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Methods to examine the progression of radiological joint damage due to rheumatoid arthritis in individual patients are presented.

At the 2003 meeting of the American College of Rheumatology (ACR) a debate on the advantages and disadvantages of glucocorticoids (GCs) in the treatment of early and late rheumatoid arthritis [...]

Background: Glucocorticoids induce hypercholesterolaemia, a cardiovascular risk factor, in patients with diseases other than rheumatoid arthritis (RA), but the data in RA are contradictory. Objective: To determine the effects of [...]

In rheumatology and other medical specialties there is a discrepancy between the widespread use and the imprecise designation of glucocorticoid treatment regimens. Verbal descriptions of glucocorticoid treatment regimens used in [...]

Objectives: To determine whether rheumatoid factors (RFs), measured as continuous variables by time resolved fluoroimmunoassay, reflect disease activity in rheumatoid arthritis (RA). Further, to study the association of RFs and [...]

Objective To investigate speech development of children aged 5 and 10 years with repaired unilateral cleft lip and palate (UCLP) and identify speech characteristics when speech proficiency is not at ‘peer level’ at 10 years. Estimate how the number of speech therapy visits are related to speech proficiency at 10 years, and what factors are predictive of whether a child's speech proficiency at 10 years is at ‘peer level’ or not.Design Longitudinal complete datasets from the Scandcleft projectParticipants 320 children from nine cleft palate teams in five countries, operated on with one out of four surgical methods.Interventions Secondary velopharyngeal surgery (VP-surgery) and number of speech therapy visits (ST-visits), a proxy for speech intervention.Main Outcome Measures ‘Peer level’ of percentage of consonants correct (PCC, > 91%) and the composite score of velopharyngeal competence (VPC-Sum, 0–1).Results Speech proficiency improved, with only 23% of the participants at ‘peer level’ at 5 years, compared to 56% at 10 years. A poorer PCC score was the most sensitive marker for the 44% below ‘peer level’ at 10-year-of-age. The best predictor of ‘peer level’ speech proficiency at 10 years was speech proficiency at 5 years. A high number of ST-visits received did not improve the probability of achieving ‘peer level’ speech, and many children seemed to have received excessive amounts of ST-visits without substantial improvement.Conclusions It is important to strive for speech at ‘peer level’ before age 5. Criteria for speech therapy intervention and for methods used needs to be evidence-based.

Abstract Objective--Validation of responsiveness and discriminative power of the World Health Organisation/International League of Associations for Rheumatology (WHO/ ILAR) core set, the American College of Rheumatology (AGR), and European League [...]

Little is known about the relationship between morning symptoms of rheumatoid arthritis (RA) and measures of disease activity currently used to assess RA. Information available from the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA‐2) study was used to investigate these relationships. CAPRA‐2 included 350 patients with RA who were symptomatic despite treatment with disease‐modifying antirheumatic drugs, randomized 2:1 to additional treatment with a 5‐mg daily dose of delayed‐release prednisone or placebo. Pearson's correlations were used to evaluate the relationships between change from baseline in symptoms (duration of morning stiffness, severity of morning stiffness, and intensity of pain on waking) and measures of disease activity (the American College of Rheumatology 20% improvement criteria [ACR20], the Disease Activity Score in 28 joints [DAS28], and the Health Assessment Questionnaire disability index). Correlations were defined as weak (<0.3), moderate (0.3–0.7), or strong (>0.7). There was a strong correlation between the severity of morning stiffness and the intensity of morning pain (Pearson's correlation 0.91, P< 0.001). There was a weak correlation between the duration of morning stiffness and measures of disease activity (0.24–0.28), with moderate correlations between the severity of morning stiffness or intensity of pain on waking and DAS28 or ACR20 scores (0.44–0.48). Severity of morning stiffness showed less variability and a greater effect size than did duration of morning stiffness. Morning symptoms and measures of disease activity show weak to moderate correlations. Severity of morning stiffness showed less variability and greater effect size than did duration of morning stiffness. These findings suggest that severity is the preferred construct to measure the impact of morning stiffness in patients with RA, information that is not fully captured in the RA core set.

