| 1. |
- Arkema, Elizabeth V, et al.
(författare)
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Incidence of progressive multifocal leukoencephalopathy in patients with rheumatoid arthritis : a national population-based study
- 2012
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 71:11, s. 1865-1867
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cases of progressive multifocal leukoencephalopathy (PML), a rare but serious disease, have been reported in patients with rheumatoid arthritis (RA) in association with biological therapy, but little is known about the incidence of PML in patients with RA in the absence of treatment exposure.OBJECTIVE: To estimate the incidence rate of PML in patients with RA compared with the general population, with and without exposure to biological agents.METHODS: Patients with adult onset RA, exposure to biological agents and a diagnosis of PML from 1999 through 2009 were identified from national registries and linked using each Swedish resident's unique personal identification number. General population comparators matched on age, sex and county were also identified. Crude and age- and sex-standardised incidence rates (cases per 100 000 person-years) were calculated with 95% CI.RESULTS: 66 278 patients with RA and 286 949 general population comparators were included in the study. The incidence rate of PML in the overall RA population was 1.0 (95% CI 0.3 to 2.5) compared with 0.3 (95% CI 0.1 to 0.6) in the general population. The difference in incidence rate was 0.7 (95% CI -0.3 to 17). Among all patients exposed to biological agents, only one patient was diagnosed with PML.CONCLUSION: Data from this national population-based cohort study suggest that patients with RA may have an increased rate of PML compared with the general population.
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| 2. |
- Askling, Helena H., et al.
(författare)
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Hepatitis A vaccine for immunosuppressed patients with rheumatoid arthritis : a prospective, open-label, multi-centre study
- 2014
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Ingår i: Travel Medicine and Infectious Disease. - : Elsevier BV. - 1477-8939 .- 1873-0442. ; 12:2, s. 134-42
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hepatitis A vaccine is the most frequently used travel vaccine, yet data are scarce about its ability to induce protection in patients with concurrent immunosuppressive treatment. We assessed the immunogenicity of this vaccine in rheumatoid arthritis (RA) patients treated with tumour necrosis factor-inhibitors (TNFi) and/or methotrexate (MTX).METHODS: Hepatitis A vaccine was administered to non-immune RA patients at 0 and 6 months. Hepatitis A virus (HAV) antibodies were assessed at 0, 1, 6, 7, 12, and 24 months with a quantitative Chemiluminescent Microparticle Immuno Assay (CMIA) for HAV-IgG. Samples from month 1, 6, and 7 were, in addition, analysed with a microparticle EIA (MEIA) for anti-HAV IgM + IgG.RESULTS: The final study population consisted of 53 patients treated with TNFi (n = 15), TNFi + MTX (n = 21) or MTX (n = 17). One and six months after the first dose, 10% and 33% of the patients had attained seroprotection. One and six months after the second dose 83% and 72% were seroprotected. At month 24, 86% of the vaccinees showed protective levels.CONCLUSIONS: Two doses of hepatitis A vaccine at a 6-month interval provided protection for most immunosuppressed RA patients. A single dose does not seem to afford sufficient protection to this group of patients.
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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. |
- Bengtsson, Anders, et al.
(författare)
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Pharmacokinetics, tolerability, and preliminary efficacy of paquinimod (ABR-215757), a new quinoline-3-carboxamide derivative: Studies in lupus-prone mice and a multicenter, randomized, double-blind, placebo-controlled, repeat-dose, dose-ranging study in patients with systemic lupus erythematosus
- 2012
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 64:5, s. 1579-1588
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Tidskriftsartikel (refereegranskat)abstract
- Objective To assess the efficacy of paquinimod, a new immunomodulatory small molecule, in a murine lupus model, and to evaluate its pharmacokinetics and tolerability in systemic lupus erythematosus (SLE) patients at doses predicted to be efficacious and safe and determine the maximum tolerated dose. Methods The efficacy of paquinimod was studied in lupus-prone MRL-lpr/lpr mice and compared with that of established SLE treatments. Dose-response data and pharmacokinetic data were used to calculate effective and safe clinical doses of paquinimod. The pharmacokinetics and tolerability of paquinimod were evaluated in a phase Ib double-blind, placebo controlled, dose-ranging study in which cohorts of SLE patients received daily oral treatment for 12 weeks. Results Paquinimod treatment resulted in disease inhibition in MRL-lpr/lpr mice, comparable to that obtained with prednisolone and mycophenolate mofetil; prominent effects on disease manifestations and serologic markers and a steroid-sparing effect were observed. In patients with SLE, the pharmacokinetic properties of paquinimod 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 with the highest dose levels of paquinimod (4.5 mg/day and 6.0 mg/day). At the 4.5 mg/day dose level and higher, some AEs of severe intensity and serious adverse events were reported. Conclusion Paquinimod effectively inhibited disease and had a steroid-sparing effect in experimental lupus. Results from preclinical models together with pharmacokinetic data were successfully translated into a safe clinical dose range, and doses of up to 3.0 mg/day were well tolerated in the SLE patients. Taken together, the promising combined data from a murine model and human SLE support the future clinical development of paquinimod.
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| 5. |
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| 6. |
- Chatzidionysiou, Katerina, et al.
