Summary Background Analysis of the Swedish Farmacotherapy (Swefot) trial at 12 months showed that the addition of an anti-tumour-necrosis-factor agent gave an improved clinical outcome compared with ...the addition of conventional disease-modifying antirheumatic drugs in patients with methotrexate-refractory early rheumatoid arthritis. Here we report the 2 year follow-up assessment. Methods In this randomised, non-blinded, parallel-group trial, we enrolled adult patients older than 18 years with rheumatoid arthritis and a symptom duration of less than 1 year from 15 rheumatology units in Sweden between December, 2002 and December, 2006. All patients were started on methotrexate. After 3–4 months, those who failed treatment were randomly assigned (1:1) to group A (conventional treatment; additional sulfasalazine and hydroxychloroquine) or group B (biological treatment; additional infliximab). Randomisation was done with a computer-generated sequence. We analysed clinical outcomes at months 18 and 24 by the response criteria of the American College of Rheumatology and the European League Against Rheumatism, and radiographs of patients' hands and feet at months 12 and 24 using the Van der Heijde modification of the Sharp score. Analysis was by intention to treat. This trial is registered with www.ClinicalTrials.gov , number NCT00764725. Findings Of 493 screened individuals, we enrolled 487, of whom 258 were randomly allocated to treatment. The proportion of patients in group B who received a EULAR-defined good response was non-significantly greater than it was in group A at 18 months (49 of 128 38% vs 38 of 130 29%) and at 24 months (49 of 128 38% vs 40 of 130 31%; p=0·204). After 24 months, radiological disease progression was greater in patients in group A than it was in those in group B (mean 7·23 SD 12·72 vs 4·00 10·0; p=0·009). We recorded three serious adverse events: an extended generalised illness in group A, an extended febrile episode in group B, and a generalised illness in group B. Interpretation Additional biological treatment is a valid option for patients who fail initial methotrexate treatment. However, improved clinical outcomes after 12 months and better radiographical results after 24 months should be weighed against the absence of a convincing clinical difference at 24 months and substantially higher costs. Therefore, for many patients who fail initial methotrexate treatment, add-on treatment with disease-modifying antirheumatic drugs is an appropriate treatment option. Funding Swedish Rheumatism Association, Stockholm County, and Schering-Plough/Merck Sharp and Dohme.
Objective
To estimate the nationwide incidence of rheumatoid arthritis (RA) in Sweden, including its variation across age, sex, geography, and demography, and to describe the sensitivity of ...register‐based incidence estimates to different RA case definitions.
Methods
Incident RA patients were identified using the Swedish National Patient Register. In the base case, incident RA was defined as first‐ever inpatient or nonprimary outpatient care visit listing an RA diagnosis in 2006–2008, with a second visit listing RA within 1 year. Patients prescribed disease‐modifying antirheumatic drugs more than 6 months prior to the first visit listing RA were not regarded as incident. The robustness of this definition was evaluated by more liberal and strict criteria, and by penetration of antirheumatic treatment.
Results
Between 2006 and 2008, 8,826 individuals were identified as incident RA patients. The overall incidence was 41 per 100,000 (56 for women, 25 for men). The incidence increased with age and peaked in the 70–79 years age group for both women and men. The age‐ and sex‐standardized incidences were lower in densely populated areas and in individuals with high educational level. No geographic trends were noted. More liberal and strict definitions of RA only altered the observed incidence by approximately 14%.
Conclusion
The overall nationwide register‐based incidence of RA was robust across different case definitions. In a country with universal access to care, RA displayed demographic and socioeconomic, but no geographic, variations in incidence, and peaks at an older age than most commonly reported, with no difference in peak age at RA onset between sexes.
Current guidelines rank abatacept, rituximab, tocilizumab and TNF-inhibitors (TNFi) as having equal effectiveness for the treatment of RA, at least as second line therapies. These recommendations are ...mainly based on meta-analysis of randomized controlled trials, with few direct drug-drug comparisons. Our objective was to compare the real-world absolute and relative effectiveness among RA patients starting any of the available biologic DMARDs (bDMARDs).
