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.

Markov model into the cost-utility over five years of etanercept and infliximab compared with usual care in patients with active ankylosing spondylitis.

OBJECTIVE: To estimate the incremental cost-utility of etanercept and infliximab compared with usual care in active ankylosing spondylitis. METHODS: A Markov model over five years with cycle times of three months was computed. Patients included all had active disease, defined as Bath ankylosing spondylitis disease activity index (BASDAI) >or=4 and could reach low disease activity, defined as BASDAI <4. Non-response to tumour necrosis factor alpha (TNFalpha) inhibitors was always followed by cessation of treatment. Response to TNFalpha inhibitors could be followed at any time by either relapse to BASDAI >or=4, leading to cessation of treatment, or toxicity, leading to cessation of treatment if major. Probabilities for efficacy, relapse, and toxicity were derived from two European randomised controlled trials. Utilities and costs assigned to the BASDAI disease states were derived from a two year observational Dutch cohort. In sensitivity analyses probabilities of effectiveness, toxicity, costs, and utilities were varied. RESULTS: Over five years the total quality adjusted life years varied from 2.57 to 2.89 for usual care, compared with 3.13 to 3.42 and 3.07 to 3.35 for etanercept or infliximab. Cumulative costs were between 49,555 to 69,982 for usual care compared with 59,574 to 91,183 or 28,3330 to 106,775 for etanercept and infliximab. This resulted in incremental cost-utility ratios varying between 42,914 and 123,761 per QALY for etanercept compared with usual care and 67,207 to 237,010 for infliximab. The model was sensitive to drug prices. CONCLUSION: Etanercept and infliximab have large clinical effects in ankylosing spondylitis. The present model suggests the high drug costs restricts efficient use in all patients who have a BASDAI >4. The validity of the model is limited by insufficient insight in the natural course of the disease and long term effectiveness and toxicity of TNFalpha inhibitors.

Willingness of patients with ankylosing spondylitis to pay for inpatient treatment is influenced by the treatment environment and expectations of improvement.

OBJECTIVE: To assess the willingness to pay (WTP) for treatment in a spa resort of patients with ankylosing spondylitis (AS) and to assess if the experience of a spa influences the WTP. METHODS: 120 patients participating in a randomised trial comparing 3 weeks' treatment in a spa resort in Austria or in the Netherlands with a control group completed a WTP questionnaire before and after spa treatment. Patients indicated on a payment card the maximal co-payment they wanted to contribute for three scenarios that included (a) two levels of improvement in pain and stiffness and (b) two treatment environments: a rehabilitation hospital and a spa resort. RESULTS: At baseline, patients wanted to contribute more for the same improvement after treatment in a spa resort compared with a rehabilitation hospital (p<0.003), and were prepared to pay more when expected effects were higher (p<0.001). No differences were found between men and women, pain, or income. After the trial none of the treatment groups showed a change in their WTP. CONCLUSION: The WTP of patients with AS for inpatient treatment is influenced by the treatment environment and the expected improvement. Experiencing treatment in a spa resort does not influence the co-payment.

Association between radiographic damage of the spine and spinal mobility for individual patients with ankylosing spondylitis: can assessment of spinal mobility be a proxy for radiographic evaluation?

OBJECTIVE: To demonstrate the association between various measures of spinal mobility and radiographic damage of the spine in individual patients with ankylosing spondylitis, and to determine whether the assessment of spinal mobility can be a proxy for the assessment of radiographic damage. METHODS: Radiographic damage was assessed by the mSASSS. Cumulative probability plots combined the radiographic damage score of an individual patient with the corresponding score for nine spinal mobility measures. Receiver operating characteristic analysis was performed to determine the cut off level of every spinal mobility measure that discriminates best between the presence and absence of radiographic damage. Three arbitrary cut off levels for radiographic damage were investigated. Likelihood ratios were calculated to explore further the diagnostic properties of the spinal mobility measures. RESULTS: Cumulative probability plots showed an association between spinal mobility measures and radiographic damage for the individual patient. Irrespective of the chosen cut off level for radiographic progression, lateral spinal flexion and BASMI discriminated best between patients with and those without structural damage. Even the best discriminatory spinal mobility assessments misclassified a considerable proportion of patients (up to 20%). Intermalleolar distance performed worst (up to 30% misclassifications). Lateral spinal flexion best predicted the absence of radiographic damage, and a modified Schober test best predicted the presence of radiographic damage. CONCLUSION: This study unequivocally demonstrated a relationship between spinal mobility and radiographic damage. However, spinal mobility cannot be used as a proxy for radiographic evaluation in an individual patient.

