Initiating disease-modifying anti-rheumatic drugs rapidly reduces purchases of analgesic drugs in juvenile idiopathic arthritis.

Objective: To describe the use of analgesics 12 months before and after initiation of the first disease-modifying anti-rheumatic drug (DMARD) in children with juvenile idiopathic arthritis (JIA). Method: A register-based study linked three nationwide registers in Finland: the Register on Reimbursement for Prescription Medicines, the Drug Purchase Register (both maintained by the Finnish Social Insurance Institution), and the Finnish Population Register. The study ran from 1 January 2010 to 31 December 2014. It included 1481 patients aged < 16 years with diagnosed JIA and 4511 matched controls. Index day was the date when reimbursement for JIA medication was approved and treatment was initiated. The study period included 12 months pre- and post-index date, and purchases of prescription drugs were assessed for 3 month periods. Results: Non-steroidal anti-inflammatory drugs (NSAIDs) were purchased for 60% of the patients. Compared to controls, NSAID purchases for JIA patients were at their highest during the last 3 months before the index day [relative rate (RR) 21.2, 95% confidence interval (CI) 17.1-26.2], and they decreased steeply over the 10-12 months post-index (RR 4.0, 95% CI 3.1-5.0). Similar trends were seen with paracetamol and opioid purchases, but only 2% of patients purchased opioids during the 12 months pre-index and 1% during the 12 months post-index. Methotrexate was the most commonly used DMARD (91.9%), biologic DMARDs were used by 2.8% and glucocorticoids by 24.8% in the 3 months after the index day. Conclusion: Initiation of DMARDs rapidly reduces the need for analgesics in patients with JIA.

Drugs used in incident systemic lupus erythematosus - results from the Finnish nationwide register 2000-2007.

The objectives of the study were to examine the initial, first-year anti-rheumatic outpatient therapy in patients with incident SLE, as well as the concomitant use of drugs for certain comorbidities, compared to the use in the general population. The Finnish nationwide register data on special reimbursements for medication costs was screened to identify the inception cohort of 566 adult SLE patients (87% females, mean age 46.5 ± 15.9 years) over the years 2000-2007. The patients were linked to the national Drug Purchase Register. Of those, 90% had purchased at least once some disease-modifying anti-rheumatic drugs (DMARDs) during the first year. Hydroxychloroquine was the most common (76%), followed by azathioprine (15%) and methotrexate (13%). With the exception of increase in mycophenolate mofetil, the proportions remained stable over the whole study period 2000-2007. Drugs for cardiovascular diseases, dyslipidemia, diabetes mellitus, hypothyroidism and obstructive pulmonary disease were more frequently purchased than in the sex- and age-adjusted population, with rate ratios ranging from 1.6 to 7.8. Over the years 2000-2007, almost all the patients with incident SLE in Finland started with a DMARD. Higher percentages of SLE patients were on medication for several common chronic diseases than in the population as a whole.

Impact of physicians' adherence to treat-to-target strategy on outcomes in early rheumatoid arthritis in the NEO-RACo trial.

OBJECTIVES: It is well recognized that medication adherence of rheumatoid arthritis (RA) patients is often poor. As less attention has been paid to physicians' adherence to targeted treatment, we aimed to investigate how it affects outcomes in aggressively treated early RA patients. METHOD: In the new Finnish RA Combination Therapy (NEO-RACo) trial, 99 patients with early active RA were treated, targeting remission, with a combination of methotrexate, sulfasalazine, hydroxychloroquine, and low-dose prednisolone for 2 years, and randomized to receive infliximab or placebo for the initial 6 months. After 2 years, therapy was unrestricted while remission was still targeted. Patients were divided into tertiles by physicians' adherence to treat-to-target, which was evaluated with a scoring system during the initial 2 years. After 5 years of follow-up, the between-tertile differences in remission rates, 28-joint Disease Activity Score (DAS28) levels, radiological changes, cumulative days off work, and the use of anti-rheumatic medication were assessed. RESULTS: Follow-up data were available for 93 patients. Physicians' good adherence was associated with improved remission rates at 2-4 years and lower DAS28 levels throughout the follow-up. In a multivariable model, physicians' adherence was the most important predictor of remission at 3 months and 2 years (p < 0.001 for both). Between 2 and 5 years, biologics were used more often in the tertile of low adherence compared with the other two groups (p = 0.024). No significant differences were observed in radiological progression and cumulative days off work. CONCLUSIONS: Physicians' good adherence is associated with improved remission rates and lesser use of biologics in early RA.

