic ulcer disease. Whenever an increased risk of gastro-duodenal damage is present, the prescribing physician can choose one of three preventive strategies: addition of misoprostol, addition of a proton-pump inhibitor, or the prescription of a COX-2-selective NSAID. Provided that adequate risk assessment has been carried out, the guideline leaves it to the patient and physician to choose which of these preventive measures, all of which result in roughly equal risk reduction and costs, is the most suitable for individual situations. The use of aspirin or a coumarin derivative increases the risk; several preventive strategies are possible; the guideline discusses the situation that arises when NSAIDs are added to the treatment.

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.

Antibiotic prophylaxis for haematogenous bacterial arthritis in patients with joint disease: a cost effectiveness analysis.

OBJECTIVE: To assess the cost effectiveness of antibiotic prophylaxis for haematogenous bacterial arthritis in patients with joint disease. METHODS: In a decision analysis, data from a prospective study on bacterial arthritis in 4907 patients with joint disease were combined with literature data to assess risks and benefits of antibiotic prophylaxis. Effectiveness and cost effectiveness calculations were performed on antibiotic prophylaxis for various patient groups. Grouping was based on (a) type of event leading to transient bacteraemia-that is, infections (dermal, respiratory/urinary tract) and invasive medical procedures-and (b) the patient's susceptibility to bacterial arthritis which was increased in the presence of rheumatoid arthritis, large joint prostheses, comorbidity, and old age. RESULTS: Of the patients with joint disease, 59% had no characteristics that increased susceptibility to bacterial arthritis, and 31% had one. For dermal infections, the effectiveness of antibiotic prophylaxis was maximally 35 quality adjusted life days (QALDs) and the cost effectiveness maximally $52 000 per quality adjusted life year (QALY). For other infections, the effectiveness of prophylaxis was lower and the cost effectiveness higher. Prophylaxis for invasive medical procedures seemed to be acceptable only in patients with high susceptibility: 1 QALD at a cost of $1300/QALY; however, the results were influenced substantially when the level of efficacy of the prophylaxis or cost of prophylactic antibiotics was changed. CONCLUSION: Prophylaxis seems to be indicated only for dermal infections, and for infections of the urinary and respiratory tract in patients with increased susceptibility to bacterial arthritis. Prophylaxis for invasive medical procedures, such as dental treatment, may only be indicated for patients with joint disease who are highly susceptible.

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.

Incidence and sources of native and prosthetic joint infection: a community based prospective survey.

OBJECTIVES: To determine the incidence and sources of bacterial arthritis in the Amsterdam health district and the maximum percentage of cases that theoretically would be preventable. METHODS: Patients with bacterial arthritis diagnosed between 1 October 1990 and 1 October 1993 were prospectively reported to the study centre by all 12 hospitals serving the district. Data were gathered on previous health status, source of infection, and microorganisms involved. RESULTS: 188 episodes of bacterial arthritis were found in 186 patients. Most of the 38 children were previously healthy. Fifty per cent of the adults were 65 years or older. Of the adults 84% had an underlying disease, in 59% a joint disorder. Joint surgery constituted the largest part of direct infections (33%) and skin defects were the most important source of haematogenous infections (67%). Infection of joints containing prosthetic or osteosynthetic material by a known haematogenous source occurred 15 times (8%). Staphylococcus aureus was the causative organism in 44% of all positive cultures. CONCLUSION: The incidence of bacterial arthritis was 5.7 per 100,000 inhabitants per year. Preventive measures directed to patients with prosthetic joints or osteosynthetic material, and a known haematogenous source would have prevented at most 8% of all cases.

The outcome of bacterial arthritis: a prospective community-based study.

OBJECTIVE: To assess the outcome and adverse prognostic factors of bacterial arthritis (BA). METHODS: In a prospective community survey of BA, data were collected at the time of diagnosis and at a mean of 2 years later. A poor patient outcome was defined as death due to BA or severe overall functional deterioration. A poor joint outcome was defined as amputation, arthrodesis, prosthetic surgery, or severe functional deterioration. Possible prognostic factors were analyzed by univariate analysis. RESULTS: BA was diagnosed in 154 patients, 121 adults and 33 children. One-half of the adults had a preexisting joint disease and 29% of the infected joints contained synthetic material. The patient outcome was poor in 21% of all patients, and the joint outcome was poor in 33% of the surviving patients. Adverse prognostic factors were an older age, preexisting joint disease, and an infected joint containing synthetic material. These factors were interrelated. There was no association between a poor outcome and young age, comorbidity, immunosuppressive medication, functional class, multiple infected joints, type of microorganism, or treatment delay. CONCLUSION: BA had a poor outcome in almost one-half of the patients. Patients who were older, had a preexisting joint disease, and/or had an infected joint containing synthetic material had the poorest prognosis.

A time-resolved immunofluorometric assay of autoantibodies to double-stranded DNA.

A time-resolved immunofluorometric assay (TRIFMA) of autoantibodies to double-stranded DNA (dsDNA) is described. Biotinylated DNA was bound to the polystyrene solid phase coated with streptavidin. F(ab1')2 fragments from antibodies raised in rabbits to human IgG were labelled with Eu3+, and used in the assay to label the bound autoantibodies to dsDNA. The measuring range covers three decades. The proposed assay has good analytical properties. For calibration the First International Standard for antibodies to double-stranded DNA Wo/80 was used. The 97.5th percentile in normal persons is 20 kIU/l. Comparison of the TRIFMA and the Farr-assay in the analysis of 56 sera from 20 patients with systemic lupus erythematosus or lupus-like disease, 13 with other autoimmune diseases, and 10 blood-bank donors indicates a high degree of concordance (Kendall's tau = 0.56, p < 0.001). Further evaluation in 102 patients with systemic lupus erythematosus, lupus-like disease and other autoimmune diseases shows that sensitivity for active classical systemic lupus erythematosus is adequate, and specificity is excellent.

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.

Extra-articular manifestations of rheumatoid arthritis: risk factors for serious gastrointestinal events.

OBJECTIVES: Serious upper gastrointestinal events are an important threat to patients with arthritis who are treated with non-steroidal anti-inflammatory drugs (NSAIDs). In this study risk factors for serious upper gastrointestinal events are identified in patients with possible or definite rheumatoid arthritis (RA). METHODS: A retrospective analysis of factors that might contribute to the risk of serious upper gastrointestinal events was performed in a cohort of 2315 consecutive patients with possible or definite RA. The relative influences of disease severity, drug treatment, particularly with corticosteroids, and history of peptic ulceration were analysed with a conditional logistic regression model for the 106 patients with serious upper gastrointestinal intestinal events and for an equal number of control patients who were matched for age, gender, number of criteria for RA, and disease duration. RESULTS: The incidence rate for serious upper gastrointestinal events was 4.0/1000 patients in each year. The study reconfirmed that age over 60 years, history of peptic ulceration, and use of corticosteroids are risk factors. The presence of extra-articular manifestations of RA was associated with a two to 11-fold increase in the risk for serious upper gastrointestinal events. This risk was independent of the use of corticosteroids. CONCLUSION: Disease severity, in particular the presence of extra-articular features, may be an important factor in the pathogenesis of upper gastrointestinal ulceration in patients with RA who are treated with NSAIDs.