Radiography as primary outcome in rheumatoid arthritis: acceptable sample sizes for trials with 3 months' follow up.

OBJECTIVES: To investigate whether plain radiographs can show changes in joint damage due to rheumatoid arthritis (RA) within 3 months. METHODS: 188 film pairs taken with a 3 month interval were evaluated. They were scored with (chronological) and without (paired) knowledge of the sequence of the films according to the Sharp/van der Heijde method. Changes in joint damage were analysed on a group and an individual level for different subsets of patients. Sample sizes required to detect statistically and clinically significant differences were estimated based on the percentages of patients with progression larger than the smallest detectable change (SDC). RESULTS: Changes in joint damage were seen by both the chronological and the paired scoring method. The percentage of patients with progression of joint damage larger than the corresponding SDCs (1.7 and 2.4) varied in the subsets from 18% to 64% if based on the chronological change-scores and from 9% to 36% using paired change-scores. Acceptable sample size estimates were seen in several subsets, depending on (a) how the investigated drug would reduce the individual risk of progression of joint damage (by an absolute or a relative risk reduction model); (b) how damage was scored (chronological or paired); (c) the baseline risk; and (d) whether a two sided or one sided test would be used. CONCLUSIONS: Changes in joint damage due to RA can be detected reliably already within 3 months. This finding can be used to plan short term, randomised controlled trials with radiographic progression as primary outcome.

Quality of life and work in patients with rheumatoid arthritis and ankylosing spondylitis of working age.

OBJECTIVE: To investigate the relationship between work and quality of life (QOL) in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) aged 16-59. METHODS: 1056 patients with RA and 658 with AS were included in the study. Data were obtained by postal questionnaire, which included several generic and disease related QOL instruments. Separate dimensions and physical and mental summary scores from the SF-36 were compared. Stepwise multiple regression was performed to study the relationship between work and physical and mental health related QOL, including disease related factors, coping, and fatigue. RESULTS: Physical health related QOL was reported to be worse, and mental health related QOL better, in RA than in AS in people of working age. No differences between RA and AS were found in somatic pain, physical role functioning, social functioning, emotional role functioning, vitality, or general health perception; nor were there any significant differences in fatigue and behavioural coping styles. Work was positively associated with physical health related QOL in both groups and, after disease characteristics, was the most important determinant. No association was found with mental health related QOL. CONCLUSIONS: Although physical health related QOL was worse in patients with RA, the impact on several dimensions of health related QOL in patients with RA and AS of working age under rheumatological care was comparable. Patients with RA and AS experienced similar limitations in physical role functioning, including work. Work is an important independent external determinant of physical health related QOL, but not of mental health related QOL.

Initiation of biological agents in patients with ankylosing spondylitis: results of a Delphi study by the ASAS Group.

BACKGROUND: There is ample evidence of important symptomatic efficacy of tumour necrosis factor alpha (TNFalpha) inhibition in ankylosing spondylitis (AS). Moreover, studies suggest that anti-TNF could be considered as the first disease controlling antirheumatic treatment (DC-ART) for AS. OBJECTIVE: To determine precisely which patients with AS are most likely to benefit from anti-TNFalpha treatment because of the cost and possible long term side effects of such treatment. METHODS: Assessment in Ankylosing Spondylitis (ASAS) members were asked to use a Delphi technique to name the characteristics of patients with AS for whom they would start DC-ART, in three different clinical presentations (isolated axial involvement, peripheral arthritis, enthesitis). RESULTS: Among the 62 invited ASAS members, more than 50% actively participated in the four phases of definition according to the Delphi technique. For each of the three clinical presentations, a combination of five to six domains was proposed, with an evaluation instrument and a cut off point defining a minimum level of activity for each domain. CONCLUSION: This study provides a profile for a patient with AS for considering initiation of biological agents that reflects the opinion of the ASAS members, using a Delphi exercise. Further studies are required to assess their relevance and their consistency with clinical practice.

