| 1. |
- Askling, Johan, et al.
(författare)
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Cancer risk in patients with rheumatoid arthritis treated with anti-tumor necrosis factor alpha therapies : does the risk change with the time since start of treatment?
- 2009
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:11, s. 3180-3189
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:To determine the short-term and medium-term risks of cancer in patients receiving anti-tumor necrosis factor alpha (anti-TNFalpha) therapies that have proven effective in the treatment of chronic inflammatory conditions.METHODS:By linking together data from the Swedish Biologics Register, Swedish registers of RA, and the Swedish Cancer Register, we identified and analyzed for cancer occurrence a national cohort of 6,366 patients with RA who first started anti-TNF therapy between January 1999 and July 2006. As comparators, we used a national biologics-naive RA cohort (n = 61,160), a cohort of RA patients newly starting methotrexate (n = 5,989), a cohort of RA patients newly starting disease-modifying antirheumatic drug combination therapy (n = 1,838), and the general population of Sweden. Relative risks (RRs) were estimated using Cox regression analyses, examining overall RR as well as RR by time since the first start of anti-TNF therapy, by the duration of active anti-TNF therapy, and by the anti-TNF agent received.RESULTS:During 25,693 person-years of followup in 6,366 patients newly starting anti-TNF, 240 first cancers occurred, yielding an RR of 1.00 (95% confidence interval 0.86-1.15) versus the biologics-naive RA cohort, and similar RRs versus the other 2 RA comparators. RRs did not increase with increasing time since the start of anti-TNF therapy, nor with the cumulative duration of active anti-TNF therapy. During the first year following the first treatment start, but not thereafter, dissimilar cancer risks for adalimumab, etanercept, and infliximab were observed.CONCLUSION:During the first 6 years after the start of anti-TNF therapy in routine care, no overall elevation of cancer risk and no increase with followup time were observed.
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| 2. |
- Askling, Johan, et al.
(författare)
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Time-dependent increase in risk of hospitalisation with infection among Swedish RA patients treated with TNF antagonists
- 2007
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 66:10, s. 1339-1344
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES:The degree to which treatment with tumour necrosis factor (TNF) antagonists may be associated with increased risks for serious infections is unclear. An observational cohort study was performed using prospectively collected data from the Swedish Biologics Register (ARTIS) and other national Swedish registers.METHODS:First, in the ARTIS, all 4167 rheumatoid arthritis (RA) patients starting TNF antagonist treatment between 1999 and 2003 were identified. Secondly, in the Swedish Inpatient Register, all individuals hospitalised for any reason and who also carried a diagnosis of RA, between 1964 and 2003 (n = 44 946 of whom 2692 also occurred in ARTIS), were identified. Thirdly, in the Swedish Inpatient Register, all hospitalisations listing an infection between 1999 and 2003 were identified. By cross-referencing these three data sets, RRs for hospitalisation with infection associated with TNF antagonist treatment were calculated within the cohort of 44 946 RA patients, using Cox regression taking sex, age, geography, co-morbidity and use of inpatient care into account.RESULTS:Among the 4167 patients treated with TNF antagonists, 367 hospitalisations with infections occurred during 7776 person-years. Within the cohort of 44 496 RA patients, the RR for infection associated with TNF antagonists was 1.43 (95% CI 1.18 to 1.73) during the first year of treatment, 1.15 (95% CI 0.88 to 1.51) during the second year of treatment, and 0.82 (95% CI 0.62 to 1.08) for subjects remaining on their first TNF antagonist treatment after 2 years.CONCLUSION:Treatment with TNF antagonists may be associated with a small to moderate increase in risk of hospitalisation with infection, which disappears with increasing treatment duration.
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| 3. |
- Bengtsson, Anders A, et al.
