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Biomedical subjects

J W J Bijlsma

Publications and source records attributed to J W J Bijlsma.

At least 19 recordsLinked to original sources
PubMed2007

The intra-articular distribution of 90yttrium does not influence the clinical outcome of radiation synovectomy of the knee.

OBJECTIVES: To assess the impact of the intra-articular distribution of (90)yttrium-citrate ((90)Y) on the clinical effect of radiosynoviorthesis (RSO) of the knee and on (90)Y leakage from this joint. METHODS: Patients with arthritis of the knee received 185 MBq (90)Y combined with a glucocorticoid, followed by clinical bed rest. Intra-articular (90)Y distribution, measured with a dual-head gamma camera immediately or after 24 hours, was scored as mainly diffuse or mainly focal. Leakage to regional lymph nodes, the liver and spleen was assessed with a dual-head gamma camera after 24 hours. Clinical effect was scored after 6 months by a composite change index (CCI), range 0-12; responders were defined as having a CCI > or =6. RESULTS: Seventy-eight knees of 69 patients, mostly suffering from undifferentiated arthritis (42%) or RA (28%), were treated. (90)Y distribution was mainly diffuse in 54% and mainly focal in 46% with clinical response rates of 40% versus 56%, respectively, p = 0.3. CCI was not correlated with distribution. (90)Y leakage was found only to the liver and the spleen (mean leakage 0.4% and 1.1%, respectively). Leakage was significantly less in case of diffuse intra-articular (90)Y distribution, whereas leakage to the liver was correlated with distribution (r = 0.68, p<0.001). (90)Y leakage was not correlated with CCI. CONCLUSIONS: Intra-articular (90)Y distribution does not influence the clinical effect of RSO of the knee. Although (90)Y leakage from the joint is less if (90)Y distributes diffusely in the joint cavity, leakage does not seem to hamper the clinical effect.

Adult↗
PubMed2007

Safety and efficacy of leflunomide in primary Sjögren's syndrome: a phase II pilot study.

BACKGROUND: For invalidating symptoms in primary Sjögren's syndrome (pSS), there is still a need for easy-to-administer, cost-effective and well-tolerated systemic treatment. Leflunomide (LEF) is structurally unrelated to other immunomodulatory drugs and might be efficacious in pSS, given its characteristic immunoregulatory modes of action. OBJECTIVE: To investigate the safety and efficacy of LEF in pSS in a phase II open-label pilot study. METHODS: 15 patients with pSS with early and active disease received LEF 20 mg once daily for 24 weeks. Tolerability, safety and efficacy of LEF were evaluated every 8 weeks. Additional safety visits were performed every fortnight. RESULTS: Mild gastrointestinal discomfort (including diarrhoea) and hair loss were mainly reported. Five patients developed lupus-like skin lesions on the face, arms or trunk, responding well to topical corticosteroids, nevertheless causing the withdrawal of one patient. Two patients with pre-existing hypertension had to increase dosages of anti-hypertensive drugs. Increased levels of alanine aminotransferase normalised after dose reduction in two patients. A decrease in general fatigue and an increase in physical functioning were observed after 24 weeks. Serum IgG levels decreased from 8 weeks onwards. Schirmer test values increased, not reaching statistical significance, whereas sialometry values did not change. In four of five repeated biopsies, the lymphocytic focus score decreased at the rate of 1 focus/4 mm(2). A remarkable amelioration of leucocytoclastic vasculitis was observed in three patients. CONCLUSIONS: Although the safety profile seems fairly acceptable, the observed indications for efficacy were modest and may be doubtful in justifying a randomised controlled trial of LEF in pSS.

Adult↗
PubMed2006

Utility and direct costs: ankylosing spondylitis compared with rheumatoid arthritis.