Psychiatric and cardiovascular comorbidities as causes of long-term work disability among individuals with recent-onset rheumatoid arthritis.

OBJECTIVES: With the ameliorating prognosis of rheumatoid arthritis (RA), the role of comorbidities as causes of work disability (WD) may increase. The aim of this study was to determine the contribution of psychiatric and cardiovascular (CV) comorbidities as the leading causes of long-term WD among patients with recent-onset RA. METHOD: Between 2000 and 2007, all incident, working-age and non-retired RA patients were identified from a Finnish nationwide register. From other registers, we identified the RA patients who were granted a permanent or temporary disability pension by 31 December 2008. The incidences of disability pensions with CV diseases (ICD-10 codes I00-I99) or psychiatric disorders (F20-F69) as the leading causes were assessed and compared with the general population. RESULTS: We identified a cohort of 7831 patients with RA. During follow-up, 1095 patients were granted a disability pension. After adjusting for competing risks, the 9-year cumulative incidence of WD caused by RA, a psychiatric comorbidity, or a CV disease was 11.9, 1.3, and 0.5%, respectively. Compared to the general population, the age- and sex-specific standardized incidence ratio (SIR) of WD due to psychiatric comorbidities was 0.99 [95% confidence interval (CI) 0.80-1.23] and due to CV disease 1.75 (95% CI 1.23-2.51). CONCLUSIONS: In the study cohort with recent-onset RA, the 9-year cumulative incidence of disability pensions caused by psychiatric or CV comorbidities was only 11% or 4%, respectively, of that caused by RA itself. Compared to the general population, the risk of WD due to CV disease was increased.

Mortality and causes of death among incident cases of systemic lupus erythematosus in Finland 2000-2008.

The objectives of the study were to investigate mortality and causes of death in patients with recent-onset systemic lupus erythematosus (SLE) in Finland. Data for patients with SLE for the study were collected (2000-2007) from the nationwide register on decisions of special reimbursements for drugs, maintained by the Social Insurance Institution (SII) in Finland. Data on deaths of the patients were obtained from the official death certificate statistics of Statistics Finland until the end of 2008. Of the 566 incident SLE patients, median follow-up time was 5.4 (IQR 3.3, 7.1) years, and 30 patients (23 females, seven males) died in the years 2000 through 2008. Mean age at death was 67.8 ± 17.2 years for females and 62.3 ± 15.2 years for males. The 5-year survival rates were 94.8% (95%CI 92.0-96.6%) and 88.2% (95%CI 76.5-94.3%), respectively. The age- and sex-adjusted standardized mortality ratio was 1.48 (95%CI 1.01-2.12). Primary causes of death were cardiovascular diseases, malignancy and SLE itself. In conclusion, survival of the patients with SLE was inferior to that of the general population. Cardiovascular diseases were responsible for 37% of deaths.

Antidepressant use among persons with recent-onset rheumatoid arthritis: a nationwide register-based study in Finland.

OBJECTIVES: The aim of this study was to investigate antidepressant use in a nationwide cohort of persons with incident rheumatoid arthritis (RA) in 2000-2007 in Finland. METHOD: Register data from the Social Insurance Institution of Finland were used to evaluate antidepressant use in ≥ 50-year-old incident RA patients (n = 10,356) and the same-age general population. RESULTS: Of the RA patients, 10.0% (n = 1034) had used antidepressants during the year preceding RA diagnosis. The cumulative incidence of antidepressant initiations after RA diagnosis was 11.4% [95% confidence interval (CI) 10.0-12.9] for men and 16.2% (95% CI 14.9-17.5) for women at the end of follow-up (mean 4.4 years). Female gender [age-adjusted hazard ratio (HR) 1.39, 95% CI 1.21-1.60] and increasing number of comorbidities (p for linearity < 0.001) predicted antidepressant initiations. In the last follow-up year, antidepressant use was at the same level among men with RA [prevalence rate ratio (PRR) 0.93, 95% CI 0.82-1.06] but lower among women (PRR 0.89, 95% CI 0.83-0.95) when compared to the general population. CONCLUSIONS: Antidepressant initiations in early RA were associated with female gender and comorbidity. Although depression is stated to be a sizeable problem in RA, the prevalence of antidepressant use did not exceed the population level.