(författare)
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Pharmacokinetics, tolerability, and preliminary efficacy of ABR-215757, a new quinoline-3-carboxamide derivative, in murine and human SLE
- 2012
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 64:5, s. 1579-1588
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To assess the efficacy of ABR-215757, a new immunomodulatory small molecule in a murine SLE model, to evaluate the pharmacokinetics and tolerability in SLE patients at doses predicted to be efficacious and safe, and to determine the maximum tolerated dose (MTD). METHODS: The efficacy of ABR-215757 was studied in lupus prone MRLlpr/lpr mice and compared with established SLE treatments. Dose response data of ABR-215757 were together with pharmacokinetic data used to calculate effective and safe clinical doses. The pharmacokinetics and tolerance of ABR-215757 were evaluated in a Phase Ib double-blind, placebo controlled, dose-escalation study where cohorts of SLE patients received daily oral treatment for 12 weeks. RESULTS: Disease inhibition in MRLlpr/lpr mice, comparable to that of prednisolone and mycophenolate mofetil, was obtained with ABR-215757. Prominent effects on disease manifestations, serological markers and a steroid sparing effect were seen for ABR-215757. The pharmacokinetic properties in SLE patients were linear and well suitable for once daily oral treatment. The majority of the adverse events (AEs) were mild or moderate and transient. The most frequent AEs were arthralgia and myalgia, reported at the highest (4.5 and 6 mg/day) dose levels. At 4.5 mg and higher some AEs of severe intensity and serious adverse events (SAEs) were reported. CONCLUSION: ABR-215757 effectively inhibited disease and had a steroid sparing effect in experimental lupus. Clinical doses up to 3 mg/day, dose levels predicted from pre-clinical studies to be efficacious and safe, were well tolerated in the SLE patients. The MTD was concluded to be 4.5 mg/day.
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| 4. |
- Fisher, Benjamin A., et al.
(författare)
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Antibodies to citrullinated α-enolase peptide 1 and clinical and radiological outcomes in rheumatoid arthritis
- 2011
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 70:6, s. 1095-1098
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION:The anticyclic citrullinated peptide 2 (anti-CCP2) assay is a generic test for antibodies to citrullinated proteins, among which there is a subset of about 50% with antibodies to citrullinated enolase peptide 1 (CEP-1). The anti-CEP-1 positive subset is strongly associated with the HLA-DRB1 shared epitope and its interaction with smoking.OBJECTIVE:To investigate whether anti-CEP-1 antibodies may be helpful in predicting outcome.METHODS: Anti-CEP-1 and anti-CCP2 antibodies were measured in two prospective cohorts of patients (Karolinska n=272, Norfolk Arthritis Register (NOAR) n=408) with early rheumatoid arthritis (RA). Outcomes measured were C-reactive protein, erythrocyte sedimentation rate, visual analogue scales for pain and global assessment of disease activity, Health Assessment Questionnaire, physician's assessment, swollen and tender joint counts and radiological progression.RESULTS: Anti-CCP2 antibodies were present in 57% and 50%, and anti-CEP-1 in 27% and 24% of the Karolinska and NOAR cohorts, respectively. Importantly, no statistically significant differences in clinical outcomes were demonstrated between the anti-CEP-1-/CCP2+ and the anti-CEP-1+/CCP2+ subsets in either cohort, or in radiological outcomes in the Karolinska cohort.CONCLUSION: Although antibodies to specific citrullinated proteins may have distinct genetic and environmental risk factors, the similarity in clinical phenotype suggests that they share common pathways in the pathogenesis of joint disease in RA.
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| 5. |
- Eriksson, Jonas K., et al.
