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Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
12379614 Is NF-kappaB a useful therapeutic target in rheumatoid arthritis? 2002 Nov There is increasing evidence that NF-kappaB is a major, if not the major transcription factor regulating inflammation and immunity. While this implies that blocking NF-kappaB might be therapeutically beneficial, it raises clear questions regarding the balance between efficacy and safety. In this brief review we discuss the effects of NF-kappaB blockade in rheumatoid arthritis, inflammation and immunity, and consider possible therapeutic targets within the NF-kappaB family.
11920399 Smoking and disease severity in rheumatoid arthritis: association with polymorphism at the 2002 Mar OBJECTIVE: To determine whether the relationship between smoking and disease severity in women with rheumatoid arthritis (RA) is associated with polymorphism at the glutathione S-transferase (GST) M1 locus. METHODS: Genotyping for GSTM1 was carried out using polymerase chain reaction methodology on 164 women with established RA. Smoking history was obtained on each patient. Radiographic damage was measured by the Larsen score, and functional outcome was assessed by the Health Assessment Questionnaire (HAQ). Data were analyzed by multiple regression analyses, with correction for age and disease duration. RESULTS: Ever having smoked was associated with a worse radiographic and functional outcome than was never having smoked. Both past and current smoking were associated with increased disease severity. Stratification by GSTM1 status revealed that polymorphism at this locus affected the relationship between smoking and disease outcome measures. Patients who lacked the GSTM1 gene and had ever smoked had significantly higher Larsen and HAQ scores than did those who lacked the gene and had never smoked. Radiographic outcome in these patients was worse than that in patients who had the GSTM1 gene and who had smoked. The associations were not affected by correction for socioeconomic status. Rheumatoid factor (RF) production was found to be associated with smoking in only the GSTM1-null patients. CONCLUSION: Our data suggest that disease outcome in female RA patients with a history of smoking is significantly worse than in those who have never smoked. Smoking was associated with the most severe disease in patients who carried the GSTM1-null polymorphism. This association may be due in part to a relationship between the GSTM1 polymorphism and RF production in smokers.
15137951 Biomarker discovery by comprehensive phenotyping for autoimmune diseases. 2004 May There is a well-recognized but unmet need for biological markers to characterize disease type, status, progression, and response to therapy in autoimmune diseases. We are developing and applying an integrated bioanalytical platform and clinical research program to facilitate comprehensive differential phenotyping of patient samples and enable the discovery of biomarkers. Our measurement platform includes microvolume laser scanning cytometry for the quantification of hundreds of cellular parameters in whole blood and other samples, liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry for the quantification of proteins and low molecular weight biomolecules in serum and other fluids or tissues, and specific immunoassays for the quantification of trace proteins in serum. We describe the technologies and discuss initial applications to the analysis of subjects with rheumatoid arthritis (RA) and healthy controls.
15283621 Predictors of exercise behavior in patients with rheumatoid arthritis 6 months following a 2004 Aug BACKGROUND AND PURPOSE: When factors that influence exercise behavior are known, health care professionals can more likely design and modify patient education materials targeted to promote exercise behavior. This study aimed to identify predictors of exercise behavior in patients with rheumatoid arthritis 6 months after a visit with their rheumatologist. SUBJECTS AND METHODS: Twenty-five rheumatologists and 132 patients with rheumatoid arthritis participated. One hundred thirteen patients (85.6%) completed the 6-month follow-up. Rheumatologists and patients completed baseline questionnaires and were audiotaped during a subsequent visit. Physical function and exercise behavior were ascertained via questionnaire 6 months following the visit. Multivariate logistic regression identified predictors of exercise behavior at 6 months. Eighty-nine patients (79%) were female. The average age was 54.8 years (SD=14.4, range=20-94). The mean duration of illness was 9.8 years (SD=8.7, range= <1-35). Patients were moderately impaired (mean Medical Outcomes Study 36-Item Short-Form Health Survey [SF-36] function score=49.3, SD=27.5). Thirty-four patients (27%) were exercising 6 months after visiting their rheumatologist. More than 50% of the rheumatologists had 5 or more years of clinical experience, 18 (72%) were male, and 10 (42%) reported they exercised regularly. RESULTS: Predictors of exercise behavior at 6 months were patients' past history of exercise (odds ratio=6.8, 95% confidence interval=3.1-15) and rheumatologists' current exercise behavior (odds ratio=0.26, 95% confidence interval=0.09-0.77). DISCUSSION AND CONCLUSION: Patients were nearly 7 times more likely to exercise 6 months after visiting their rheumatologist if they participated in exercise in the past. If a patient's rheumatologist was currently performing aerobic exercise, the patient was 26% more likely to be engaged in exercise at follow-up. These data may be useful in understanding patient motivation to participate in exercise.