Cost-effectiveness modelling of sequential biologic strategies for the treatment of moderate to severe rheumatoid arthritis in Finland.

OBJECTIVE: The main objective was to compare the cost-effectiveness of therapeutic options in moderate or severe rheumatoid arthritis (RA) when a clinical response to a first TNF-blocker, either etanercept (ETA), adalimumab (ADA), or infliximab (INF), is insufficient. METHODS: Effectiveness criteria were defined as remission (RS), low disease activity (LDAS), and moderate to high disease activity (MHDAS). Cost-effectiveness was derived as cost per day in RS and in LDAS using simulation modelling to assess six sequential biologic strategies over 2 years. Each sequential treatment strategy was composed of three biologic agents and included a first anti-TNF agent, ETA, ADA or INF, followed by either abatacept (ABA) or rituximab (RTX) as a second therapeutic option in case of an insufficient response, followed by another anti-TNF agent in case of further insufficient response. RESULTS: Over two years and taking into account biologic costs, the following estimated mean costs per day in RS and LDAS were respectively of €829 and €428 for the biologic sequence composed of ADA-ABA-ETA, €1292 and €516 for the sequence ADA-RTX-ETA, €829 and €429 for the sequence ETA-ABA-ADA, €1292 and €517 for the sequence ETARTX- ADA, €840 and €434 for the sequence INF-ABA-ETA, and €1309 and €523 for the sequence INF-RTX-ETA. CONCLUSION: The treatment sequences including ABA as the second biologic option appear more cost-effective than those including RTX in a patients with moderate to severe RA and an insufficient response to a first anti-TNF agent.

Cost-effectiveness of adalimumab, etanercept, and tocilizumab as first-line treatments for moderate-to-severe rheumatoid arthritis.

OBJECTIVE: The aim of this study was to assess the cost-utility and value of reducing the uncertainty associated with the decision to use first-line biologic treatment (bDMARD) after the failure of one or more traditional drugs (tDMARD) in moderate-to-severe rheumatoid arthritis (msRA) in Finland. RESEARCH DESIGN AND METHODS: The treatment sequences were compared among 3000 hypothetical Finnish msRA patients using a probabilistic microsimulation model in a lifetime scenario. Adalimumab + methotrexate, etanercept + methotrexate, or tocilizumab + methotrexate were used as first biologics followed by rituximab + methotrexate and infliximab + methotrexate. Best supportive care (BSC), including tDMARDs, was assumed to be used after the exhaustion of the biologics. Methotrexate alone was added as a further comparator. Efficacy was based on ACR responses that were obtained from a mixed treatment comparison. The resources were valued with Finnish unit costs (year 2010) from the healthcare payer perspective. Additional analyses were carried out, including productivity losses. The Health Assessment Questionnaire (HAQ) values were mapped to the EQ-5D values using the tocilizumab trials; 3% annual discounting for costs and quality-adjusted life years (QALY) and extensive sensitivity analyses were completed. MAIN OUTCOME MEASURES: Incremental cost per QALY gained and multinomial expected value of perfect information (mEVPI). RESULTS: bDMARDs significantly increase the QALYs gained when compared to methotrexate alone. Tocilizumab + methotrexate was more cost-effective than adalimumab + methotrexate or etanercept + methotrexate in comparison with methotrexate alone, and adalimumab + methotrexate was dominated by etanercept + methotraxate. A QALY gained with retail-priced (wholesale-priced) tocilizumab + methotrexate costs €18,957 (€17,057) compared to methotrexate alone. According to the cost-effectiveness efficiency frontier and cost-effectiveness acceptability frontier (CEAF), tocilizumab + methotrexate should be considered before rituximab + methotrexate, infliximab + methotrexate, and BSC. Based on the CEAF, tocilizumab + methotrexate had a 60-93% probability of being cost-effective with €20,000 per QALY gained (mEVPI €230-2182). CONCLUSIONS: Tocilizumab + methotrexate is a potentially cost-effective bDMARD treatment for msRA, indicating a low value of additional research information with the international threshold values. LIMITATIONS: Efficacy based on an indirect comparison (certolizumab pegol, golimumab excluded), fixed treatment sequence after the exhaustion of first bDMARD, Swedish resource use data according to HAQ scores, and inpatient costs assumed to include surgery.