We used the Swedish Rheumatology Register to identify patients with RA initiating TNFi, rituximab, abatacept or tocilizumab in 2010-2016 as first bDMARD (n = 9333), or after switch from TNFi as first bDMARD (n = 3941). National Swedish registers provided additional covariates and censoring events. Effectiveness was assessed 3 and 12 months after treatment start, as the proportion remaining on therapy and with EULAR Good Response, HAQ improvement >0.2, zero swollen/tender joints and CDAI remission. Adjusted differences were estimated with multivariable linear regression.
Patients starting non-TNFi (vs TNFi) as first bDMARD had a higher proportion remaining on drug and reaching most response outcomes as first bDMARD (1-year EULAR Good Response/HAQ improvement: TNFi 24.9/25.4%, rituximab 28.6/37.2%, abatacept 31.9/33.7%, tocilizumab 50.9/43.1%). After switch from a first TNFi, rituximab and tocilizumab, but not abatacept, were associated with significantly better response measures than TNFi (1-year EULAR Good Response/HAQ improvement: TNFi 11.6/16.1%, rituximab 24.8/33.2%, abatacept 13.1/17.5%, tocilizumab 34.1/29.4%). Differences remained significant after adjusting for potential confounders.
Treatment outcomes among RA patients treated in Swedish clinical practice are in line with a superior effectiveness of non-TNFi bDMARDs, in particular tocilizumab and rituximab, compared with TNFi.
Abstract
Objectives
To investigate the association between psychosocial vulnerability, defined as either low social support or low decision latitude at work, and disease remission at 3, 12, and 60 ...months in patients with rheumatoid arthritis (RA).
Methods
This cohort study included all patients enrolled in both the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) 1996–2015 and the Swedish Rheumatology Quality Register (SRQ,
n
= 2820). Information on social support and decision latitude at work at RA diagnosis were identified from the EIRA questionnaire. Indexes for levels of social support and decision latitude at work, respectively, were calculated based on the questionnaire. Low social support and low decision latitude at work, respectively, were identified by a score in the lowest quartile and compared with the three other quartiles (not low). Disease-activity parameters were retrieved from SRQ at 3, 12, and 60 months. The associations between social support or decision latitude at work, respectively, and Disease Activity Score 28 joint count with C-reactive protein (DAS28-CRP) remission were analysed using logistic regression models adjusted for age, sex, smoking habits, alcohol habits, symptom duration, and educational level.
Results
Having low social support (
n
= 591) was not associated with DAS28-CRP remission at 3 (OR 0.93, 95% CI 0.74–1.16), 12 (OR 0.96, 95%CI 0.75–1.23), or 60 (OR 0.89, 95%CI 0.72–1.10) months compared to not low social support (
n
= 2209). No association was observed for low (
n
= 212) versus not low (
n
= 635) decision latitude at work and DAS28-CRP remission at 3 (OR 0.84, 95%CI 0.54–1.31), 12 (OR 0.81, 95%CI 0.56–1.16), or 60 (OR 1.37, 95%CI 0.94–2.01) months.
Conclusion
In a country with general access to healthcare, psychosocial vulnerability does not influence the likelihood of achieving remission in early RA.
To determine the relationship between changes in antibody levels towards citrullinated peptides derived from different candidate autoantigens and therapeutic outcome in early rheumatoid arthritis ...(RA).
Baseline and 3-month serum samples from 316 patients with early RA enrolled in the Swedish Farmacotherapy (SWEFOT) trial were analysed for antibodies against cyclic citrullinated peptides (CCP) and citrullinated peptides derived from vimentin (cVim), fibrinogen (cFib) and α-enolase (CEP-1). At 3-month follow-up, methotrexate monotherapy-inadequate responders were randomised to add-on therapy with sulfasalazine and hydroxychloroquine or infliximab. In these patients, anticitrullinated peptide antibodies (ACPA) were also assessed at 12 and 24 months. The proportion of antibody-positive patients and relative changes in antibody levels were compared across ACPA specificities and related to therapeutic response and radiographic progression.
