Administrative database as a source for assessment of systemic lupus erythematosus prevalence: Estonian experience.

BACKGROUND: Administrative database research is widely applied in the field of epidemiology. However, the results of the studies depend on the type of database used and the algorithms applied for case ascertainment. The optimal methodology for identifying patients with rheumatic diseases from administrative databases is yet not known. Our aim was to describe an administrative database as a source for estimation of epidemiological characteristics on an example of systemic lupus erythematosus (SLE, ICD-10 code M32) prevalence assessment in the database of the Estonian Health Insurance Fund (EHIF). METHODS: Code M32 billing episodes were extracted from the EHIF database 2006-2010. For all cases where M32 was assigned by a rheumatologist less than four times during the study period, diagnosis verification process using health care providers' (HCP) databases was applied. For M32 cases assigned by a rheumatologist four times or more, diagnoses were verified for a randomly selected sample. RESULTS: From 677 persons with code M32 assigned in EHIF database, 404 were demonstrated having "true SLE". The code M32 positive predictive value (PPV) for the whole EHIF database was 60%; PPV varies remarkably by specialty of a physician and repetition of the code assignment. The false positive M32 codes were predominantly initial diagnoses which were not confirmed afterwards; in many cases, a rheumatic condition other than SLE was later diagnosed. CONCLUSIONS: False positive codes due to tentative diagnoses may be characteristic for conditions with a complicated diagnosis process like SLE and need to be taken into account when performing administrative database research.

Validity of the rheumatoid arthritis impact of disease (RAID) score and definition of cut-off points for disease activity states in a population-based European cohort of patients with rheumatoid arthritis.

OBJECTIVES: To assess the validity of the rheumatoid arthritis impact of disease (RAID) for measuring disease activity of rheumatoid arthritis (RA) and to determine cut-off values for defining the disease activity states. METHODS: A total of 622 RA patients from an European database have been included. Cross-validation was based on assessment of convergent and discriminant validity. Optimal cut-offs were determined against external criteria by calculating the respective 25th and 75th percentiles mean values of RAID. External criteria included definitions for remission (REM), low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA), cut-offs of the 28-joint disease activity score-C-reactive protein (DAS28-CRP) score. RESULTS: The RAID showed a moderate degree of correlation with respect to DAS28-CRP (rho=0.417; P<0.0001). The receiver operating characteristic (ROC) curves to discriminate the ability of RAID to distinguish patients with active and non-active disease was very good with an area under the curve (AUC) of 0.847 (95% confidence interval [CI]: 0.816 to 0.878; P<0.0001). Based on the distributions of RAID in the different disease activity groups, we propose the following cut-off values for REM: RAID ≤3; for LDA: RAID >3 and ≤4; for MDA: RAID >4 and ≤6; for HDA: RAID >6. Mean RAID differed significantly between patients classified as REM, LDA, MDA or HDA (P=0.001). CONCLUSIONS: The cut-offs revealed good measurement characteristics in cross-validation analysis, had great discriminatory performance in distinguishing patients with different levels of disease activity and are suited for widespread use in everyday practice application and research.

European multicentre pilot survey to assess vitamin D status in rheumatoid arthritis patients and early development of a new Patient Reported Outcome questionnaire (D-PRO).