12114292 Immunopathogenesis of rheumatic diseases in the context of neuroendocrine interactions. 2002 Jun Growing evidence supports the hypothesis that alterations of the stress response and interactions between the neuroendocrine and immune systems contribute to the pathogenesis of rheumatic diseases such as rheumatoid arthritis (RA). In particular, the hypothalamus-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS) are of special interest. Polymorphisms of the corticotropin-releasing hormone (CRH)-regulating region have been described recently. These polymorphisms are differentially distributed in RA patients and healthy subjects of various ethnic origin, thus supporting the hypothesis that they represent a new genetic marker for RA susceptibility. The decreased expression of beta(2)-adrenergic receptors (beta(2)-R) on lymphatic cells in rheumatic diseases like RA, together with an impaired influence of catecholamines on immune function in these patients, further underlines the concept of a dysfunction of the ANS in rheumatic diseases. Results from work in this field will provide more insight into the pathogenesis of RA and help to establish novel therapies for this chronic rheumatic disease.
11824971 A population based assessment of the use of orthopedic surgery in patients with rheumatoid 2002 Jan OBJECTIVE: To describe the use of orthopedic surgery, including joint replacement surgery, in a well defined population based cohort of patients with rheumatoid arthritis (RA) and to identify characteristics that predict such use. METHODS: A retrospective medical record review was performed of cases of RA incident in Rochester, MN, during the years 1955-85. Patients were followed until 1998. All joint surgeries were recorded, including joint reconstructive surgeries, total joint arthroplasty (TJA), and other joint reconstructive procedures (JRP) such as tendon transfers and resections, joint fusions, and surgeries for fractures and infections involving joints. RESULTS: Of the total 424 RA incident cases, 148 (34.9%) patients underwent one or more (maximum of 20/patient) surgical procedures involving joints during their followup (median 14.8 yrs, range 0.2-42.8 yrs). Overall, this RA cohort had 9.7 surgeries per 100 person-yrs of followup. The estimated cumulative incidence of surgical procedures for RA at 30 yrs was 52.7% +/- SE 4.2. Surgeries for arthritis related joint disease of RA included: primary TJA 76 patients (31.3 +/- 4.1); JRP joint fusion 78 patients (29.4 +/- 3.5); JRP soft tissue 92 patients (29.8 +/- 3.3); and cervical spine fusion one patient. Non-RA (trauma and other) joint surgeries included TJA 26 patients (13.5 +/- 3.4) and arthrotomy for septic arthritis 8 patients (2.4 +/- 0.9). Based on Cox proportional hazards regression, the risk of having a disease related joint surgery for RA is increased in patients who are younger (p < 0.001), have positive rheumatoid factor (p = 0.01), and those with rheumatoid nodules (p < 0.001). There was a borderline significant increase in the risk of first joint surgery in women (p = 0.09). Women also had significantly more joint surgeries (11.5/100 person-yrs) than men (4.9/100 person-yrs; p < 0.001). Survival of patients who had surgery for RA related joint disease was similar to those who did not. CONCLUSION: This is the first population based assessment of joint surgeries performed in patients with RA. Reconstructive surgeries were common, and women had significantly more surgeries than men. Survivorship among patients with RA undergoing surgeries was similar to that of the RA patient population at large.