In contrast to the usual step-up approach to treating rheumatoid arthritis (RA), Boers and colleagues found that intensive step-down combination therapy with sulfasalazine plus tapered doses of oral prednisolone and [...]

The purpose of this study was to assess the reproducibility and clinical impact of positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) in patients with (suspected) recurrent melanoma. The clinical value of PET was prospectively measured in 58 consecutive patients referred for PET because of unresolved clinical questions after conventional work-up. Diagnostic understanding and therapy choice by referring physicians were evaluated before, directly after, and 6 months after PET. Observer agreement of PET readings was measured with respect to various parameters (interpretation, number and localization of lesions, ‘clinically decisive’ metastases), using intra-class correlation coefficients. FDG PET improved diagnostic understanding in 33 cases (57). In six patients (10), diagnostic understanding was solely based on PET information. According to the attending clinicians, PET contributed to a positive change of planned treatment in 23 patients (40) and increased confidence in the chosen treatment in 23 (40). Observer agreement of PET readings was very high (intra-class correlation coefficients were between 0.87 and 0.94). The diagnostic value related especially to the whole-body scan technique and the superior specificity, compared to conventional work-up. It is concluded that, in problematical cases with (suspected) recurrent melanoma, 18F-FDG PET had considerable impact on diagnostic understanding and management. Together with the excellent observer reliability, these results justify further studies to determine the optimal place of PET in routine diagnostic algorithms in recurrent melanoma.

The presence of certain HLA class II antigens is strongly associated with the progression of joint destruction in rheumatoid arthritis (RA). Such antigens may be more effective than other class II antigens in inducing the formation of autoreactive T cells after presentation of (auto)antigens. We investigated whether early and aggressive treatment with disease-modifying antirheumatic drugs could modify this relationship. We analyzed data from 2 studies of patients with early RA treated according to different strategies. The first study consisted of 2 cohorts, one (n = 109; median disease duration before treatment 4 months) was treated according to the pyramid strategy (initial nonsteroidal antiinflammatory drugs, followed by chloroquine [CQ] or sulfasalazine [SSZ] when necessary), and the other (n = 97; median disease duration before treatment 2 weeks) was immediately treated with CQ or SSZ. The second study comprised 155 patients (median disease duration 4 months) from the Combinatietherapie Bij Reumatoide Artritis (COBRA) trial, in which patients were randomly assigned to combination treatment with step-down prednisolone, methotrexate (MTX), and SSZ (n = 76) or with SSZ alone (n = 79). Prednisolone and MTX dosages were tapered and stopped after 28 and 40 weeks, respectively. The extent of joint damage was measured by the modified Sharp method. In the pyramid treatment cohort, the median increase in Sharp score after 2 years was 12 in patients positive for the shared epitope (SE) and 1 in SE− patients. In the immediate treatment cohort, the median increase was 3 in SE+ patients and 2 in SE− patients. In the SSZ group of the COBRA study, the median increase in Sharp score after 1 year was 11 in DR4+ patients and 3 in DR4− patients. In the combination treatment group, the median increase was 4 in DR4+ patients and 2 in DR4− patients. Significance was confirmed by multiple regression using log-transformed scores. Early and aggressive antirheumatic drug treatment affects the association of HLA class II alleles with progression of joint damage in RA.