OBJECTIVE: To collect data on vitamin D (25(OH)D) serum levels in a large number of rheumatoid arthritis (RA) patients from different European countries, to investigate their relation with disease activity, disability, quality of life, and possibly to construct a new Patient Reported Outcome (PRO) questionnaire in order to self-estimate if they are at risk for vitamin D insufficiency/deficiency-related clinical implications (D-PRO). METHODS: This was a European League Against Rheumatism (EULAR) supported cross-sectional study (project No CLI064) which involved 625 RA patients (mean age 55±11years, mean disease duration 11±9years), 276 age and sex matched healthy subjects, and rheumatologists working in academic institutions or hospital centres, as well as PARE organizations (patient representatives) from 13 European countries. Serum samples for 25(OH)D level measurement were collected during winter time and analyzed in a central laboratory using chemiluminescence immunoassay (DiaSorin). Patient past medical history was recorded. RA patients were provided with three questionnaires: the Rheumatoid Arthritis Impact Diseases score (RAID), the Health Assessment Questionnaire (HAQ), and the new D-PRO questionnaire at the time of 25(OH)D serum sampling. D-PRO questionnaire consisted of three domains, Symptom Risk Score (SRS), Habitus Risk Score (HRS) and Global Risk Score (SRS+HRS=GRS), constructed with items possibly related to vitamin D deficiency. D-PRO was correlated with both clinical and PRO scores. DAS28-CRP was also evaluated. Statistical analysis was performed by non parametric tests. RESULTS: Mean serum concentration of 25(OH)D in RA patients (17.62±9.76ng/ml) was found significantly lower if compared to the levels obtained in matched controls (18.95±9.45ng/ml) (p=0.01), with statistically significant differences among several European countries. Negative correlations were found between 25(OH)D serum levels and DAS28-CRP (p<0.001), RAID (p=0.05) and HAQ (p=0.04) scores in the RA patients group. Negative correlations were also found in the cohort of enrolled RA patients between 25(OH)D serum concentrations and SRS (p=0.04), HRS (p=0.02) and GRS (p=0.02) domains of the D-PRO questionnaire. CONCLUSIONS: This first multicentre European survey add new evidences that vitamin D insufficiency/deficiency is frequent in RA patients with statistically significant differences among several countries. Vitamin D serum concentrations seem to correlate negatively and significantly with the D-PRO Global Risk Score, clinimetric indexes for quality of life, disease activity and disability in present cohort of RA European patients.

Determinants of Patient-Physician Discordance in Global Assessment in Psoriatic Arthritis: A Multicenter European Study.

OBJECTIVE: Patient-physician discordance in global assessment of disease activity concerns one-third of patients, but what does it reflect? We aimed to assess patient-physician discordance in psoriatic arthritis (PsA) and patient-reported domains of health (physical and psychological) associated with discordance. METHODS: We analyzed the PsAID (Psoriatic Arthritis Impact of Disease), a cross-sectional, multicenter European study of patients with PsA according to expert opinion. Patient global assessment (PGA) and physician global assessment (PhGA) were rated on a 0-10 numeric rating scale. Discordance was defined as the difference (PGA-PhGA) and as the absolute difference |PGA-PhGA| ≥3 points. Determinants of PGA-PhGA were assessed by a stepwise multivariate linear regression among 12 physical and psychological aspects of impact: pain, skin problems, fatigue, ability to work/leisure, functional incapacity, feeling of discomfort, sleep disturbance, anxiety/fear, coping, embarrassment/shame, social participation, and depressive affects. RESULTS: In 460 patients (mean ± SD age 50.6 ± 12.9 years, 52.2% female, mean ± SD disease duration 9.5 ± 9.5 years, mean ± SD Disease Activity Index for Psoriatic Arthritis score 30.8 ± 32.4, and 40.4% undergoing treatment with biologic agents), the mean ± SD PGA was higher than the mean PhGA, with a mean absolute difference of 1.9 ± 1.8 points. Discordance defined by |PGA-PhGA| ≥3 of 10 concerned 134 patients (29.1%), and 115 patients (85.8% of the patients with discordance) had PGA>PhGA. Higher fatigue (ß = 0.14), lower self-perceived coping (ß = 0.23), and impaired social participation (ß = 0.16) were independently associated with a higher difference (PGA-PhGA). CONCLUSION: Discordance concerned 29.1% of these patient/physician dyads, mainly by PGA>PhGA. Factors associated with discordance were psychological rather than physical domains of health. Discordance was more frequent in patients in remission, indicating more work is needed on the patient perspective regarding disease activity.

Associations Between Five Important Domains of Health and the Patient Acceptable Symptom State in Rheumatoid Arthritis and Psoriatic Arthritis: A Cross-Sectional Study of 977 Patients.

