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1.
  • AbdGawad, Mohamed, et al. (author)
  • Decreased Neutrophil Apoptosis in Quiescent ANCA-Associated Systemic Vasculitis
  • 2012
  • In: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 7:3
  • Journal article (peer-reviewed)abstract
    • Background: ANCA-Associated Systemic Vasculitis (AASV) is characterized by leukocytoclasis, accumulation of unscavenged apoptotic and necrotic neutrophils in perivascular tissues. Dysregulation of neutrophil cell death may contribute directly to the pathogenesis of AASV. less thanbrgreater than less thanbrgreater thanMethods: Neutrophils from Healthy Blood Donors (HBD), patients with AASV most in complete remission, Polycythemia Vera (PV), Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA) and renal transplant recipients (TP) were incubated in vitro, and the rate of spontaneous apoptosis was measured by FACS. Plasma levels of cytokines and sFAS were measured with cytometric bead array and ELISA. Expression of pro/anti-apoptotic factors, transcription factors C/EBP-alpha, C/EBP-beta and PU.1 and inhibitors of survival/JAK2-pathway were measured by real-time-PCR. less thanbrgreater than less thanbrgreater thanResults: AASV, PV and RA neutrophils had a significantly lower rate of apoptosis compared to HBD neutrophils (AASV 50 +/- 14% vs. HBD 64 +/- 11%, p andlt; 0.0001). In RA but not in AASV and PV, low apoptosis rate correlated with increased plasma levels of GM-CSF and high mRNA levels of anti-apoptotic factors Bcl-2A1 and Mcl-1. AASV patients had normal levels of G-CSF, GM-CSF and IL-3. Both C/EBP-alpha, C/EBP-beta were significantly higher in neutrophils from AASV patients than HBD. Levels of sFAS were significantly higher in AASV compared to HBD. less thanbrgreater than less thanbrgreater thanConclusion: Neutrophil apoptosis rates in vitro are decreased in AASV, RA and PV but mechanisms seem to differ. Increased mRNA levels of granulopoiesis-associated transcription factors and increased levels of sFAS in plasma were observed in AASV. Additional studies are required to define the mechanisms behind the decreased apoptosis rates, and possible connections with accumulation of dying neutrophils in regions of vascular lesions in AASV patients.
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2.
  • AbdGawad, Mohamed, et al. (author)
  • Elevated neutrophil membrane expression of proteinase 3 is dependent upon CD177 expression
  • 2010
  • In: Clinical and Experimental Immunology. - Chichester, West Sussex, United Kingdom : Wiley-Blackwell. - 0009-9104 .- 1365-2249. ; 161:1, s. 89-97
  • Journal article (peer-reviewed)abstract
    • Proteinase 3 (PR3) is a major autoantigen in anti-neutrophil cytoplasmic antibodies (ANCA)-associated systemic vasculitis (AASV), and the proportion of neutrophils expressing PR3 on their membrane (mPR3+) is increased in AASV. We have shown recently that mPR3 and CD177 are expressed on the same cells in healthy individuals. In this study we try to elucidate mechanisms behind the increased mPR3 expression in AASV and its relationship to CD177. All neutrophils in all individuals were either double-positive or double-negative for mPR3 and CD177. The proportion of double-positive neutrophils was increased significantly in AASV and systemic lupus erythematosus patients. The proportion of mPR3+/CD177+ cells was not correlated to general inflammation, renal function, age, sex, drug treatment and levels of circulating PR3. AASV patients had normal levels of granulocyte colony-stimulating factor and granulocyte–macrophage colony-stimulating factor. Pro-PR3 was found to constitute 10% of circulating PR3 but none of the mPR3. We found increased mRNA levels of both PR3 and CD177 in AASV, but they did not correlate with the proportion of double-positive cells. In cells sorted based on membrane expression, CD177–mRNA was several-fold higher in mPR3+ cells. When exogenous PR3 was added to CD177-transfected U937 cells, only CD177+ cells bound PR3 to their membrane. In conclusion, the increased membrane expression of PR3 found in AASV is not linked directly to circulating PR3 or PR3 gene transcription, but is dependent upon CD177 expression and correlated with the transcription of the CD177 gene.
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4.