15278755 Successful treatment of rheumatoid arthritis is associated with a reduction in serum sE-se 2004 Oct The aim of this study was to investigate the changes in serum levels of endothelial cell injury markers, soluble (s) E-selectin and thrombomodulin (TM), in patients with rheumatoid arthritis (RA) before and after antirheumatic drug treatment and to assess the relationship between these changes and clinical responses to the drug treatment. Eleven patients with RA having active arthritis and 12 healthy volunteers were enrolled in the study. They were monitored by clinical and laboratory parameters while receiving a combination of methotrexate, hydroxychloroquine and sulphasalazine. Pre- and post-treatment clinical and laboratory parameters, including sE-selectin and sTM levels, were measured. The ages of the patients were comparable with those of the control groups. Significant improvements were detected in erythrocyte sedimentation rate, C-reactive protein, hemoglobin, morning stiffness, patients' global assessment, physicians' global assessment, number of tender joints and number of swollen joints improved at the end of the therapy (for each parameter p < 0.05). Significant improvements were detected in clinical and laboratory parameters. In the patient group there were significant decreases in the levels of sTM and sE-selectin after treatment (p < 0.05). The patient group had significantly higher sTM and sE-selectin levels than the control group at the beginning of the study (p < 0.01), but the difference returned to normal after the treatment (p > 0.05). The sE-selectin and sTM levels significantly correlated with each other, and also with clinical and laboratory findings. Combination treatment successfully treated RA patients. sE-selectin and sTM levels probably reflect disease activity and can be helpful in monitoring disease status and response to therapy.
15188356 Regulation of interleukin-18 binding protein production by blood and synovial cells from p 2004 Jun OBJECTIVE: To study the regulation of interleukin-18 binding protein (IL-18BP) production by rheumatoid arthritis (RA) or control peripheral blood mononuclear cells (PBMCs) and by RA synovial tissue cells, and to compare the levels of IL-18BP messenger RNA (mRNA) expression in whole blood from RA patients and controls. METHODS: Unstimulated or phytohemagglutinin and phorbol myristate acetate (PHA/PMA)-stimulated PBMCs from 10 RA patients and 12 healthy controls and unstimulated or PHA/PMA-stimulated synovial tissue cells from 8 RA patients were cultured with or without IL-12 (1 ng/ml) and IL-18 (5 ng/ml) alone or in combination. IL-18BP and interferon-gamma (IFN gamma) levels in supernatants were measured by enzyme-linked immunosorbent assay. Levels of IL-18BP and IFN gamma mRNA expression in whole blood samples from 22 RA patients and 12 healthy controls were determined by quantitative reverse transcriptase-polymerase chain reaction. RESULTS: IL-12 decreased the basal levels of IL-18BP production by freshly isolated RA or control PBMCs, but increased those of synovial cells or PHA/PMA-stimulated PBMCs. IL-18 alone had no direct effect on IL-18BP production by PBMCs or RA synovial cells, with or without stimulation. Unstimulated whole blood samples from RA patients showed lower levels of IL-18BP mRNA expression than those from healthy controls. CONCLUSION: The production of IL-18BP in response to IL-12 and IL-18 was regulated differently in blood and synovial cells. The difference appears to be related to the level of cell activation.
12823856 The expansion of CD4+CD28- T cells in patients with rheumatoid arthritis. 2003 Clonal expansion of CD4+CD28- T cells is a characteristic finding in patients with rheumatoid arthritis (RA). Expanded CD4+ clonotypes are present in the peripheral blood, infiltrate into the joints, and persist for years. CD4+CD28- T cells are oligoclonal lymphocytes that are rare in healthy individuals but are found in high percentages in patients with chronic inflammatory diseases. The size of the peripheral blood CD4+CD28- T-cell compartment was determined in 42 patients with RA and 24 healthy subjects by two-color FACS analysis. The frequency of CD4+CD28- T cells was significantly higher in RA patients than in healthy subjects. Additionally, the number of these cells was significantly higher in patients with extra-articular manifestations and advanced joint destruction than in patients with limited joint manifestations. The results suggest that the frequency of CD4+CD28- T cells may be a marker correlating with extra-articular manifestations and joint involvement.