OBJECTIVE: To explore the link between a patient acceptable symptom state (PASS) and patient-perceived impact in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). METHODS: This was a cross-sectional study of unselected patients with definite RA or PsA. Pain, functional capacity, fatigue, coping, and sleep disturbance were assessed using a numeric rating scale (0-10) and compared between patients in PASS or not (Cohen's effect sizes). The domains of health associated with PASS status were assessed by multivariate forward logistic regression, and PASS thresholds were determined using the 75th percentile method and receiver operating characteristic analyses. RESULTS: Among 977 patients (531 with RA, 446 with PsA), the mean ± SD age was 53.4 ± 13.2 years, mean ± SD disease duration was 11.2 ± 10.0 years, and 637 (65.8%) were women. In all, 595 patients (60.9%) were in PASS; they had lower symptom levels, and all domains of health except sleep disturbance discriminated clearly between patients in PASS or not (effect sizes 0.73-1.45 in RA and 0.82-1.52 in PsA). In multivariate analysis, less pain and better coping were predictive of being in PASS. Odds ratios were: RA pain 0.80 (95% confidence interval [95% CI] 0.67-0.96), PsA pain 0.63 (95% CI 0.52-0.75), RA coping 0.84 (95% CI 0.74-0.96), and PsA coping 0.83 (95% CI 0.71-0.97). The cutoffs of symptom intensity (range 0-10), corresponding to PASS for the 5 domains of health and the 2 diseases were similar, i.e., approximately 4-5. CONCLUSION: In RA and PsA, PASS was associated with the 5 domains of health analyzed, and in particular with less pain and better coping.

Fatigue in psoriatic arthritis - a cross-sectional study of 246 patients from 13 countries.

OBJECTIVES: Fatigue is an aspect of psoriatic arthritis (PsA), which is important to patients. The objective was to evaluate magnitude of fatigue in PsA patients and to assess factors that might explain high levels of fatigue. METHODS: This was an ancillary analysis of a cross-sectional study in 13 countries of unselected PsA patients who fulfilled the CASPAR criteria. Patient-perceived importance of fatigue was assessed through a priority exercise. Levels of fatigue were assessed by a numeric rating scale (range 0-10). Factors potentially associated with fatigue>5/10: i.e., demographic variables (age, gender, disease duration, education level) and disease related characteristics including joint counts, C-reactive protein, skin psoriasis, axial involvement, enthesitis, dactylitis, structural damage, were assessed by univariate, multivariate logistic and multiple linear regression. RESULTS: In all, 246 patients were analysed: mean±standard deviation age 51.2±13.0years, mean disease duration 9.9±10.1years, mean DAS28 3.5±1.3. Fatigue was ranked second in patient-perceived importance, after pain. Magnitude of fatigue was high: mean fatigue 5.0±3.0. Fatigue>5/10 was well explained (variance explained 73%) by skin psoriasis (odds ratio 4.67 [95% confidence interval 1.05; 20.72]), tender joints (1.30 [1.01; 1.68]) and lower education level (1.09 [1.02; 1.23]). In the multiple linear regression model, fatigue was explained by skin psoriasis, tender joints, enthesitis, female gender, education level. CONCLUSIONS: Fatigue is a priority for PsA patients. Fatigue levels were high in these patients and fatigue>5/10 was mainly associated with disease-related factors but also patient-related variables, indicating that the etiology of fatigue in PsA is multifactorial.

Patient global assessment in psoriatic arthritis - what does it mean? An analysis of 223 patients from the Psoriatic arthritis impact of disease (PsAID) study.

OBJECTIVE: Patient global assessment is a key outcome measure in psoriatic arthritis. To explore the meaning of patient global assessment in psoriatic arthritis by examining associations to domains of health assessed by the Psoriatic arthritis impact of disease score. METHODS: Post-hoc analysis of a multicentre cross-sectional study of patients with psoriatic arthritis. Data collection included patient global assessment, specific joint and skin global patient assessments, Psoriatic arthritis impact of disease questions covering physical (including joints and skin), psychological and social impact, and other comparator outcomes. Univariate analyses (Pearson correlation) and multivariate linear regression were performed to explain patient global assessment and the specific joint and skin global patient assessments. RESULTS: Among 223 patients (mean age: 51.0 [standard deviation, ±13.3] years; mean disease duration: 9.9 [±10.1] years; mean swollen joint count: 4.1 [±5.1]; 84.3% with current psoriasis [mainly of less than 5% body surface area]), 50.2% were females. Mean patient global assessment was 4.8 (±2.7), mean joint and skin patient assessments were respectively 5.6 (±2.5) and 4.1 (±3.0). Intraclass correlation between patient global assessment and joint or skin patient assessment was respectively 0.71 (95% confidence interval, 0.64-0.77) and 0.52 (95% confidence interval, 0.42-0.60). In multivariate analyses, patient global assessment was explained (R(2) of model: 0.754) by coping (ß = 0.287); pain (ß = 0.240); work and/or leisure activities (ß = 0.141); and anxiety (ß = 0.109). CONCLUSIONS: Patient global assessment in psoriatic arthritis was explained mainly by physical, but also psychological aspects of the disease.