  • Askling, Johan, et al. (author)
  • Anti-TNF therapy in RA and risk of malignant lymphomas Relative risks and time-trends in the Swedish Biologics Register
  • 2008
  • In: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 68:5, s. 648-653
  • Journal article (peer-reviewed)abstract
    • Background: Tumour necrosis factor (TNF) antagonists have proved effective as treatment against rheumatoid arthritis (RA), but the unresolved issue of whether the use of anti-TNF therapy increases the already elevated risk of lymphoma in RA remains a concern.Methods: Using the Swedish Biologics Register (ARTIS), the Swedish Cancer Register, pre-existing RA cohorts and cross-linkage with other national health and census registers, a national RA cohort (n  =  67 743) was assembled and patients who started anti-TNF therapy between 1998 and July 2006 (n  =  6604) were identified. A general population comparator (n  =  471 024) was also assembled and the incidence of lymphomas from 1999 to 31 December 2006 was assessed and compared in these individuals.Results: Among the 6604 anti-TNF-treated RA patients, 26 malignant lymphomas were observed during 26 981 person-years of follow-up, which corresponded to a relative risk (RR) of 1.35 (95% CI 0.82 to 2.11) versus anti-TNF-naive RA patients (336 lymphomas during 365 026 person-years) and 2.72 (95% CI 1.82 to 4.08) versus the general population comparator (1568 lymphomas during 3 355 849 person-years). RA patients starting anti-TNF therapy in 1998–2001 accounted for the entire increase in lymphoma risk versus the two comparators. By contrast, RR did not vary significantly by time since start of first treatment or with the accumulated duration of treatment, nor with the type of anti-TNF agent.Conclusion: Overall and as used in routine care against RA, TNF antagonists are not associated with any major further increase in the already elevated lymphoma occurrence in RA. Changes in the selection of patients for treatment may influence the observed risk.
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5.
  • Askling, Johan, et al. (author)
  • Anti-tumour necrosis factor therapy in rheumatoid arthritis and risk of malignant lymphomas : relative risks and time trends in the Swedish Biologics Register
  • 2009
  • In: Annals of the Rheumatic Diseases. - London, UK : BMJ. - 0003-4967 .- 1468-2060. ; 68:5, s. 648-653
  • Journal article (peer-reviewed)abstract
    • BACKGROUND:Tumour necrosis factor (TNF) antagonists have proved effective as treatment against rheumatoid arthritis (RA), but the unresolved issue of whether the use of anti-TNF therapy increases the already elevated risk of lymphoma in RA remains a concern.METHODS:Using the Swedish Biologics Register (ARTIS), the Swedish Cancer Register, pre-existing RA cohorts and cross-linkage with other national health and census registers, a national RA cohort (n = 67,743) was assembled and patients who started anti-TNF therapy between 1998 and July 2006 (n = 6604) were identified. A general population comparator (n = 471,024) was also assembled and the incidence of lymphomas from 1999 to 31 December 2006 was assessed and compared in these individuals.RESULTS:Among the 6604 anti-TNF-treated RA patients, 26 malignant lymphomas were observed during 26,981 person-years of follow-up, which corresponded to a relative risk (RR) of 1.35 (95% CI 0.82 to 2.11) versus anti-TNF-naive RA patients (336 lymphomas during 365,026 person-years) and 2.72 (95% CI 1.82 to 4.08) versus the general population comparator (1568 lymphomas during 3,355,849 person-years). RA patients starting anti-TNF therapy in 1998-2001 accounted for the entire increase in lymphoma risk versus the two comparators. By contrast, RR did not vary significantly by time since start of first treatment or with the accumulated duration of treatment, nor with the type of anti-TNF agent.CONCLUSION:Overall and as used in routine care against RA, TNF antagonists are not associated with any major further increase in the already elevated lymphoma occurrence in RA. Changes in the selection of patients for treatment may influence the observed risk.
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6.
  • Askling, Johan, et al. (author)
  • 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
  • In: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:11, s. 3180-3189
  • Journal article (peer-reviewed)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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7.