Objectives. Exploration of bone metabolism changes at different levels of disease activity, both with and without oral corticosteroid therapy, and prediction of changes in joint damage and bone density from the observed changes in markers of bone turnover.
Methods. Data analysis from a randomized clinical trial with 155 rheumatoid arthritis (RA) patients; median age 50 yr, early and active disease (diagnosis &lt;2 yr); one group treated with a combination of sulphasalazine (SSZ; 2000 mg/day), methotrexate (MTX; 7.5 mg/week) and prednisolone (initially 60 mg/day, tapered in six weekly steps to 7.5 mg/day), the other group with SSZ alone. Prednisolone and MTX were tapered and stopped after weeks 28 and 40, respectively, while SSZ was continued. Urine and serum samples were collected at baseline and weeks 16, 28, 40 and 56. Measurements of urinary pyridinoline (PYD) and deoxypyridinoline (DPD) and serum alkaline phosphatase (tAP) and osteocalcin (OC) were performed, as well as standard clinimetry and bone densitometry.
Results. Over time and in both treatment groups, bone formation and bone resorption markers showed a pattern similar to erythrocyte sedimentation rate (ESR): a significant decrease compared with baseline and a larger decrease with combined treatment at weeks 16 and 28. PYD excretion, tAP, OC, and joint damage scores were significantly lower in the combined treatment group. Changes in bone density (of spine and hips) did not significantly differ between treatment groups. Mainly cumulative ESR explained progression of joint damage.
Conclusions. Prednisolone and disease-modifying anti-rheumatic drug therapy in patients with early and active RA are both independently associated with decreased levels of urinary excretion of bone collagen resorption markers PYD and DPD. Markers of bone formation and resorption closely followed changes in ESR in both treatment groups. Reduced bone resorption together with reduced bone formation--initially at a somewhat faster pace--resulted in less bone turnover and explain the observed (non-significant and partially reversible) extra bone loss in the lumbar spine associated with prednisolone (combined treatment).

We describe the progress towards developing a patient rated toxicity index that meets all of the patient-important attributes defined by the OMERACT Drug Safety Working Party. These attributes are frequency, severity, importance to patient, importance to the clinician, impact on economics, impact on activities, and integration of adverse effects with benefits. The Stanford Toxicity Index (STI) has been revised to collect all attributes with the exception of impact on activities. However, since the STI is a part of the Health Assessment Questionnaire (HAQ), impact on activities is collected by the HAQ. In particular, a new question asks patients to rate overall satisfaction, taking into consideration both benefits and adverse effects. The next step in the development of this tool is to ensure that the STI meets the OMERACT filter of truth, discrimination, and feasibility. Although truth and feasibility have been confirmed by comparisons within the ARAMIS database, discrimination needs to be assessed in clinical trials.

OBJECTIVE: To evaluate the effect of high dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (ASCT) in comparison to conventional pharmacological therapy in the treatment of patients with refractory, progressively erosive rheumatoid arthritis (RA). METHODS: Decision analysis using a Markov model with a 5.5 year time horizon. Probabilities of transition towards 5 different health states, ranging from 70% improvement to death, were derived from published case reports, patient series, and expert panels. Quality of life (QOL) estimates were obtained from 2 RA clinical trials. Patients were hypothetical cohorts of 50-year-old female patients with progressively erosive, active RA, who failed treatment with methotrexate, combination therapy, and tumor necrosis factor blocking agents. Interventions were HDC + ASCT versus conventional pharmacological treatment with a (combination) therapy of disease modifying antirheumatic drugs. As main outcome measures, we included the number of quality adjusted life years (QALY) after HDC + ASCT compared to conventional therapy. Sensitivity analysis was performed to investigate the influence of treatment related mortality (TRM) and the influence of QOL during HDC + ASCT, and to assess the minimal desired effectiveness of HDC + ASCT for a given TRM of 1% and 10%. RESULTS: HDC + ASCT and conventional pharmacological treatment were equally effective in the base-case analysis (3.48 vs 3.46 QALY). A TRM of less than 3.3% favored HDC + ASCT as the preferred treatment. The analysis showed that when TRM was set at 1%, a relatively short period of efficacy was sufficient to remain the preferred strategy, whereas a TRM of 10% would require a sustained response for several years. CONCLUSION: This model predicted equally favorable effects of HDC + ASCT and conventional therapy in the treatment of refractory RA in the base-case. The minor differences in terms of QALY seem to indicate that clinical decision making should be guided by patient preferences. However, better clinical efficacy might be achieved by adaptation of the treatment regimen of HDC + ASCT and patient selection. The model supports the need for randomized clinical trials and may contribute to an optimal study design.