MRI assessment of suppression of structural damage in patients with rheumatoid arthritis receiving rituximab: results from the randomised, placebo-controlled, double-blind RA-SCORE study.

OBJECTIVE: To evaluate changes in structural damage and joint inflammation assessed by MRI following rituximab treatment in a Phase 3 study of patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) who were naive to biological therapy. METHODS: Patients were randomised to receive two infusions of placebo (n=63), rituximab 500 mg (n=62), or rituximab 1000 mg (n=60) intravenously on days 1 and 15. MRI scans and radiographs of the most inflamed hand and wrist were acquired at baseline, weeks 12 (MRI only), 24 and 52. The primary end point was the change in MRI erosion score from baseline at week 24. RESULTS: Patients treated with rituximab demonstrated significantly less progression in the mean MRI erosion score compared with those treated with placebo at weeks 24 (0.47, 0.18 and 1.60, respectively, p=0.003 and p=0.001 for the two rituximab doses vs placebo) and 52 (-0.30, 0.11 and 3.02, respectively; p<0.001 and p<0.001). Cartilage loss at 52 weeks was significantly reduced in the rituximab group compared with the placebo group. Other secondary end points of synovitis and osteitis improved significantly with rituximab compared with placebo as early as 12 weeks and improved further at weeks 24 and 52. CONCLUSIONS: This study demonstrated that rituximab significantly reduced erosion and cartilage loss at week 24 and week 52 in MTX-inadequate responder patients with active RA, suggesting that MRI is a valuable tool for assessing inflammatory and structural damage in patients with established RA receiving rituximab. TRIAL REGISTRATION NUMBER: NCT00578305.

A patient-derived and patient-reported outcome measure for assessing psoriatic arthritis: elaboration and preliminary validation of the Psoriatic Arthritis Impact of Disease (PsAID) questionnaire, a 13-country EULAR initiative.

INTRODUCTION: The objective was to develop a questionnaire that can be used to calculate a score reflecting the impact of psoriatic arthritis (PsA) from the patients' perspective: the PsA Impact of Disease (PsAID) questionnaire. METHODS: Twelve patient research partners identified important domains (areas of health); 139 patients prioritised them according to importance. Numeric rating scale (NRS) questions were developed, one for each domain. To combine the domains into a single score, relative weights were determined based on the relative importance given by 474 patients with PsA. An international cross-sectional and longitudinal validation study was performed in 13 countries to examine correlations of the PsAID score with other PsA or generic disease measures. Test-retest reliability and responsiveness (3 months after a treatment change) were examined in two subsets of patients. RESULTS: Two PsAID questionnaires were developed with both physical and psychological domains: one for clinical practice (12 domains of health) and one for clinical trials (nine domains). Pain, fatigue and skin problems had the highest relative importance. The PsAID scores correlated well with patient global assessment (N=474, Spearman r=0.82-0.84), reliability was high in stable patients (N=88, intraclass correlation coefficient=0.94-0.95), and sensitivity to change was also acceptable (N=71, standardised response mean=0.90-0.91). CONCLUSIONS: A questionnaire to assess the impact of PsA on patients' lives has been developed and validated. Two versions of the questionnaire are available, one for clinical practice (PsAID-12) and one for clinical trials (PsAID-9). The PsAID questionnaires should allow better assessment of the patient's perspective in PsA. Further validation is needed.

Vitamin D in rheumatoid arthritis.