(författare)
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Effectiveness of TNF inhibitor switch in RA: results from the national Swedish register
- 2014
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 74:5, s. 890-896
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Tidskriftsartikel (refereegranskat)abstract
- Background Switching to a second tumour necrosis factor inhibitor (TNFi) after discontinuation of a first in rheumatoid arthritis (RA) is a common strategy. The reason for the switch from the first TNFi could potentially influence the response to therapy. Data on direct comparisons between TNFi after switching are limited. Methods The national Swedish register was used. RA patients who switched to a second TNFi (infliximab, etanercept or adalimumab) after failure of a TNFi as first-ever biologic were identified. Effectiveness of treatment was compared across the three drugs according to the first TNFi used, the reason for discontinuing and the drug survival. Drug survival across TNFi used as second biologic was compared. Results Half of all patients starting infliximab, adalimumab or etanercept during the period 2005-2012 discontinued treatment for various reasons. Of these patients, a third switched within 2 months to a second TNFi (infliximab, etanercept or adalimumab). Around 35% of all patients achieved low disease activity or remission at 6 months. Regarding the switching strategy, best results were observed among patients who switched from infliximab to etanercept because of (secondary) inefficacy. Etanercept as second TNFi was associated with longer drug survival compared with infliximab. Conclusions Switching to a second TNFi after the failure of the first may lead to good clinical results. The inter-drug differences in drug survival on the second TNFi mirror those reported previously for the first TNFi, suggesting that these differences are not solely due to channelling bias.
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| 7. |
- 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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| 8. |
- 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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| 9. |
- Gabay, Cem, et al.
(författare)
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Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA) : a randomised, double-blind, controlled phase 4 trial.
- 2013
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 381:9877
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Roughly a third of patients with rheumatoid arthritis treated with biological treatments receive them as monotherapy. Tocilizumab--an inhibitor of interleukin 6 receptor signalling--has been studied as monotherapy in several clinical trials. We assessed the efficacy and safety of tocilizumab monotherapy compared with adalimumab monotherapy for patients with rheumatoid arthritis.METHODS: We did this randomised, double-blind, parallel-group, phase 4 superiority study in 76 centres in 15 countries in North and South America, Australasia, and Europe. We enrolled patients who were aged at least 18 years, had severe rheumatoid arthritis for 6 months or more, and were intolerant to methotrexate or were inappropriate for continued methotrexate treatment. Patients were randomly assigned (1:1; block size of four) to receive tocilizumab 8 mg per kg bodyweight intravenously every 4 weeks plus placebo subcutaneously every 2 weeks or adalimumab 40 mg subcutaneously every 2 weeks plus placebo intravenously every 4 weeks for 24 weeks. Investigators, patients, and sponsor personnel were masked to assignment. The primary endpoint was change in disease activity score using 28 joints (DAS28) from baseline to week 24. This trial is registered with ClinicalTrials.gov, number NCT01119859.FINDINGS: We screened 452 patients and enrolled 326 patients. The intention-to-treat population contained 325 patients (163 assigned to tocilizumab, 162 assigned to adalimumab). Week 24 mean change from baseline in DAS28 was significantly greater in the tocilizumab group (-3·3) than in the adalimumab group (-1·8) patients (difference -1·5, 95% CI -1·8 to -1·1; p<0·0001). 16 of 162 (10%) patients in the adalimumab group versus 19 of 162 (12%) in the tocilizumab group had serious adverse events. More patients in the tocilizumab group than in the adalimumab group had increased LDL-cholesterol, increased alanine aminotransferase concentrations, and reduced platelet and neutrophil counts.INTERPRETATION: Tocilizumab monotherapy was superior to adalimumab monotherapy for reduction of signs and symptoms of rheumatoid arthritis in patients for whom methotrexate was deemed inappropriate. The adverse event profiles of tocilizumab and adalimumab were consistent with previous findings.FUNDING: F Hoffmann-La Roche.
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| 10. |
- Hanly, John G., et al.
(författare)
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Headache in Systemic Lupus Erythematosus Results From a Prospective, International Inception Cohort Study
- 2013
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 65:11, s. 2887-2897
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveTo examine the frequency and characteristics of headaches and their association with global disease activity and health-related quality of life (HRQOL) in patients with systemic lupus erythematosus (SLE). MethodsA disease inception cohort was assessed annually for headache (5 types) and 18 other neuropsychiatric (NP) events. Global disease activity scores (SLE Disease Activity Index 2000 [SLEDAI-2K]), damage scores (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI]), and Short Form 36 (SF-36) mental and physical component summary scores were collected. Time to first headache and associations with SF-36 scores were analyzed using Cox proportional hazards and linear regression models with generalized estimating equations. ResultsAmong the 1,732 SLE patients enrolled, 89.3% were female and 48.3% were white. The mean SD age was 34.6 +/- 13.4 years, duration of disease was 5.6 +/- 5.2 months, and length of followup was 3.8 +/- 3.1 years. At enrollment, 17.8% of patients had headache (migraine [60.7%], tension [38.6%], intractable nonspecific [7.1%], cluster [2.6%], and intracranial hypertension [1.0%]). The prevalence of headache increased to 58% after 10 years. Only 1.5% of patients had lupus headache, as identified in the SLEDAI-2K. In addition, headache was associated with other NP events attributed to either SLE or non-SLE causes. There was no association of headache with SLEDAI-2K scores (without the lupus headache variable), SDI scores, use of corticosteroids, use of antimalarials, use of immunosuppressive medications, or specific autoantibodies. SF-36 mental component scores were lower in patients with headache compared with those without headache (mean +/- SD 42.5 +/- 12.2 versus 47.8 +/- 11.3; P < 0.001), and similar differences in physical component scores were seen (38.0 +/- 11.0 in those with headache versus 42.6 +/- 11.4 in those without headache; P < 0.001). In 56.1% of patients, the headaches resolved over followup. ConclusionHeadache is frequent in SLE, but overall, it is not associated with global disease activity or specific autoantibodies. Although headaches are associated with a lower HRQOL, the majority of headaches resolve over time, independent of lupus-specific therapies.
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