During the 2-year follow-up, the proportion of patients testing positive declined significantly regarding antibodies to cVim, cFib and CEP-1, while anti-CCP antibody occurrence remained stable over time. Turning anti-cVim antibody negative was most common, and anti-cVim antibody seroreversion during the first three months associated with significantly less 2-year radiographic progression compared with patients who remained positive. Median antibody levels of all tested ACPAs declined uniformly during initial methotrexate therapy and following response to add-on therapy, with no significant relation to treatment regimen or radiographic progression.
The influence of early antirheumatic therapy on ACPA seroreversions was markedly different across specificities, and early disappearance of anti-cVim antibodies associated with better radiological outcome. Thus, these data suggest that the disappearance of particular ACPA reactivities may be beneficial in early RA.
WHO database at the Karolinska institute: CT20080004; and clinicaltrials.gov: NCT00764725.
To determine if major reduction of inflammation with longterm tumor necrosis factor (TNF) antagonist treatment has any influence on the adrenal and gonadal axes in patients with rheumatoid arthritis ...(RA).
Forty-eight patients with RA were treated with infliximab or etanercept for 2 years. Disease activity, clinical response, and physical function were evaluated and serum levels of high sensitivity C-reactive protein and interleukin 6 were analyzed before start of treatment and after 1 and 2 years. At the same timepoints adrenocorticotropic hormone (ACTH), cortisol, and dehydroepiandrosterone sulfate (DHEAS) were analyzed; luteinizing hormone (LH), estradiol, and testosterone were analyzed as well in 18 male patients.
DHEAS increased (p <or= 0.05) after 1 and 2 years of treatment with TNF antagonists. No change in serum levels of ACTH, cortisol, LH, estradiol, or testosterone was recorded during the 2 years. The increased levels of DHEAS correlated with improved physical function measured by Health Assessment Questionnaire (p <or= 0.01). There was no correlation between hormone levels and clinical response or inflammatory markers. A longitudinal stability in individual hormone levels was found between baseline and 2 years, most markedly for DHEAS levels (rs = 0.90, p <or= 0.01). A female subgroup characterized by low levels of DHEAS had a lower age at disease onset.
The increased DHEAS levels may indicate an improved adrenal function during 2 years' treatment with TNF antagonists. Improved physical function, correlated to increased DHEAS levels, may be an effect of better adrenal function during powerful antiinflammatory treatment. The stability in individual hormone levels suggests a stable hormonal homeostasis, independent of inflammatory activity.
To identify predictors of response to methotrexate (MTX) in early rheumatoid arthritis (RA).
In the SWEFOT trial, patients with RA with symptom duration <1 year started MTX monotherapy (20 mg/weekly) ...and 405/487 continued until the 3-4- month visit. The primary outcome measure was the DAS28-based European League against Rheumatism (EULAR) response criteria. Multivariate logistic regression was used to study the association between response and the following baseline characteristics: gender, age, symptom duration, cigarette smoking habits, autoantibody status, Health Assessment Questionnaire (HAQ) score, concurrent prednisolone and treatment with non-steroidal anti-inflammatory drugs. Secondary response and remission measures were the American College of Rheumatology and the Simple Disease Activity Index and Clinical Disease Activity Index (SDAI/CDAI)-derived criteria.
After 3-4 months of MTX treatment, the frequency of EULAR good/moderate/no response was 34%/41%/25%, respectively. Parameters associated with a decreased likelihood of EULAR response were female gender (adjusted OR (adj OR) 0.50, 95% CI 0.31 to 0.81), symptom duration (adj OR per month increase 0.93, 95% CI 0.88 to 0.99), current smoking (adj OR 0.35, 95% CI 0.20 to 0.63) and higher HAQ (adj OR 0.56, 95% CI 0.40 to 0.80). Parameters associated with an increased likelihood of EULAR response were higher age (adj OR per 10-year increase 1.30, 95% CI 1.11 to 1.51) and prednisolone treatment (adj OR 2.84, 95% CI 1.43 to 5.63). The findings were similar when patients on prednisolone were excluded and other response criteria tested, although current smoking was the only significant predictor using all response criteria, while HAQ was the only significant predictor of all the remission criteria used. A matrix showed up to ninefold differences between subgroups stratified by the main predictors.