We evaluate measurement properties of common rheumatoid arthritis (RA) assessments. Included are a comprehensive literature review and new data on the reliability and smallest detectable difference (SDD) for different classes of these measures. We found that certain common measures such as joint counts, pain, and patient global all had poor reliability and showed large SDD compared to multi-item measures of physical/psychological function or compared to radiographic measures. We discuss the implications of these findings on the use of composite endpoints such as the ACR20 or the EULAR responder index in RA clinical trials, particularly the introduction of misclassification bias that arises from differential measurement error. Finally, we consider generically how the concept of the SDD might or might not relate to the concept of the minimal clinically important difference.

To determine the minimal clinically important difference (MCID) between hand and foot films with a 1 year interval assessed with the Sharp/van der Heijde or Larsen/Scott scoring method. Progression scores of the 2 methods were compared with the opinion of an international expert panel on clinical relevance of radiological joint damage in 4 predefined clinical settings. The expert panel consisted of 3 rheumatologists, who evaluated 46 pairs of hand and foot films, taken with 1 year intervals, of patients with early rheumatoid arthritis. Receiver operating characteristics curves analyzed the accuracy of different threshold values (progression scores) of the 2 scoring methods to detect the presence or absence of clinically important difference, as defined by the expert panel as external criterion. The threshold value with the highest accuracy was subsequently chosen as the score representing the MCID. Five Sharp/van der Heijde units and 2 Larsen/Scott units were the best cutoffs. The accompanying sensitivities ranged from 77% to 100% for the Sharp/van der Heijde method and from 73% to 84% for the Larsen/Scott method for the 4 clinical settings. The specificities were between 78% and 84% for the Sharp/van der Heijde method and between 74% and 94% for the Larsen/Scott method. The smallest progression score that can be detected apart from interobserver measurement error, the smallest detectable difference (SDD), was equal to or larger than the calculated MCID, 5 Sharp/van der Heijde units and 6 Larsen/Scott units in our study, if the mean progression scores of the same 2 observers were used. The SDD is a conservative estimate of the MCID; our panel rated progression at or below this level as clinically significant.

Analysis of progression of structural damage on an individual patient level in randomized controlled trials provides extra information in addition to the analysis on a group level. A cutoff level is required to define which patients show progression and which patients do not. The objective of the mimimal clinically important difference (MCID) module for plain films was to elaborate the various concepts to determine a MCID for plain films, and if possible, to define a MCID for specific scoring methods. The module comprised preconference reading material, a plenary session, small group discussions, and a plenary report of the group sessions, combined with interactive voting. The following conclusions and recommendations were made: the smallest detectable difference (SDD) beyond measurement error is a good starting point to define MCID; SDD is study-specific; SDD should be reported for all radiographic endpoints used in a trial as a quality control; the expert panel approach is a reasonable method to define MCID, but defined in this way MCID may be smaller than current SDD; more research is needed to validate expert panel based MCID in different datasets and with different experts; a predictive, data driven MCID is the ultimate goal, but is not yet available; the SDD can be used as a proxy for MCID until a data driven MCID is available; analysis at the group level (comparison of means or medians) should remain primary in studies that include progression of joint damage as outcome measure; the proportion of patients showing more progression than the SDD is a secondary outcome measure.

The purpose of this paper is to describe a classification system for studies of responsiveness that was designed to help organize these studies, and identify those with the potential to provide information on minimal clinically important difference (MCID). We developed a 3 dimensional cube into which studies of responsiveness can be categorized based on their evaluation of 3 attributes: 1. individual or group setting; 2. which scores are contrasted; and 3. the type of change or difference being assessed. We present and discuss examples of studies that fit into categories in the classification cube. This classification system helps to focus attention on whether the literature is able to provide information on the specific type of change a person is interested in. It reinforces that the ability of an instrument to detect a certain category of discrimination within the cube does not mean it will necessarily be responsive to another category. The cube has been shown here as a means to separate out studies that address important change. These studies can then be examined as the source of information on MCID.