(författare)
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Biological vs Conventional Combination Treatment and Work Loss in Early Rheumatoid Arthritis A Randomized Trial
- 2013
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Ingår i: JAMA Internal Medicine. - : American Medical Association (AMA). - 2168-6114 .- 2168-6106. ; 173:15, s. 1407-1414
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE The introduction of biological tumor necrosis factor inhibitors has improved the treatment of rheumatoid arthritis (RA) but at a substantial cost. These drugs have been shown to lead to superior radiological outcomes compared with a combination of conventional disease-modifying antirheumatic drugs over 2 years. OBJECTIVE To investigate whether radiological superiority translates into better work loss outcomes. DESIGN, SETTING, AND PARTICIPANTS Multicenter, 2-arm, parallel, randomized, active-controlled, open-label trial. Patients with early RA (symptom duration <1 year) were recruited from 15 rheumatology clinics in Sweden from October 1, 2002, through December 31, 2005. The study population was restricted to working-age patients (aged <63 years). INTERVENTIONS Patients who did not achieve low disease activity after 3 to 4 months of methotrexate therapy were randomized to receive additional biological treatment with infliximab or conventional combination treatment with sulfasalazine plus hydroxychloroquine. MAIN OUTCOMES AND MEASURES Monthly sick leave and disability pension days 21 months after randomization retrieved from the nationwide Swedish Social Insurance Office register. Main analyses were by intention to treat, including all patients, and adjusted for baseline sick leave and disability pension. RESULTS Of 204 eligible patients, 105 were randomized to biological and 99 to conventional treatment. Seven patients in the biological and 4 in the conventional treatment group never received the study drug, and 72 and 52 patients, respectively, followed the study per protocol for 21 months. The baseline mean (SD) work loss was 17 (13) d/mo (median, 16 d/mo) in both groups (mean difference, 0.6 d/mo; 95% CI, -3.0 to 3.9). The mean changes in work loss at 21 months were -4.9 d/mo in the biological and -6.2 d/mo in the conventional treatment group (adjusted mean difference, 1.6 d/mo; 95% CI, -1.2 to 4.4). Including only patients receiving at least 1 dose of assigned treatment, the adjusted mean difference was 1.5 d/mo (95% CI, -1.5 to 4.4), and in per-protocol analysis the adjusted mean difference was 0.3 d/mo (95% CI, -2.8 to 3.8). CONCLUSIONS AND RELEVANCE The radiological superiority of biological compared with conventional combination therapy did not translate into better work loss outcomes in patients with early RA who had experienced an insufficient response to methotrexate.
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| 6. |
- Kastbom, Alf, et al.
(författare)
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Changes in the anticitrullinated peptide antibody response in relation to therapeutic outcome in early rheumatoid arthritis: results from the SWEFOT trial
- 2016
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ PUBLISHING GROUP. - 0003-4967 .- 1468-2060. ; 75:2, s. 356-361
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Tidskriftsartikel (refereegranskat)abstract
- Objective 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). Methods 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 a-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. Results 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. Conclusions 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.
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| 7. |
- Riazzoli, Jenny, et al.
(författare)
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Patient-reported 28 swollen and tender joint counts accurately represent RA disease activity and can be used to assess therapy responses at the group level
- 2010
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Ingår i: Rheumatology. - : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 49:11, s. 2098-2103
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Formal joint assessments are critically important to improve rheumatological care of patients with RA. The aim of this study was to determine the usefulness of patient-recorded 28 tender joint counts (TJCs) and swollen joint counts (SJCs) using a tablet personal computer and to explore the possibility of using patient-recorded data to calculate 28-joint DAS (DAS-28) and EULAR response. Methods. Forty-seven patients were included before initiation of adalimumab therapy and assessed at baseline and after 3 months. SJC and TJC were registered by the patients and thereafter by an experienced rheumatology specialist. Changes were correlated using Spearman’s rank correlation test. Results. The correlations between SJC and TJC derived by the physician and the patient at baseline were excellent (r = 0.78 and 0.87, respectively P < 0.01 for both). After 3 months, the correlations were less strong (0.645 and 0.745, respectively, P < 0.001 for both). When using the patient-derived SJC/TJC for calculation of the DAS-28 (patDAS-28), similar values were obtained, and correlations between DAS-28 and patDAS-28 were excellent (r = 0.91 at baseline, r = 0.90 at 3 months). According to the EULAR response criteria, the percentage of responders at the group level was nearly identical, although there was some disagreement at the individual level when DAS-28 and patDAS-28 were used to determine response to therapy. Conclusion. Patient-reported SJC and TJC can in research settings be used instead of physician-reported ones. Patient-derived SJC and TJC may also make it possible for rheumatologists to obtain quantitative joint count recordings much more frequently than is feasible for traditional joint counts.