Trends in treatment strategies and the usage of different disease-modifying anti-rheumatic drugs in early rheumatoid arthritis in Finland. Results from a nationwide register in 2000-2007.

OBJECTIVES: To determine which disease-modifying anti-rheumatic drugs (DMARDs) are currently used by Finnish rheumatologists to treat early rheumatoid arthritis (RA). METHODS: Information on sex, date of birth, and date of special medicine reimbursement decision for all new RA patients was collected from a nationwide register maintained by the Social Insurance Institution (SII) during the time period from 1 January 2000 to 31 December 2007. Patient cohorts were registered in 2-year time periods (2000-01, 2002-03, 2004-05, 2006-07) and DMARDs purchased by the patient cohorts during the first year after the date of reimbursement decision for RA were registered. The frequencies of early drug treatment strategies (combination of DMARDs, single DMARD, or no DMARDs) were evaluated. RESULTS: A total of 14 878 (68.0% female, 62.6% rheumatoid factor (RF)-positive) patients were identified. Between 2000 and 2001 the most commonly used treatment strategy for early RA during the first 3 months was single DMARD treatment (56.1%) and the most commonly used DMARD during the first year was sulfasalazine (63.0%), while between 2006 and 2007 the respective treatments were combination DMARDs (55.3%) and methotrexate (69.0%). The change in treatment strategies as well as in DMARDs used was highly significant (p < 0.001 for linearity). At the end of the study period only 4.9% of the patients with early RA were not receiving DMARDs during the first 3 months. CONCLUSIONS: Currently, combination therapy including methotrexate is the most commonly prescribed treatment strategy for early RA in Finland. In recent years, an increasing number of active drug treatments have been taken into practice.

A mismatch between self-reported physical work load and the HAQ: early identification of rheumatoid arthritis patients at risk for loss of work productivity.

OBJECTIVE: To explore the combination of data on functioning and work load for early identification of patients at risk for diminished work productivity in rheumatoid arthritis (RA). PATIENTS AND METHODS: In the FIN-RACo trial, 162 patients with recent onset RA and available for the workforce were treated with either a combination of disease-modifying antirheumatic drugs (DMARDs) or a single DMARD for 2 years. Otherwise, they received routine care and were followed up for 5 years. Data on their individual income and lost work days came from official registers. Loss of productivity was computed by the human capital approach. Self-reported data on physical work demand (Finnish Institute for Occupational Health Questionnaire) at baseline and on functioning (HAQ) at 6 months were linked according to the International Classification of Functioning, Disability and Health. RESULTS: Data on 112 patients were analyzable at 6 months; 35 (31%) of them had diminished capacity in functions required at paid work. Any mismatch between perceived abilities and requirements predicted future (7 through 60 months) loss of productivity - on average Euro 14,040 (95% confidence interval (CI): 9,143-20,511) per year in patients with the mismatch compared to Euro 3,043 (1,623-5,534) in those without any mismatch - and was associated with RA-related permanent work disability (hazard ratio: 11.6; 95%CI: 4.0-33.4). CONCLUSION: Linking together self-reported data about functioning and work load helps in early identification of the RA patients at risk for loss of working days.

Early improvement of health-related quality of life during treatment with etanercept and adalimumab in patients with rheumatoid arthritis in routine practice.