International ASAS consensus statement for the use of anti-tumour necrosis factor agents in patients with ankylosing spondylitis.

OBJECTIVE: To obtain an international consensus about the use of anti-tumour necrosis factor alpha (anti-TNF alpha) for treating patients with ankylosing spondylitis (AS). METHODS: These recommendations were developed by a review of published reports in combination with expert opinion, including a Delphi exercise, and a consensus meeting of the ASsessments in AS (ASAS) Working Group. RESULTS: The final consensus comprises the following requirements: (1) For the initiation of anti-TNF alpha therapy: (a) a diagnosis of definitive AS; (b) presence of active disease for at least four weeks as defined by both a sustained Bath AS Disease Activity Index (BASDAI) of at least 4 and an expert opinion based on clinical features, acute phase reactants, and imaging modalities; (c) presence of refractory disease defined by failure of at least two non-steroidal anti-inflammatory drugs during a single three month period, failure of intra-articular steroids if indicated, and failure of sulfasalazine in patients with peripheral arthritis; (d) application and implementation of the usual precautions and contraindications for biological therapy. (2) For the monitoring of anti-TNF alpha therapy: both the BASDAI and the ASAS core set for clinical practice should be followed regularly. (3) For the discontinuation of anti-TNF alpha therapy: in non-responders, consideration should be made after 6-12 weeks' treatment. Response is defined as improvement of (a) at least 50% or 2 units (on a 0-10 scale) of the BASDAI, (b) expert opinion that treatment should be continued. CONCLUSION: This consensus statement on anti-TNF alpha treatment in AS may be used for guidance in clinical decision making and as the basis for the development of guidelines. Evaluation of the healthcare consequences of this consensus is subject to further research by the ASAS group.

Influence of glucocorticoids and disease activity on total and high density lipoprotein cholesterol in patients with 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 antirheumatic treatment, including prednisolone (combination) therapy on total and high density lipoprotein (HDL) cholesterol levels in RA, taking disease activity into account. METHODS: HDL cholesterol and total cholesterol levels were determined in:(a) established RA (b) two cohorts with early active RA, (c) a previously conducted 56 week trial among patients with early RA comparing the value of intensive combination therapy (that included glucocorticoids) with sulfasalazine alone (COBRA trial). RESULTS: In established RA total cholesterol levels were only slightly raised, irrespective of disease activity. However, HDL cholesterol was significantly higher in patients in remission than in patients with active disease. In contrast, in active early RA at baseline total cholesterol was low normal: between 4.6 and 5.1 mmol/l in the different populations. The level of HDL cholesterol was highly dependent on the duration of storage. In both COBRA groups total cholesterol increased by a mean of 0.6 mmol/l. HDL cholesterol increased by more than 50% after treatment, leading to an improvement of the total cholesterol/HDL ratio (atherogenic index). This increase (and index improvement) was much more rapid in the group receiving combination treatment. A similar pattern was seen in the 2001 cohort with early RA. In all the groups with active disease HDL and total cholesterol levels correlated inversely with disease activity. CONCLUSION: In established, but especially in early RA, disease activity is accompanied by atherogenic lipid levels. This dyslipidaemia can be rapidly reversed by aggressive antirheumatic treatment including glucocorticoids.

Direct costs of ankylosing spondylitis and its determinants: an analysis among three European countries.