OBJECTIVES: To compare utility and disease-specific direct costs between patients with ankylosing spondylitis (AS) and patients with rheumatoid arthritis (RA) in the Netherlands. METHODS: Patients with AS and those with RA completed questions on disease characteristics, the EuroQol-5D (EQ-5D) to assess utility, and questionnaire resource utilisation. Resource utilisation was assessed prospectively in AS, but retrospectively in RA. True cost estimates (2003) were used to calculate the costs. Differences in disease characteristics between AS and RA were described, and determinants of EQ-5D utility and costs were explored by Cox proportional hazard regressions. RESULTS: 576 patients with RA and 132 with AS completed the questionnaires. EQ-5D utility (0.63 vs 0.7) was lower, and annual direct costs higher in RA (euro5167 vs euro2574). In multivariate Cox proportional hazard regressions, there was no difference in utility between the diagnostic groups, but patients with RA incurred higher direct costs after controlling for age, gender and disease duration. CONCLUSIONS: In patients with RA and patients with AS, who are under the care of a rheumatologist, utility is equally reduced, but healthcare costs are higher in RA after controlling for age, gender and disease duration. These data can be helpful to provide insights into the differences and similarities between the healthcare needs of both patient groups and to identify issues for further research and for policy in healthcare organisations.

Adult↗
PubMed2006

[Effectiveness of dietary supplements in patients with osteoarthritis: the doubt persists].

Earlier studies with glucosamines in patients with osteoarthritis have shown conflicting results. A placebo-controlled randomised trial was now carried out in 1583 patients with osteoarthritis. The primary endpoint was a 20% reduction in knee pain between baseline and week 24 according to the 'Western Ontario and McMaster Universities arthritis index'(WOMAC)-score. No statistically significant difference was found between the groups using placebo (60% response), glucosamine (64%), chondroitin sulphate (65%) or combination therapy (67%). The results of this trial do not support the hypothesis that glucosamines have a positive effect on symptoms in patients with osteoarthritis of the knee. However, (a) the chance of a statistically significant difference decreases with increasing magnitude of the placebo response, (b) there was a statistically significant reduction in the patients with moderate to severe pain, (c) when the pain was assessed with the more sensitive 'Outcome measures in rheumatology clinical trials'(OMERACT)-'Osteoarthritis Research Society International'(OARSI)-score, there was a better response in the group given combined treatment, (d) the data on radiological progression and the effects on cartilage markers must still come in, and (e) the efficacy may have been higher ifa different dietary supplement had been used. These questions on the design and the robustness of the study indicate that further studies are necessary.

Chondroitin Sulfates↗
PubMed2006

Joint surgery in the Utrecht Rheumatoid Arthritis Cohort: the effect of treatment strategy.

OBJECTIVE: To investigate the prevalence and prognostic factors of joint surgery in a large cohort of patients with rheumatoid arthritis, whose treatment, clinical and radiographic data have been assessed at predefined points in time since disease onset. METHODS: Data on surgical interventions were retrospectively obtained from 482 patients with rheumatoid arthritis whose follow-up data for at least 2 years were available, including treatment and response to treatment during the first 2 years. Survival time until the first surgical intervention and until the first major surgical intervention was determined for the total study population by Kaplan-Meier survival curves. Three separate Cox regression analyses were carried out to determine which variables measured at baseline, during the first year and during the first 2 years were predictors for joint surgery. RESULTS: 27% of the patients underwent surgical interventions. Mean survival time until the first surgical intervention was 10.4 years. The percentage of patients with a surgical intervention was 10% lower in the group with response to treatment when compared with the non-response group. Next to a delayed start with disease-modifying antirheumatic drugs, fast radiographic progression during the first year and first 2 years was a predictor of joint surgery in the multivariate regression analyses. CONCLUSION: Treatment with disease-modifying antirheumatic drugs immediately after diagnosis results in less joint surgery when compared with a delayed start. Furthermore, joint surgery is carried out more often in patients who do not respond to treatment.

Adult↗
PubMed2006

Radiation synovectomy with yttrium-90 for persisting arthritis has direct harmful effects on human cartilage that cannot be prevented by co-administration of glucocorticoids: an in vitro study.