Determining a minimal clinically important difference to be detected in a clinical trial is a critical methodological step in the design of a study. In this review, the different methods that have been used in detecting important changes or differences are considered and categorized according to a classification system consisting of which groups are contrasted, the setting of the results, and the type of change of difference being quantified. It was found that most methods and procedures for deriving minimal clinically important differences considered important changes from the viewpoint of a group of patients. Development of methods that focus on individuals should be a goal of the future.

Objective. To determine the influence of reading series of films in chronological order, in pairs with unknown time sequence, or as single films, on precision and sensitivity to change.Methods. Two studies were performed with 10 and 12 patients fulfilling the American College of Rheumatology criteria. In Study 1, two sets of films with a 1 yr interval were scored in chronological order, in pairs, and as single films. In Study 2, four sets of films, with a 1 yr interval each, were scored in chronological order, as single films and as single-pair (right and left together). All films were scored with the Sharp/van der Heijde method by two independent observers. Data were analysed with a repeated measures ANOVA using a full mixed effects model. Two generalizability (G) coefficients were constructed for reliability and for change.Results. Study 1: the interobserver reliability was similar for the three methods (Greliability chronological 0.94, paired 0.88, single 0.93); progression was a mean increase (averaged over patients, observers and methods) from 26 to 37 (P=0.046). The sensitivity for change was greater for the chronological than for the paired and single scoring (Gchange 0.39, 0.22 and 0.24, respectively). Study 2: the interobserver reliability was 0.86 for chronological, 0.76 for single-pair and 0.91 for single readings. Significantly more progression was measured with the chronological compared with the single-paired and single methods (15.9 vs 8.5 and 8.3; P=0.0001). A constant progression was suggested by chronological reading, in contrast to a stabilization in the other two methods after 1 yr.Conclusion. Reading films in chronological order is most sensitive to change in a time period up to 3 yr follow-up; this was already present after 1 yr, but even more pronounced with longer follow-up.

Objective. To determine the reliability and sensitivity to change of a simplified radiological scoring method [simple erosion narrowing score (SENS)] for rheumatoid arthritis (RA). SENS was compared to the Sharp/van der Heijde score (SHS) as a gold standard.Methods. Sets of seven radiographs of hands and feet were taken of 20 RA patients with a wide spectrum of radiological damage. For 14 patients, these seven radiographs were taken during a follow-up period of 5 yr, and for six patients during a follow-up of 10 yr. Each set of radiographs was scored twice by the same observer (DvdH). Erosions and joint space narrowing were scored with SHS (range 0–448) in 32 and 30 joints in the hands, respectively, and both in 12 joints in the feet. SENS gives a score of 1 if there is any erosion in a joint and also 1 if there is any narrowing in the joint (range 0–86). In each case, SENS was derived from SHS. To analyse data, generalizability theory and repeated measurements ANOVA were used.Results. The overall reliability coefficient was 0.81 for SHS and 0.80 for SENS. Intra-observer reliability [intraclass correlation coefficient (ICC)] was 0.99 and 0.98 for SHS and SENS, respectively. The ICC for the sensitivity to change was 0.84 for SHS and 0.88 for SENS. The smallest detectable difference (SDD) could be determined for both methods. The presence of progression based on this SDD was very comparable between the two methods.Conclusion. The measurement properties of SENS are good and comparable to SHS. This makes SENS suitable for use in clinical practice and in large (epidemiological) studies, especially in the first years of disease.