The discovery of the vitamin D receptor (VDR) in the cells of the immune system and the fact that activated dendritic cells produce the vitamin D hormone suggested that vitamin D could have immunoregulatory properties. VDR, a member of the nuclear hormone receptor superfamily, was identified in mononuclear cells, dendritic cells, antigen-presenting cells, and activated T-B lymphocytes. In synthesis, the most evident effects of the D-hormone on the immune system seem to be in the downregulation of the Th1-driven autoimmunity. Low serum levels of vitamin D3 might be partially related, among other factors, to prolonged daily darkness (reduced activation of the pre vitamin D by the ultra violet B sunlight), different genetic background (i.e. vitamin D receptor polymorphism) and nutritional factors, and explain to the latitute-related prevalence of autoimmune diseases such as rheumatoid arthritis (RA), by considering the potential immunosuppressive roles of vitamin D. 25(OH)D3 plasma levels have been found inversely correlated at least with the RA disease activity showing a circannual rhythm (more severe in winter). Recently, greater intake of vitamin D was associated with a lower risk of RA, as well as a significant clinical improvement was strongly correlated with the immunomodulating potential in vitamin D-treated RA patients.

Circadian rhythms: glucocorticoids and arthritis.

Circadian rhythms are driven by biological clocks and are endogenous in origin. Therefore, circadian changes in the metabolism or secretion of endogenous glucocorticoids are certainly responsible in part for the time-dependent changes observed in the inflammatory response and arthritis. More recently, melatonin (MLT), another circadian hormone that is the secretory product of the pineal gland, has been found implicated in the time-dependent inflammatory reaction with effects opposite those of cortisol. Interestingly, cortisol and MLT show an opposite response to the light. The light conditions in the early morning have a strong impact on the morning cortisol peak, whereas MLT is synthesized in a strictly nocturnal pattern. Recently, a diurnal rhythmicity in healthy humans between cellular (Th1 type) or humoral (Th2 type) immune responses has been found and related to immunomodulatory actions of cortisol and MLT. The interferon (IFN)-gamma/interleukin (IL)-10 ratio peaked during the early morning and correlated negatively with plasma cortisol and positively with plasma MLT. Accordingly, the intensity of the arthritic pain varies consistently as a function of the hour of the day: pain is greater after waking up in the morning than in the afternoon or evening. The reduced cortisol and adrenal androgen secretion, observed during testing in rheumatoid arthritis (RA) patients not treated with glucocoticoids, should be clearly considered as a "relative adrenal insufficiency" in the presence of a sustained inflammatory process, and allows Th1 type cytokines to be produced in higher amounts during the late night. In conclusion, the right timing (early morning) for the glucocorticoid therapy in arthritis is fundamental and well justified by the circadian rhythms of the inflammatory mechanisms.

Nocturnal hormones and clinical rhythms in rheumatoid arthritis.

It is well known that some clinical signs and symptoms of rheumatoid arthritis (RA) vary within a day and between days; the morning stiffness that is observed in patients who have RA has become one of the diagnostic criteria of the disease. The circadian changes in the metabolism or nocturnal secretion of endogenous corticosteroids is certainly responsible, in part, for the time-dependent changes that are observed in the inflammatory response and related clinical symptoms. More recently, melatonin (mLT), another circadian nocturnal hormone that is the secretory product of the pineal gland, has been implicated in time-dependent inflammatory reactions, with effects that are opposite of those of corticosteroids. Therefore, altered functioning of the hypothalamic-pituitary-adrenocortical axis (reduced corticosteroid production) and of the pineal gland (increased mLT production) found in RA patients seem to be important factors in the perpetuation and clinical circadian symptoms of the disease. Consistently, human proinflammatory Th1-type cytokine production (related to mLT stimulation) exhibits a diurnal rhythmicity, with peak levels during the night and early morning, at a time when plasma cortisol (inducing Th2-type cytokine production) is lowest and mLT is highest. Reduced daily light exposure as observed in northern Europe (Estonia), at least during the winter, might explain the higher and more prolonged mLT concentrations as well as some epidemiological features that are observed in northern European patients with RA versus southern European patients.