BACKGROUND: It was recently shown that radiation synovectomy with yttrium-90 (90Y) and glucocorticoids is not superior to intra-articular glucocorticoids alone in the treatment of persistent gonarthritis. In that study, it seemed that in patients treated by radiation synovectomy, progression of radiographic joint damage occurred. OBJECTIVE: To test in vitro the direct effects of radiation synovectomy with 90Y on human cartilage. METHODS: Human cartilage tissue was exposed to 90Y, glucocorticoids or the combination. 1:2000 to 1:20 dilutions of the clinical dose of 5 mCi/ml 90Y and 20 mg/ml glucocorticoids were used. After a 4-day exposure and a subsequent 12-day recovery period, proteoglycan synthesis, proteoglycan release and proteoglycan content were measured. In addition, human synovial tissue was cultured for 4 days with 90Y or glucocorticoids. Culture supernatants were analysed for cartilage-destructive activity. RESULTS: 90Y, glucocorticoids and the combination inhibited proteoglycan synthesis considerably and dose dependently, an effect that sustained for at least 12 days. Proteoglycan release was transiently increased by 90Y, an effect that was not changed by addition of glucocorticoids, which had no effect on its own. Proteoglycan content was eventually adversely affected by 90Y, an effect hardly influenced by glucocorticoids. Neither 90Y nor glucocorticoids changed the cartilage-destructive properties of synovial tissue. CONCLUSIONS: 90Y, but not glucocorticoids, has direct harmful effects on cartilage in vitro. Indirect beneficial effects of 90Y via inhibition of cartilage-destructive properties of synovial tissue could not be shown. These observations may explain the possible radiographic joint damage on radiation synovectomy.

Aged↗
PubMed2006

Pretreatment macrophage infiltration of the synovium predicts the clinical effect of both radiation synovectomy and intra-articular glucocorticoids.

OBJECTIVE: To explore whether pretreatment features of synovial tissue in patients with gonarthritis could predict the clinical effect of radiation synovectomy with yttrium-90 (90Y) and glucocorticoids or with intra-articular glucocorticoids alone. METHODS: A synovial biopsy was carried out blindly 2 weeks before treatment in 66 patients with persistent gonarthritis, who were randomised to treatment either with 90Y and triamcinolone or with placebo and triamcinolone. Immunohistochemistry was used to detect T cells, macrophages, B cells, plasma cells, fibroblast-like synoviocytes, adhesion molecules and pro-inflammatory cytokines. Stained sections were evaluated by digital image analysis. Individual patient improvement was expressed using a composite change index (CCI; range 0-12). Successful treatment was defined as CCI > or = 6 after 6 months. RESULTS: Patients with rheumatoid arthritis, psoriatic arthritis, undifferentiated arthritis and other causes of gonarthritis were included. The overall response rate was 47%. Clinical efficacy in both therapeutic groups was similar and not dependent on diagnosis. No significant differences were noted between baseline microscopic features of synovial tissue inflammation in patients with rheumatoid arthritis and in those with non-rheumatoid arthritis (ie, all diagnoses other than rheumatoid arthritis). The number of macrophages in the synovial sublining was significantly higher in responders than in non-responders (p = 0.002), independent of treatment group and diagnosis. The clinical effect was positively correlated with pretreatment total macrophage numbers (r = 0.28; p = 0.03), sublining macrophage numbers (r = 0.34; p = 0.005) and vascular cell adhesion molecule 1 expression (r = 0.25; p = 0.04). CONCLUSION: The observations support the view that intra-articular treatment either with 90Y and glucocorticoids or with glucocorticoids alone is especially successful in patients with marked synovial inflammation.

Adult↗
PubMed2006

[New developments in glucocorticoid therapy: selective glucocorticoid receptor agonists, nitrosteroids and liposomal glucocorticoids].

Two mechanisms of the genomic action ofglucocorticoids (GCs) can be distinguished: transrepression, yielding mainly an anti-inflammatory effect, and transactivation, resulting mainly in metabolic-endocrine side effects. Selective glucocorticoid receptor agonists (SEGRAs) cause selective transrepression, yielding the same anti-inflammatory effect as GCs, but with fewer side effects. NO is bound to several drugs to increase their effect; in nitrosteroids, NO is coupled to GC, resulting in a synergistic anti-inflammatory effect. Drug targeting can be achieved with GCs by incorporation of GC into polyethyleneglycol(PEG)-liposomes, resulting in very high concentrations ofGCs at the site of inflammation. Well-designed studies are needed to determine the place of SEGRAs, nitrosteroids and liposomal GCs in clinical practice.