OBJECTIVE: To assess direct costs associated with ankylosing spondylitis (AS). To determine which variables, including country, predict costs. METHODS: 216 patients with AS from the Netherlands, France, and Belgium participated in a two year observational study and filled in bimonthly economic questionnaires. Disease related healthcare resource use was measured and direct costs were calculated from a societal perspective (true cost estimates) and from a financial perspective (country-specific tariffs). Predictors of costs were assessed using Cox's regression analysis. RESULTS: 209 patients provided sufficient data for cost analysis. Mean annual societal direct costs for each patient were euro;2640, of which 82% were direct healthcare costs. In univariate analysis costs were higher in the Netherlands than in Belgium, but this difference disappeared after adjusting for baseline differences in patients' characteristics among countries. Longer disease duration, lower education, worse physical function, and higher disease activity were predictors of costs. Mean annual direct costs from a financial perspective were euro;2122, euro;1402, and euro;941 per patient in the Netherlands, France, and Belgium, respectively. For each country, costs from a financial perspective were significantly lower than costs from a societal perspective. CONCLUSION: Direct costs for AS are substantial in three European countries but not significantly different after adjusting for baseline characteristics among countries. Worse physical function and higher disease activity are important determinants of costs, suggesting better disease control might reduce the costs of AS. The difference in costs from a societal and financial perspective emphasises the importance of an economic analysis.

Costs of ankylosing spondylitis in three European countries: the patient's perspective.

OBJECTIVE: To assess a patient's out of pocket costs, income loss, time consumption, and quality of life (QoL) due to ankylosing spondylitis (AS) in three European countries and to assess variables predicting these outcomes. METHODS: 216 patients with AS from the Netherlands, France, and Belgium participated in a two year study. Health resource use, days absent from work, time lost, and quality of life (EuroQol) were assessed by bimonthly questionnaires. AS related healthcare and non-healthcare expenditure and income loss were calculated taking into account country-specific regulations. Predictors of costs, time consumption, and QoL were analysed by Cox's regression. RESULTS: 209 patients provided data for cost analysis. Average annual healthcare and non-healthcare expenditure was euro;431 per patient and average annual income loss was euro;1371 per patient. Healthcare costs were highest for Belgian and lowest for French patients, while non-healthcare costs were highest for Dutch patients. A patient's total costs were associated with higher age and worse physical function. On average, patients with AS needed 75 minutes additional time a day because of AS. Worse physical function and higher disease activity predicted time consumption. After adjusting for baseline confounders, QoL was worse in Belgian and French than in Dutch patients. Peripheral arthritis, worse physical function, higher disease activity, and loss of income contributed to worse QoL. CONCLUSION: AS is time consuming and associated with substantial out of pocket costs. Belgian patients incur the highest healthcare payments. Poor physical function increases patient's costs and time consumption. Loss of income is associated with lower QoL.

Radiographic assessment of sacroiliitis by radiologists and rheumatologists: does training improve quality?

OBJECTIVE: To assess performance of radiologists and rheumatologists in detecting sacroiliitis METHODS: 100 rheumatologists and 23 radiologists participated. One set of films was used for each assessment, another for training, and the third for confidence judgment. Films of HLA-B27+ patients with AS were used to assess sensitivity. For specificity films of healthy HLA-B27- relatives were included. Plain sacroiliac (SI) films with simultaneously taken computed tomographic scans (CTs) were used for confidence judgment. Three months after reading the training set, sensitivity and specificity assessments were repeated. Next, participants attended a workshop. They also rated 26 SI radiographs and 26 CTs for their trust in each judgment. Three months later final assessments were done. RESULTS: Sensitivity (84.3%/79.8%) and specificity (70.6%/74.7%) for radiologists and rheumatologists were comparable. Rheumatologists showed 6.3% decrease in sensitivity after self education (p=0.001), but 3.0% better specificity (p=0.008). The decrease in sensitivity reversed after the workshop. Difference in sensitivity three months after the workshop and baseline was only 0.5%. Sensitivity <50% occurred in 13% of participants. Only a few participants showed changes of >5% in both sensitivity and specificity. Intraobserver agreement for sacroiliitis grade 1 or 2 ranged from 65% to 100%. Sensitivity for CT (86%) was higher than for plain films (72%) (p<0.001) with the same specificity (84%). Confidence ratings for correctly diagnosing presence (7.7) or absence (8.3) of sacroiliitis were somewhat higher than incorrectly diagnosing the presence (6.6) or absence (7.4) of sacroiliitis (p<0.001). CONCLUSION: Radiologists and rheumatologists show modest sensitivity and specificity for sacroiliitis and sizeable intraobserver variation. Overall, neither individual training nor workshops improved performance.