12486539 [Differential therapy for the rheumatoid shoulder]. 2002 Dec Despite frequent involvement, the rheumatoid shoulder is neglected in operative treatment of the upper extremities. The slow course of omarthritis, the compensation mechanism of scapulothoracic motion and neighbouring joints as well as dominating disabilities of the lower extremities and the rheumatoid hand are possible explanations. The pattern of destruction of the rheumatoid shoulder is characterized by progressive joint and soft tissue deterioration. Soft tissue involvement determines the course of the shoulder joint. The subacromial space is a common and early site for rheumatoid involvement, often leading to bursitis, tenosynovitis of the biceps tendon and rotator cuff rupture. Sonography and MRI enable the early detection of subacromial and glenohumeral pathology before deterioration is visible radiologically. Surgical intervention in patients with rheumatoid arthritis of the shoulder is based on the degree of radiological destruction according to Larsen, the natural course of the shoulder joint and the soft-tissue condition. The goals of surgery are to relieve pain, increase motion and restore shoulder function. Surgery should be carried out early in the course of the disease, thus determining the long-term prognosis and the remaining surgical options. Depending on the pattern of destruction of the rheumatoid shoulder, the options for treatment can be divided into early and late procedures.Joint-preserving surgery is indicated in the early stages of radiological destruction according to Larsen classification O-III, whereas the late stages of destruction (Larsen IV-V) require reconstructive surgery. The introduction of arthroscopic and semiarthroscopic techniques has improved the acceptance of early synovectomy for the rheumatoid shoulder, but there is still a place for open synovectomy in patients with extensive soft-tissue repair and bone-remodelling procedures. Arthroscopic and open synovectomy are supplementary and noncompetitive surgical procedures for the rheumatoid shoulder. With proceeding bone and soft-tissue destruction corresponding to Larsen stage IV and V, synovectomy is not successful and reconstructive surgery is necessary. Resection-interposition-arthroplasty (RAIP) remains a controversial alternative to arthroplasty in young patients with sufficient bone stock and a reconstructable rotator cuff. The success of cup-replacement will additionally restrict the indications for RAIP. RIAP remains a possible salvage procedure after aseptic and septic loosening of shoulder arthroplasty. Glenohumeral replacement arthroplasty has become the procedure of choice in reconstructive surgery of the shoulder. The severity of soft-tissue and bone destruction determines the choice of shoulder prosthesis. Current modular shoulder systems with increased numbers of humeral-head stem combinations are calculated to achieve a better adjustment of the soft-tissue tension and to optimize the adaptation between head geometry and the natural shape of the glenoid.The surrounding soft-tissue structure, especially the condition of the rotator cuff, is very important for the functional recovery after shoulder arthroplasty. We prefer a hemiarthroplasty of the rheumatoid shoulder joint to avoid critical glenoid fixation. Patients with irreparable rotator cuff tears and severe glenohumeral arthritis remain a difficult challenge in shoulder surgery and the ideal procedure has not yet been found.Pain relief and a modest increase in active motion are the main goals in operative treatment. Bipolar shoulder arthroplasty represents an adequate alternative to currently favoured hemiarthroplasty in patients with cuff-deficient shoulders.
11886970 Radiographic outcome after three years of patients with early erosive rheumatoid arthritis 2002 Feb OBJECTIVE: To compare the radiographic outcomes after 36 months in patients with early erosive rheumatoid arthritis (RA) who were treated with methotrexate (MTX) or gold sodium thiomalate (GSTM). METHODS: In a randomized, double-blind fashion, 174 patients from two centres were assigned to receive weekly intramuscular injections of either 15 mg MTX or 50 mg GSTM. After 12 months, the study was continued as an open prospective study for an additional 2 yr, administering the same amount of MTX and half of the GSTM dose. Radiographic outcomes were assessed by standardized methods in all patients at baseline and after 6, 12, 24 and 36 months. RESULTS: Intention-to-treat analysis showed that patients treated with MTX had higher radiographic scores and more erosive joints at all follow-up points. However, there was no statistically significant difference between the two treatment groups. The progression rate was significantly slower during the second and third years of follow-up in both groups. Baseline and time-integrated (area under the curve over 6 months) disease activity parameters were good predictors of radiographic outcome after 3 yr. Seropositivity was not an independent predictor of progression. However, patients who were positive for rheumatoid factor had higher time-integrated disease activity (with less response to treatment) and thus their disease was significantly more progressive. CONCLUSION: Both of the disease-modifying compounds used in this study, MTX and GSTM, were able to reduce the slope of radiographic progression during 3 yr of follow-up. There was some advantage for parenteral gold but no significant intergroup difference.