Anti-Inflammatory Agents↗
PubMed2006

Positive effect of alendronate on bone mineral density and markers of bone turnover in patients with rheumatoid arthritis on chronic treatment with low-dose prednisone: a randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Alendronate has been described to have a bone-sparing effect in patients treated with moderate and high dosages of prednisone for heterogeneous diseases, however no data are available on groups of patients with the same underlying diseases who receive chronic low-dose prednisone treatment. The objective of the investigation reported here was, therefore, to study the effect of alendronate on bone mineral density (BMD) of the lumbar spine and hips in patients with rheumatoid arthritis (RA) who are on chronic low-dose prednisone treatment. METHODS: A total of 163 patients with RA, according to the ACR-criteria, were enrolled in a double-blind, placebo-controlled trial. The patients were treated with low-dose prednisone (<or=10 mg/day) for at least 3 months. The patients were randomized to receive daily doses of alendronate or placebo: men and premenopausal women received 5 mg alendronate (or placebo) daily; postmenopausal women received 10 mg alendronate (or placebo) daily. All patients received daily calcium (500 mg, or 1000 mg, depending on baseline dietary calcium intake) and vitamin D3 (400 IU) supplementation. BMD of the lumbar spine (L1-L4) and the (total) hip was measured at baseline and after 6 and 12 months. The primary endpoint was change in BMD of the lumbar spine after 12 months (ITT). At baseline and after 3 and 12 months, serum bone-specific alkaline phosphatase (BAP) and urinary excretion of N-telopeptide (NTX) were measured. Radiographs of the thoracic and lumbar spine were made at baseline and after 12 months and subsequently scored for vertebral deformities. RESULTS: The groups were comparable at baseline in age, gender, daily dosage of prednisone, BMD at the spine and the hip and markers of bone turnover, while the number of patients with prevalent vertebral deformities was slightly higher in the alendronate-treated patients (54% versus 39%, not significant). After 12 months, BMD at the lumbar spine had increased by 3.7% in the alendronate-treated patients and decreased by -1.0% in the placebo-treated patients (p<0.0001); at the hip, the changes were +1.0% and -0.1%, respectively (not significant). After 3 months, serum BAP had decreased by 16.9% in the alendronate group versus 3.3% in the placebo group (p=0.0005), while urinary NTX had decreased by 46.4% in the alendronate group versus 12.1% in the placebo group (p<0.0001). After 12 months, no statistically significant difference was found between the groups with respect to number of patients with incident vertebral or non-vertebral fractures. Adverse effects were relatively common in these patients with severe RA: adverse effects were observed in 68% of the alendronate-treated patients and in 73% of the placebo patients (not significant), while serious adverse events were observed in 13% and 17%, respectively (not significant). CONCLUSION: We observed a favourable effect of alendronate on the BMD of the lumbar spine and on the markers of bone turnover in patients with RA treated with low-dose prednisone. These data support the conclusion that the prescribing of alendronate is not only beneficial in patients treated with high-dose prednisone but also in RA patients chronically treated with low-dose prednisone.

Absorptiometry, Photon↗
PubMed2006

Radiographic joint damage in rheumatoid arthritis is associated with differences in cartilage turnover and can be predicted by serum biomarkers: an evaluation from 1 to 4 years after diagnosis.

INTRODUCTION: The objective of this study was to determine whether serum biomarkers for degradation and synthesis of the extracellular matrix of cartilage are associated with, and can predict, radiographic damage in patients with rheumatoid arthritis (RA). METHODS: Clinical and radiographic data of 87 RA patients were recorded 1 year after disease onset and then annually up to four years. Serum concentrations of four cartilage biomarkers were determined at these time points: a neoepitope formed by collagenase cleavage of type II collagen (C2C), a neoepitope formed by collagenase cleavage of type II collagen as well as type I collagen (C1,2C), a carboxy propeptide of type II procollagen formed during synthesis (CPII), and a cartilage proteoglycan aggrecan turnover epitope (CS846-epitope). Biomarker concentrations between patients with rapid radiographic progression (>7.3 Sharp/van der Heijde units per year) and those with slow radiographic progression (<2.3 units per year) were compared. In addition, we evaluated the long-term and short-term predictive value of each biomarker for progression of radiographic damage. RESULTS: Patients with rapid radiographic progression had higher C2C, higher C1,2C, and higher CS846-epitope levels than slow progressors. CPII levels showed no differences. Most importantly, the long-term radiographic progression for C2C, for C1,2C, and for CS846-epitope can be predicted by the biomarker value at year 1 after disease onset. C2C was also a predictor for joint space narrowing and annual radiographic damage during the subsequent year. CONCLUSION: This study shows that the concentration of serum biomarkers of cartilage collagen breakdown and proteoglycan turnover, but not of collagen synthesis, are related to joint destruction in RA. The use of these biomarkers may be of value when studying progression of joint damage in patients with RA.