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| 8. |
- Simard, Julia F., et al.
(författare)
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Ten years with biologics : to whom do data on effectiveness and safety apply?
- 2011
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Ingår i: Rheumatology. - : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 50:1, s. 204-213
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Tidskriftsartikel (refereegranskat)abstract
- Methods. We identified all adult patients with RA (n = 9612), PsA (n = 1417) and other SpA (n = 1652) initiating a first biologic therapy between 1 January 1999 and 31 December 2008, registered in the Swedish Biologics Register (ARTIS), including information on demographics, disease characteristics and 1-year risk of first-line treatment discontinuation. Results. Over calendar time, measures of disease activity at start declined substantially for all indications, and diminished between first-, second- and third-line therapy starts. One-year risks of first-line therapy discontinuation increased. Switchers to anti-TNF and non-TNF biologics had different comorbidities. Despite < 50% drug retention at 5 years, most patients remained exposed to some biologic. Conclusions. The trends in baseline characteristics and drug retention underscores that any effects of biologics, including comparison between different biologics, must be interpreted in light of the characteristics of the population treated. The observed differences further call for continued vigilance to properly evaluate the safety profiles of biologic treatments as they are currently used. Exposure to multiple biologics presents a challenge for attribution of long-term effects.
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| 9. |
- Waldheim, Eva, et al.
(författare)
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Health-related quality of life, fatigue and mood in patients with SLE and high levels of pain compared to controls and patients with low levels of pain
- 2013
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Ingår i: Lupus. - London : Sage Publications. - 0961-2033 .- 1477-0962. ; 22:11, s. 1118-1127
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The objective of this paper is to investigate health-related quality of life (HRQoL), fatigue, anxiety and depression in patients with systemic lupus erythematosus (SLE) and higher levels of pain and to compare them to patients with lower levels of pain and controls.Method: Patients were dichotomized into two groups based on SLE-related pain score on the visual analog scale (VAS): low-pain group (76%, n=64, VAS 0-39 mm) and high-pain group (24%, n=20, VAS 40-100 mm). Sex- and age-matched controls were randomly selected from the general population. Participants were asked to complete questionnaires regarding self-reported pain, HRQoL, fatigue, anxiety and depression. Medical assessments also were recorded.Result: Fatigue score in the high-pain group (median, 36.5; interquartile range (IQR), 32.5-39.7) was significantly higher (p<0.001) compared to the low-pain group (median, 23; IQR, 14.6-34.1), as well as scores for anxiety (median, 9; IQR, 6.5-11.5) and depression (median, 7.5; IQR, 5.5-9) (p<0.001). The high-pain group had significantly lower scores compared to the low-pain group in all dimensions in the SF-36 (p ≤ 0.001-0.007). No statistical differences were detected between the low-pain group and controls in any measurement except for the dimensions physical function, general health, vitality and social function in SF-36. Conclusion Patients with SLE scoring higher degrees of pain were burdened with more fatigue, anxiety and depression and lower levels of HRQoL compared to patients with lower levels of pain who did not differ significantly from the general population in most dimensions. These results elucidate the importance of identifying patients with higher degrees of pain who are probably in need of more extensive multidimensional interventions to decrease symptom burden.
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| 10. |
- van Vollenhoven, Ronald F., et al.
(författare)
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Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial
- 2012
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Ingår i: The Lancet. - 1474-547X. ; 379:9827, s. 1712-1720
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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