20217671 Control perceptions in patients with rheumatoid arthritis: the role of social support. 2003 Sep OBJECTIVE: To identify factors that patients perceive as influencing control in living with rheumatoid arthritis. METHOD: A sample of 40 patients with rheumatoid arthritis were randomly recruited from an outpatient population and partook in an in depth, qualitative interview by one researcher to identify control perceptions. The data were analysed utilizing Colaizzi's procedural steps. RESULTS: Four major categories were identified that positively influenced control perceptions: The reduction of physical symptoms. Social support matching perceived need. The provision of information. The nature of the clinical consultation. Three components were identified in relation to social support: Remaining involved in family activities. Ongoing support from family members. Achieving a balance between support needs and support provision. CONCLUSION: The categories identified can be influenced by practitioners enabling patients with RA to obtain perceived control over their condition.
14962962 Radiological outcome after four years of early versus delayed treatment strategy in patien 2004 Mar OBJECTIVE: To determine the effect of different treatment strategies (early versus delayed) on the radiological progression of joint damage during 4 years. Additionally, to determine the effect of treatment strategy on the association of HLA class II alleles and joint damage. METHODS: Progression of radiographic damage and association of radiographic damage and genetic predisposition were compared in two cohorts, one treated according to the delayed treatment strategy (initial treatment with analgesics), the other treated according to the early treatment strategy (treatment with disease modifying antirheumatic drugs (DMARDs) chloroquine or sulfasalazine). Radiographic damage was measured by the modified Sharp-van der Heijde method. Genetic predisposition was determined by high resolution HLA-DR and DQ typing. RESULTS: A completers-only analysis of 153 patients (originally 206 patients) in a non-randomised design showed less radiographic progression from 0 to 4 years in the early treatment group (median Sharp progression rate 1.3 points/year, n = 75) than in the delayed treatment group (2.5 points/year, n = 78) (p = 0.03). The progression from 1 to 4 years did not differ significantly between the groups. At 4 years, joint destruction in both groups was positively correlated with the presence of the shared epitope. CONCLUSIONS: The beneficial effect of early DMARD treatment on the radiological progression of joint damage is still present at 4 years. However, the rate of joint destruction from 1 to 4 years did not differ between the delayed and early treatment group. Neither the radiographic nor the immunogenetic data suggest that longlasting disease modification has been induced by early treatment.
15477921 Anti-cyclic citrullinated antibodies: complementary to IgM rheumatoid factor in the early 2004 Oct 8 AIMS: To compare the diagnostic sensitivity of anti-cyclic citrullinated (CCP) antibodies and rheumatoid factor (RF) in rheumatoid arthritis (RA) within a general hospital setting. METHOD: Using the American College of Rheumatology (ACR) classification criteria as a gold standard, the frequency of RF and anti-CCP antibody positivity was compared between two groups of RA patients: those with disease duration less than 2 years (early RA, ERA) and those with disease duration more than 2 years (late RA, LRA). RESULTS: In ERA, the diagnostic sensitivity of RF and anti-CCP antibodies was 57% and 79% respectively. In LRA, it was 81% and 84% respectively. CONCLUSION: Anti-CCP antibodies are 20% more sensitivity than RF in the diagnosis of early RA.
12910171 [Value of US imaging of metacarpophalangeal joints in patients with early rheumatoid arthr 2003 Jun Technological advances in the field of ultrasound imaging may have, especially in metacarpophalangeal joints, an impact on decision making in patients with early rheumatoid arthritis. First, the normal anatomy of the metacarpophalangeal joints is briefly reviewed. Then, the authors describe the main ultrasound imaging findings of early RA. The role of ultrasound imaging in the assessment of therapeutic response as well as the benefit of microbubble ultrasound contrast agents are considered.
12955192 [Arthroscopic elbow surgery in rheumatoid arthritis]. 2003 Aug The technique of arthroscopic elbow surgery and its possibilities in the rheumatoid arthritic elbow is discussed. Emphasis is placed on the description of arthroscopic anterior (anterolateral, anteromedial, superomedial) and posterior approaches (straight lateral, posterolateral, straight posterior) to the elbow and the surrounding neurovascular anatomy. Technical hints for elbow arthroscopy especially with relevance to the rheumatoid population are given.