OBJECTIVES: To assess health-related quality of life (HRQoL) in patients with rheumatoid arthritis (RA) treated with etanercept or adalimumab in routine clinical practice. METHODS: Patients with RA who started etanercept or adalimumab at Helsinki University Central Hospital or Lappeenranta Central Hospital during 2003-2006 were asked to participate in the study. In 97 patients, HRQoL was measured by the RAND 36-Item Health Survey 1.0 (RAND-36) at baseline and after three months of the treatment. HRQoL of the RA patients was compared to the Finnish age- and sex-matched general population values. In addition, changes in clinical parameters and disability index measured by the health assessment questionnaire (HAQ) were recorded. RESULTS: Treatment with etanercept and adalimumab increased the values in all domains of the RAND-36 during the first three months in routine practice. The improvement in both groups was statistically significant: with etanercept p=0.041 and with adalimumab p=0.019. The efficacy of etanercept and adalimumab in improving HRQoL during the first three months was comparable. The patients reported their best improvement in the subscales of bodily pain, role functioning/physical, energy, social functioning, and role functioning/emotional. Compared to the Finnish age- and sex-matched general population values, the HRQoL of the patients with RA was significantly lower at baseline and remained low at follow-up. The change in clinical parameters and the HAQ paralleled the improvement in HRQoL. CONCLUSION: Treatment of patients with RA with etanercept and adalimumab in routine clinical practice provides clinically important and statistically significant improvement in HRQoL already in the first three months.

Use of the Stanford Health Assessment Questionnaire in estimation of long-term productivity costs in patients with recent-onset rheumatoid arthritis.

OBJECTIVE: To evaluate the utility of the Stanford Health Assessment Questionnaire (HAQ) in the estimation of loss of productivity due to early rheumatoid arthritis (RA) and to develop a simple model for analysis of the cost-benefit of therapies. METHODS: In the Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) trial, 162 patients with recent-onset RA who were available for the workforce were randomized to receive either a combination of three disease-modifying anti-rheumatic drugs (DMARDs) or a single DMARD for 2 years and were followed up for 5 years. No biological drugs were used. Data on sick leave and RA-related disability pensions came from official register records. Loss of productivity was computed by both the human capital approach (HCA) and the friction cost approach (FCA). Functional capacity was assessed by the HAQ at baseline and at 6 months. RESULTS: Over 5 years, mean loss of productivity per year was EUR 8344 by the HCA and EUR 1928 by the FCA. The level of the HAQ index at 6 months, but not the change in HAQ from baseline, determined productivity costs. With the HCA, a monotonous association between annual loss of productivity and the 6-month HAQ was found: EUR 2087 [95% confidence interval (CI) 1340-2903] per one step (0.13) on the HAQ scale from 0 to 1.88. With the FCA, the increase in loss of productivity was cut at the HAQ level of 0.5 to 0.75 (EUR 17 740 in 5 years). CONCLUSION: The HAQ index at 6 months may serve as a determinant of long-term RA-related indirect costs in economic analyses in early RA.

Risk factors for back pain-related loss of working time after surgery for lumbar disc herniation: a 5-year follow-up study.

The aim of this study is to explore the occurrence and the risk factors of back-related loss of working time in patients undergoing surgery for lumbar disc herniation. One hundred and fifty-two gainfully employed patients underwent surgery for lumbar disc herniation. Two months postoperatively, those patients completed a self-report questionnaire including queries on back and leg pain (VAS), functional capacity (Oswestry disability index--ODI, version 1.0), and motivation to work. After 5 years, lost working time was evaluated by means of a postal questionnaire about sick leave and disability pensions. The cumulative number of back pain-related days-off work was calculated for each patient. All 152 patients, 86 men and 66 women, were prescribed sick leave for the first 2 months. Thereafter, 80 (53%) of them reported back pain-related sick leave or early retirement. A permanent work disability pension due to back problems was awarded to 15 (10%) patients, 5 men (6%) and 10 women (15%). Median number of all work disability days per year was 11 (interquartile range [IQR] 9-37); it was 9 days (IQR 9-22) in patients with minimal disability (ODI score 0-20) at 2 months postoperatively and 67 days (IQR 9-352) in those with moderate or severe disability (ODI > 20; P < 0.001). The respective means were 61, 29, and 140 days/year. Multivariate analysis showed ODI > 20, leg pain, and poor motivation to work to be the risk factors for extension of work disability. Results of the present study show that after the lumbar disc surgery, poor outcome in questionnaire measures the physical functioning (ODI) and leg pain at 2 months postoperatively, as well as poor motivation to work, are associated with the loss of working time. Patients with unfavourable prognosis should be directed to rehabilitation before the loss of employment.

Cost of Finnish statutory inpatient rehabilitation and its impact on functional and work capacity of patients with early rheumatoid arthritis: experience from the FIN-RACo trial.