Objective. To determine the influence of reading series of films in chronological order, in pairs with unknown time sequence, or as single films, on precision and sensitivity to change.
Methods. Two studies were performed with 10 and 12 patients fulfilling the American College of Rheumatology criteria. In Study 1, two sets of films with a 1 yr interval were scored in chronological order, in pairs, and as single films. In Study 2, four sets of films, with a 1 yr interval each, were scored in chronological order, as single films and as single-pair (right and left together). All films were scored with the Sharp/van der Heijde method by two independent observers. Data were analysed with a repeated measures ANOVA using a full mixed effects model. Two generalizability (G) coefficients were constructed for reliability and for change.
Results. Study 1: the interobserver reliability was similar for the three methods (G_reliability chronological 0.94, paired 0.88, single 0.93); progression was a mean increase (averaged over patients, observers and methods) from 26 to 37 (P=0.046). The sensitivity for change was greater for the chronological than for the paired and single scoring (G_change 0.39, 0.22 and 0.24, respectively). Study 2: the interobserver reliability was 0.86 for chronological, 0.76 for single-pair and 0.91 for single readings. Significantly more progression was measured with the chronological compared with the single-paired and single methods (15.9 vs 8.5 and 8.3; P=0.0001). A constant progression was suggested by chronological reading, in contrast to a stabilization in the other two methods after 1 yr.
Conclusion. Reading films in chronological order is most sensitive to change in a time period up to 3 yr follow-up; this was already present after 1 yr, but even more pronounced with longer follow-up.

Objective. To determine the reliability and sensitivity to change of a simplified radiological scoring method [simple erosion narrowing score (SENS)] for rheumatoid arthritis (RA). SENS was compared to the Sharp/van der Heijde score (SHS) as a gold standard.
Methods. Sets of seven radiographs of hands and feet were taken of 20 RA patients with a wide spectrum of radiological damage. For 14 patients, these seven radiographs were taken during a follow-up period of 5 yr, and for six patients during a follow-up of 10 yr. Each set of radiographs was scored twice by the same observer (DvdH). Erosions and joint space narrowing were scored with SHS (range 0-448) in 32 and 30 joints in the hands, respectively, and both in 12 joints in the feet. SENS gives a score of 1 if there is any erosion in a joint and also 1 if there is any narrowing in the joint (range 0-86). In each case, SENS was derived from SHS. To analyse data, generalizability theory and repeated measurements ANOVA were used.
Results. The overall reliability coefficient was 0.81 for SHS and 0.80 for SENS. Intra-observer reliability [intraclass correlation coefficient (ICC)] was 0.99 and 0.98 for SHS and SENS, respectively. The ICC for the sensitivity to change was 0.84 for SHS and 0.88 for SENS. The smallest detectable difference (SDD) could be determined for both methods. The presence of progression based on this SDD was very comparable between the two methods.
Conclusion. The measurement properties of SENS are good and comparable to SHS. This makes SENS suitable for use in clinical practice and in large (epidemiological) studies, especially in the first years of disease.

Objective: Assessment of the cost-effectiveness and cost-utility of early intervention in rheumatoid arthritis (RA) patients, with combined step-down prednisolone, methotrexate and sulphasalazine, compared to sulphasalazine alone.Methods: Multicentre 56 week randomized double-blind trial with full economic analysis of direct costs and utility analysis with rating scale and standard gamble measurement techniques.Results: The combined-treatment group included 76 patients and the sulphasalazine group 78 patients. The mean total costs per patient in the first 56 weeks of follow-up were $5519 for combined treatment and $6511 for treatment with sulphasalazine alone (P = 0.37). Out-patient care, in-patient care and non-health care each contributed about one-third to the total costs. The combined-treatment group appeared to generate savings in the length of hospital stay for RA, non-protocol drugs and costs of home help, but comparisons were not statistically significant. Protocol drugs and monitoring were slightly more expensive in the combined-treatment group. Clinical, radiographic and functional outcomes significantly favoured combined treatment at week 28 (radiography also at week 56). Utility scores also favoured combined treatment.Conclusion: Combined treatment is cost-effective due to enhanced efficacy at lower or equal direct costs.Key words: Early rheumatoid arthritis, Cost-effectiveness, Cost-utility analysis, Combined treatment, DMARDs, Glucocorticoids, Prednisolone, Methotrexate, Sulphasalazine, Randomized double-blind trial.