15221281 No relationship of -627 interleukin-10 promoter polymorphism in Chinese patients with rheu 2005 Oct The aim of this study was to examine whether -627 interleukin-10 (IL-10) promoter polymorphism is a marker of susceptibility to or severity of rheumatoid arthritis (RA) in Chinese patients in Taiwan. The study included 198 Chinese patients with RA. One hundred unrelated healthy individuals living in central Taiwan served as the control subjects. The relationship between IL-10 gene polymorphism and clinical manifestations of RA was evaluated. For the genotype, allelic frequency, and carriage rate of IL-10 polymorphism, there were no statistically significant differences found between patients and controls. Furthermore, we did not detect any association of IL-10 genotype with rheumatoid factor (RF), extra-articular involvement, or bone erosion in the RA patients. The lack of association of -627 IL-10 gene polymorphism with RA and the clinical findings in our study implies that the IL-10 gene polymorphism cannot serve as a candidate gene marker for screening RA patients.
15168148 Diagnostic value of antiagalactosyl IgG antibodies in rheumatoid arthritis. 2004 Jun Our objective in this study was to explore the diagnostic value of antiagalactosyl IgG antibodies in rheumatoid arthritis (RA). The study comprised 266 Japanese patients with systemic autoimmune diseases, including 60 with RA. Human agalactosyl IgG was prepared enzymatically, and the serum levels of antiagalactosyl IgG antibodies were determined using a lectin enzyme immunoassay. Serum IgG and IgM rheumatoid factors (RF) were measured using laser nephelometry for IgM (LN-RF) and an enzyme-linked immunosorbent assay for IgG (IgG-RF). Antiagalactosyl IgG antibodies were significantly more common in patients with RA than in those without (78% vs. 18%, odds ratio (OR) 16.51, 95% confidence interval (CI) 8.12-33.58, p<0.0001). Patients with RA also had a higher frequency of LN-RF than those without RA (75% vs. 28%, OR 7.81, 95% CI 3.91-15.58, p< 0.001). The specificity of antiagalactosyl IgG antibodies for RA was significantly higher than that of LN-RF (82% vs. 72%, p<0.0011). There was a significant correlation between titers of antiagalactosyl IgG antibodies and C-reactive protein levels. Antiagalactosyl IgG antibodies are more specific markers for RA than conventional LN-RF, and may provide useful information for the diagnosis of RA.
12819464 Tumor necrosis factor biology in experimental and clinical arthritis. 2003 Jul The successful introduction of antitumor necrosis factor treatments in clinical practice confirmed the biologic relevance of tumor necrosis factor function in chronic inflammatory conditions in humans, mainly in the pathogenesis of rheumatoid arthritis and inflammatory bowel disease. Studies on patients receiving antitumor necrosis factor treatments offered deeper insights into the mechanisms of antitumor necrosis factor action in arthritis and revealed a master regulatory role for tumor necrosis factor in a multitude of biologic processes underlying pathogenesis. However, within such pleiotropism of key functions, blockade of tumor necrosis factor has also led to a significant incidence of unwanted clinical complications. Experimental work in animal models is providing additional clues on the specific function of tumor necrosis factor and its receptors in disease, especially on the molecular and cellular pathways through which tumor necrosis factor orchestrates beneficial and deleterious responses.
12672221 Rheumatology outcomes: the patient's perspective. 2003 Apr Our aim was to explore the patient's perspective of outcomes in rheumatoid arthritis (RA) to identify which outcomes are important to patients and how patients calibrate what constitutes a meaningful change in those outcomes. A qualitative study was performed using focus groups in 5 clinical centers in different geographical locations in the UK. Each group contained 6 to 9 patients with RA who were purposefully sampled to include men and women with a range of age, disease duration, functional disability, work disability, and current disease activity. Each focus group lasted around 1 h and addressed 3 questions: What outcomes from treatment are important to RA patients? What makes patients satisfied or dissatisfied with a treatment? How do patients decide that a treatment is working? Patients identified as important not only physical outcomes such as pain and disability, but also fatigue and a general feeling of wellness. The relative importance of these outcomes depended on the stage of disease and on specific situations, such as a disease flare. Satisfaction was influenced by communication, access to treatment, and treatment efficacy. Treatment efficacy was related to symptom reduction, with the magnitude of reduction necessary for efficacy dependent on the stage of disease. For example, large changes were deemed necessary with disease of long duration, while in early disease, even small changes could be important. Our data support existing knowledge of the importance of pain and mobility as treatment outcomes, but raise new and important issues: Some outcomes of importance to patients are not currently measured and there are no measures available to capture them. Existing measures need to be calibrated to take account of the differing importance of outcomes at different stages of disease and variations in the magnitude of change within the same outcome that indicate treatment efficacy.