OBJECTIVE: To explore the cost of the statutory inpatient rehabilitation system in Finland and its impact on the functional and work capacity of patients with early rheumatoid arthritis (RA). METHODS: In the Finnish Rheumatoid Arthritis Combination-Therapy trial (FIN-RACo), 195 patients with recent-onset RA, 162 of them available for the work force, were randomly assigned to two different drug treatment strategies for 2 years. Otherwise, the patients received routine multidisciplinary care and, if their functional or work capacity was endangered, were referred to inpatient rehabilitation. After a 5-year follow-up, data on rehabilitation, sick leave, and RA-related disability pensions were obtained from official registers. RESULTS: Of the 162 patients, 49 (30%) underwent inpatient rehabilitation at an average cost of EURO5400. The rehabilitated patients more often worked in white-collar jobs and had more pain and a worse Health Assessment Questionnaire (HAQ) score (1.0 vs. 0.78; p = 0.01) at baseline. Their HAQ scores remained higher throughout follow-up (p<0.001); no change appeared over inpatient periods [mean 0.01; 95% confidence interval (CI) -0.13 to 0.16]. No independent impact of rehabilitation on the HAQ score emerged in an adjusted generalized estimating equations (GEE) model (p = 0.55). Nor did any improvement in work capacity appear: average lost productivity (human capital approach) per patient-year was EURO10 155 (95% CI 6994-14 196) before and EUR 12 839 (95% CI 8589-19 139) after the start of rehabilitation. CONCLUSION: For patients with recent-onset RA, the Finnish statutory inpatient rehabilitation system had no positive impact on either functional or work capacity during the first few years, despite its considerable cost.

Remission as the treatment goal--the FIN-RACo trial.

The Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) trial is the first rheumatoid arthritis (RA) clinical trial in which remission served as the primary outcome measure. This chapter reviews the philosophical background, study design, and results of the FIN-RACo trial. The study showed that a third of patients with active early RA may achieve remission with a combination of methotrexate (MTX), sulfasalazine (SSZ), hydroxychloroquine (HCQ), and prednisolone.

Polymorphism at position +896 of the toll-like receptor 4 gene interferes with rapid response to treatment in rheumatoid arthritis.

The aim of this study was to determine whether the +896 A-->G substitution of the Toll-like receptor 4 (TLR4) gene, causing the Asp299-->Gly change in the extracellular domain of TLR4, influences treatment response in recent-onset rheumatoid arthritis. 169 patients with rheumatoid arthritis were genotyped from the Finnish Rheumatoid Arthritis Combination Therapy trial, in which they were treated either with only one disease-modifying antirheumatic drug (DMARD) with or without prednisolone (single group), or with three DMARDs and prednisolone (combination group). Patients homozygotic for the wild-type +896A allele were compared with those having the polymorphic G allele in terms of early clinical response (at 6 months) by the 28-joint Disease Activity Score (DAS28). 1 of 20 (5%; (95% (confidence interval (CI) 1 to 5)) patients of the single group with TLR4 +896AG or GG and 29 of 67 (43%; (95% CI 31 to 56)) patients with AA were in remission (p = 0.001). DAS28 of the single group with TLR4 +896AG or GG was higher than with AA (p = 0.019). In the combination group, remission rates and DAS28 values were comparable between the genotypes. The polymorphic TLR4 +896G allele may impair treatment response to single DMARD treatment in recent-onset rheumatoid arthritis.

Biological treatment in rheumatic diseases: results from a longitudinal surveillance: adverse events.

The objective of this study was to assess the long-term safety and tolerability of biologicals in a clinical setting. Data on adverse events (AEs) have been collected over a 5-year period by means of detailed reports sent in to the National Register of Biological Treatment in Finland (ROB-FIN) and validated by information collected by the National Agency for Medicines. Three hundred and eight reports on AEs were filed, concerning a total of 248 patients; this corresponds to 17% of all patients in the ROB-FIN register who started biological treatments. Skin reactions and infections comprised 35 and 28% of the AEs, respectively. Some cases of tuberculosis and other infections, heart failure and demyelinating conditions were seen. Our work demonstrates no unexpected AEs in a Finnish patient cohort consisting of rheumatoid arthritis and spondylarthropathy patients, although many of them were treated with combination treatments in common use in Finland. Biological treatment appears safe in the hands of the Finnish rheumatologists.