Applying low disease activity criteria using the DAS28 to assess stability in patients with rheumatoid arthritis.

OBJECTIVES: To examine whether low disease activity criteria using the disease activity score (DAS28) can be applied to identify a reasonably large number of patients with stable low disease activity of rheumatoid arthritis (RA) over a six month period, with the ultimate intention of including these patients in a substitution based, shared care model. Additionally, to assess the reliability of the DAS28 for selecting patients with stable disease from an outpatient population. METHODS: Patients regularly seen at the rheumatology outpatient department of the university hospital Maastricht, were invited for assessment of the stability of their RA. The shared care model was intended to provide care to patients with stable, low disease activity of RA by nurse specialists. For this, patients underwent assessments using the DAS28 criteria at entry and three and six months later. Test-retest reliability was assessed for composing measures as well as for the DAS28. RESULTS: Of the 97 outpatients included, one third (31 patients) did not complete the study. Patients with missing data were older and assessed their disease activity as greater than patients with complete data. Applying the low disease activity criteria to assess stability over a period of six months (DAS28(T0)

Comparison of statistically derived ASAS improvement criteria for ankylosing spondylitis with clinically relevant improvement according to an expert panel.

OBJECTIVE: To investigate whether the recently developed (statistically derived) "ASsessment in Ankylosing Spondylitis Working Group" improvement criteria (ASAS-IC) for ankylosing spondylitis (AS) reflect clinically relevant improvement according to the opinion of an expert panel. METHODS: The ASAS-IC consist of four domains: physical function, spinal pain, patient global assessment, and inflammation. Scores on these four domains of 55 patients with AS, who had participated in a non-steroidal anti-inflammatory drug efficacy trial, were presented to an international expert panel (consisting of patients with AS and members of the ASAS Working Group) in a three round Delphi exercise. The number of (non-)responders according to the ASAS-IC was compared with the final consensus of the experts. The most important domains in the opinion of the experts were identified, and also selected with discriminant analysis. A number of provisional criteria sets that best represented the consensus of the experts were defined. Using other datasets, these clinically derived criteria sets as well as the statistically derived ASAS-IC were then tested for discriminative properties and for agreement with the end of trial efficacy by patient and doctor. RESULTS: Forty experts completed the three Delphi rounds. The experts considered twice as many patients to be responders than the ASAS-IC (42 v 21). Overall agreement between experts and ASAS-IC was 62%. Spinal pain was considered the most important domain by most experts and was also selected as such by discriminant analysis. Provisional criteria sets with an agreement of >or=80% compared with the consensus of the experts showed high placebo response rates (27-42%), in contrast with the ASAS-IC with a predefined placebo response rate of 25%. All criteria sets and the ASAS-IC discriminated well between active and placebo treatment (chi(2)=36-45; p<0.001). Compared with the end of trial efficacy assessment, the provisional criteria sets showed an agreement of 71-82%, sensitivity of 67-83%, and specificity of 81-88%. The ASAS-IC showed an agreement of 70%, sensitivity of 62%, and specificity of 89%. CONCLUSION: The ASAS-IC are strict in defining response, are highly specific, and consequently show lower sensitivity than the clinically derived criteria sets. However, those patients who are considered as responders by applying the ASAS-IC are acknowledged as such by the expert panel as well as by patients' and doctors' judgments, and are therefore likely to be true responders.

Staging of patients with ankylosing spondylitis: a preliminary proposal.

Patients with ankylosing spondylitis (AS) are characterised by a wide range of clinical presentations, radiographic profiles, and outcomes, which are not well differentiated by current diagnostic and classification systems for the disorder. Inadequacies in these systems may limit clinicians' ability to manage their patients with AS appropriately and act as an obstacle to reasonable comparison of therapeutic trial results. A standardised staging system for AS is therefore proposed that would provide a more detailed categorisation of patients based on assessment of structural damage, peripheral joint and organ involvement, presence of concomitant diseases, and the severity and extent of disease activity and functional impairment. The proposed system needs to be evaluated closely and amended as needed to assure its usefulness in clinical and research settings.