Aged↗
PubMed2006

Clinical assessment of the long-term risk of fracture in patients with rheumatoid arthritis.

OBJECTIVE: To determine whether patients with rheumatoid arthritis (RA) have an increased risk of fracture, and to estimate their long-term absolute fracture risk. METHODS: We studied patients with RA ages >or=40 years in the British General Practice Research Database, each matched by age, sex, calendar time, and practice to 3 control patients. Incident fractures, as recorded in the computerized medical records, were ascertained over a median followup of 7.6 years. The fracture rate in RA patients compared with controls was adjusted for smoking, body mass index (BMI), and several clinical risk factors, and Cox proportional hazards models were used to calculate the relative risk (RR) of fracture in RA. A risk score was then developed to provide an estimate of the 5- and 10-year fracture risk among RA patients. RESULTS: There were 30,262 patients with RA, of whom 2,460 experienced a fracture during followup. Compared with controls, patients with RA had an increased risk of fracture, which was most marked at the hip (RR 2.0, 95% confidence interval [95% CI] 1.8-2.3) and spine (RR 2.4, 95% CI 2.0-2.8). Indicators of a substantially elevated risk of fracture (at the hip) included >10 years' duration of RA (RR 3.4, 95% CI 3.0-3.9), low BMI (RR 3.9, 95% CI 3.1-4.9), and use of oral glucocorticoids (RR 3.4, 95% CI 3.0-4.0). Modeling of the long-term risk profiles revealed that, for example, in a woman age 65 years with longstanding RA whose risk factors also included low BMI, a history of fracture, and frequent use of oral glucocorticoids, the 5-year risk of hip fracture was 5.7% (95% CI 5.3-6.1%). CONCLUSION: Patients with RA are at increased risk of osteoporotic fractures. This increased risk is attributable to a combination of disease activity and use of oral glucocorticoids.

Adult↗
PubMed2006

Interleukin-7 induced immunopathology in arthritis.

Interleukin (IL)-7 is a potent immunoregulatory cytokine that is detected in joints of patients with rheumatoid and juvenile idiopathic arthritis and which correlates with parameters of disease. Several synovial cell types that play an important role in inflammation and immunopathology, such as macrophages, dendritic cells, and fibroblasts, produce IL-7. IL-7 induces cytokines produced by arthritogenic T cells (for example, interferon gamma (IFNgamma), IL-17), T cell differentiating factors (for example, IL-12), chemokines capable of attracting inflammatory cells (for example, macrophage induced gene (MIG), macrophage inflammatory protein (MIP)-1alpha) as well as molecules involved in cell adhesion, migration, and costimulation (for example, lymphocyte function associated antigen (LFA)-1, CD40, CD80). In addition, IL-7 can induce bone loss by stimulating osteoclastogenesis that is dependent on receptor activator of nuclear factor kappaB ligand (RANKL). IL-7 induces tumour necrosis factor alpha (TNFalpha) secretion by T cells and by monocytes after T cell dependent monocyte/macrophage activation. Importantly, induction of both IL-7 and IL-7 induced effects seems to be able to operate independent of TNFalpha. Together this suggests that IL-7 is an important cytokine in several rheumatic conditions, capable of inducing inflammation and immunopathology. Thus it may be an important target for immunotherapy.

Animals↗
PubMed2005

Clinical significance of quantitative immunohistology in labial salivary glands for diagnosing Sjogren's syndrome.