Current smoking, female sex, longer symptom duration and younger age predict a worse response to MTX in patients with new-onset RA. TrialRegNo NCT00764725.
Objective
To compare the pain course between methotrexate (MTX)‐refractory early rheumatoid arthritis (RA) patients randomized to infliximab (IFX) versus sulfasalazine (SSZ) plus hydroxychloroquine ...(HCQ).
Methods
The randomized, controlled, open‐label Swedish Pharmacotherapy (SWEFOT) trial enrolled new‐onset RA patients from October 2002 to December 2005. After 3 months of receiving MTX, patients not reaching low disease activity (Disease Activity Score in 28 joints score ≤3.2) were randomized to adding IFX (n = 128) or SSZ plus HCQ (n = 130) and followed for 21 months. Here, outcomes included area under the curve (AUC) for visual analog scale (VAS) scores for pain, unacceptable pain (VAS pain score >40 mm range 0–100), and unacceptable pain despite inflammation control (refractory pain; VAS pain score >40 plus C‐reactive protein level <10 mg/liter). Between‐group differences were analyzed with multivariate regression models.
Results
Overall, 50% of randomized patients (n = 258) in the crude setting reported unacceptable pain at randomization, declining to 29% at 21 months (P < 0.001), when refractory pain constituted 82% of all unacceptable pain. Comparing randomized arms (intent‐to‐treat analysis), the AUC for VAS pain was lower in the MTX plus IFX group (P = 0.01), and at 21 months, 32% of patients receiving MTX plus IFX and 45% receiving MTX plus SSZ plus HCQ had unacceptable pain (adjusted relative risk 0.68 95% confidence interval 0.51, 0.90; P = 0.008). Regarding refractory pain, no between‐group differences were observed.
Conclusion
Despite active combination treatment, almost one‐third of new‐onset RA patients reported unacceptable pain after 21 months, and refractory pain constituted more than 4/5 of this pain load. Adding IFX versus SSZ plus HCQ to MTX reduced both cumulative pain and unacceptable pain at 21 months, suggesting less long‐term pain for the biologic therapy. These results display insufficient effects of current treatment strategies on inflammation‐independent pain components, warranting alternative approaches in affected patients.
Abstract
Objectives
The aims of this national study in Sweden of patients with RA were to: examine the prevalence of sustained remission (SR), that is, remission lasting for at least 6 months; ...compare the prevalence of SR in patients with early RA and established RA; study the timing of onset of and time spent in SR; and study possible predictors of SR.
Methods
Adult patients with RA included in the Swedish Rheumatology Quality registry were studied. The registry was searched for patients fulfilling remission criteria: DAS28-ESR, Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI) and ACR/EULAR remission for at least 6 months. Early RA was defined as symptom duration ⩽6 months at inclusion in the Swedish Rheumatology Quality.
Results
Of 29 084 patients, 12 193 (41.9%) reached DAS28 SR at some time point during follow-up compared with 6445 (22.2%), 6199 (21.3%) and 5087 (17.5%) for CDAI, SDAI and ACR/EULAR SR, respectively. SR was more common in early RA (P < 0.001). The median time from symptom onset to SR was 1.9, 2.4, 2.4 and 2.5 years according to DAS28, CDAI, SDAI and ACR/EULAR criteria, respectively. Lower age, male sex and milder disease characteristics were associated with SR.
Conclusion
The majority of patients in this nationwide study never reached SR. Patients with early RA are more likely to reach SR than patients with established RA.
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