OBJECTIVES: Because patients with primary Sjögren's syndrome (pSS) are at risk of developing other autoimmune phenomena and malignant lymphoma, it is important to distinguish pSS from non-Sjögren's (nSS) sicca syndrome. However, this distinction might be difficult because of the lack of a gold standard for pSS. We studied the clinical significance of quantitative immunohistology (QIH) in labial salivary glands for diagnosing pSS. METHODS: In a model mimicking the making of a clinical diagnosis, five experts diagnosed 396 patients as nSS, 'indefinite', pSS or secondary SS (sSS) using 25 clinical parameters. Patients were diagnosed twice, namely without (yielding gold-standard diagnoses) and with knowledge of QIH. The numbers of changes in diagnosis from 'indefinite' to 'definite' (nSS, pSS or sSS) or vice versa were compared. Patient groups with vs without a changed diagnosis in the four gold-standard diagnosis groups were compared regarding objective autoimmune parameters. RESULTS: Sensitivity, specificity, positive and negative predictive value for abnormal QIH in pSS vs nSS were 93, 86, 76 and 96%, respectively. Changes in diagnosis from 'indefinite' to 'definite' (31%) were found more often (P = 0.00) than changes from 'definite' to 'indefinite' (10%). Knowledge of QIH distinguished patient groups within the gold-standard nSS, indefinite and pSS patient group with regard to autoimmune parameters. CONCLUSION: In view of the consequences of distinguishing pSS from nSS, these results point to an additional diagnostic role for QIH in clinical practice.

Autoantibodies↗
PubMed2005

[The practice guideline 'Dermatomyositis, polymyositis and sporadic inclusion body myositis'].

This guideline presents recommendations for the diagnosis and treatment of dermatomyositis, polymyositis and sporadic inclusion body myositis (sIBM) according to the best available evidence. Characteristic skin abnormalities can be sufficient for the diagnosis of dermatomyositis. In case of doubt, a skin biopsy is advisable. A muscle biopsy is indicated when other examinations are inconclusive and the musculature is involved. The working group considers screening for cancer to be required in adults with dermatomyositis and presents recommendations for the way that this should be done. At least one-third of all patients with polymyositis has, or will develop, an associated inflammatory connective tissue disease. If a patient with a connective tissue disease develops symmetrical, proximal muscle weakness in the course of weeks or months, this may be assumed to be due to polymyositis. In the absence ofpre-existing connective tissue disease, demonstration of a mononuclear cell infiltrate in muscle tissue is a prerequisite for the diagnosis ofpolymyositis. The histopathology of muscle tissue is used as the gold standard for the diagnosis of sIBM. The practice guideline presents criteria for the concept 'activity' of myositis. Disease activity serves as a guideline for the treatment of polymyositis and dermatomyositis. The treatment of choice for dermatomyositis and polymyositis is high-dose prednisone. Physical activity does not have a negative effect on the course of these diseases. The long-term prognosis ofdermatomyositis and polymyositis is not well known. The clinical course of sIBM is slowly progressive.

Anti-Inflammatory Agents↗
PubMed2005

[Polymyalgia rheumatica and temporal arteritis].

Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are closely related and frequently occurring inflammatory diseases with an incidence of 50 and 18 per 100,000 per year, respectively, in people aged 50 years or over. The most frequent symptom of PMR is aching and morning stiffness lasting more than 1 month and exacerbated by movement, occurring in the shoulder and pelvic girdles and in the neck region. GCA is vasculitis of the large and medium-sized arteries that originate from the aortic arch, causing new and marked headache localised over the temporal or occipital areas, jaw claudication, visual impairment or claudication of the arms. GCA is characterised by histopathological panarteritis with a predominantly lymphohistiocytic cell infiltrate. Activation of macrophages is central to the arteritis. Standard treatment for PMR and GCA is glucocorticoids, which may consist of prednisone 10-20 mg/day or its equivalent for PMR patients and prednisone 30-40 mg to 1 mg/kg body weight for GCA patients. For GCA patients with recently impaired vision, treatment should start with high doses of intravenously administered glucocorticoids, such as methylprednisolone 1 g/day for 3 consecutive days. A treatment duration of 1-2 years is often required for patients with PMR or GCA; because of the side effects associated with long-term use of glucocorticoids, osteoporosis prophylaxis with oral calcium supplementation, vitamin D and bisphosphonates is appropriate.

Age Factors↗
PubMed2005

Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data.

Adverse effects of glucocorticoids have been abundantly reported. Published reports on low dose glucocorticoid treatment show that few of the commonly held beliefs about their incidence, prevalence, and impact are supported by clear scientific evidence. Safety data from recent randomised controlled clinical trials of low dose glucocorticoid treatment in RA suggest that adverse effects associated with this drug are modest, and often not statistically different from those of placebo.

Antirheumatic Agents↗