  • Askling, J, et al. (author)
  • Haematopoietic malignancies in rheumatoid arthritis : lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists
  • 2005
  • In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 64:10, s. 1414-1420
  • Journal article (peer-reviewed)abstract
    • BACKGROUND:Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas, and maybe also of leukaemia and multiple myeloma. The effect of tumour necrosis factor (TNF) antagonists on lymphoma risk and characteristics is unclear.OBJECTIVE:To assess expected rates and relative risks of haematopoietic malignancies, especially those associated with TNF antagonists, in large population based cohorts of patients with RA.METHODS:A population based cohort study was performed of patients with RA (one prevalent cohort (n = 53,067), one incident cohort (n = 3703), and one TNF antagonist treated cohort 1999 through 2003 (n = 4160)), who were linked with the Swedish Cancer Register. Additionally, the lymphoma specimens for the 12 lymphomas occurring in patients with RA exposed to TNF antagonists in Sweden 1999 through 2004 were reviewed.RESULTS:Study of almost 500 observed haematopoietic malignancies showed that prevalent and incident patients with RA were at increased risk of lymphoma (SIR = 1.9 and 2.0, respectively) and leukaemia (SIR = 2.1 and 2.2, respectively) but not of myeloma. Patients with RA treated with TNF antagonists had a tripled lymphoma risk (SIR = 2.9) compared with the general population. After adjustment for sex, age, and disease duration, the lymphoma risk after exposure to TNF antagonists was no higher than in the other RA cohorts. Lymphomas associated with TNF antagonists had characteristics similar to those of other RA lymphomas.CONCLUSION:Overall, patients with RA are at equally increased risks for lymphomas and leukaemias. Patients with RA treated with TNF antagonists did not have higher lymphoma risks than other patients with RA. Prolonged observation is needed to determine the long term effects of TNF antagonists on lymphoma risk.
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8.
  • Askling, Johan, et al. (author)
  • Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden
  • 2005
  • In: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 52:7, s. 1986-1992
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE:Because treatment with tumor necrosis factor (TNF) antagonists may increase the risk of tuberculosis (TB), and because knowledge of the risk of TB in rheumatoid arthritis (RA) not treated with biologics is scarce and of uncertain generalizability to low-risk populations, this study sought to determine the risk of TB among Swedish patients with RA.METHODS:Using data from Swedish nationwide and population-based registers and data from an ongoing monitoring program of TNF antagonists, the relative risks of TB in patients with RA (versus the general population) and of TB associated with TNF antagonists (versus RA patients not treated with biologics) were determined by comparing the incidence of hospitalization for TB in 3 RA cohorts and 2 general population cohorts from 1999 to 2001. We also reviewed the characteristics of all reported cases of TB in RA patients treated with TNF antagonists in Sweden and calculated the incidence of TB per type of TNF antagonist between 1999 and 2004.RESULTS:During 1999-2001, RA patients who were not treated with TNF antagonists were at increased risk of TB versus the general population (relative risk 2.0, 95% confidence interval [95% CI] 1.2-3.4). RA patients treated with TNF antagonists had a 4-fold increased risk of TB (relative risk 4.0, 95% CI 1.3-12) versus RA patients not treated with TNF antagonists. The reported TB cases during 1999-2004 in RA patients exposed to TNF antagonists (9 infliximab, 4 etanercept, 2 both) were predominantly pulmonary. TB occurred up to 3 years following the start of treatment.CONCLUSION:Irrespective of whether TNF antagonists are administered, Swedish patients with RA are at increased risk of TB. During 1999-2001, TNF antagonists were associated with an increased risk of TB, up to 4-fold in magnitude. This increased risk may persist over time during treatment and is related to both infliximab and etanercept.
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9.
  • Askling, J, et al. (author)
  • Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists
  • 2005
  • In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 64:10, s. 1421-1426
  • Journal article (peer-reviewed)abstract
    • BACKGROUND:Existing studies of solid cancers in rheumatoid arthritis (RA) reflect cancer morbidity up until the early 1990s in prevalent cohorts admitted to hospital during the 1980s.OBJECTIVE:To depict the cancer pattern of contemporary patients with RA, from updated risk data from prevalent and incident RA populations. To understand the risk of solid cancer after tumour necrosis factor (TNF) treatment by obtaining cancer data from cohorts treated in routine care rather than trials.METHODS:A population based study of three RA cohorts (one prevalent, admitted to hospital 1990-2003 (n = 53,067), one incident, diagnosed 1995-2003 (n = 3703), and one treated with TNF antagonists 1999-2003 (n = 4160)), which were linked with Swedish nationwide cancer and census registers and followed up for cancer occurrence through 2003.RESULTS:With 3379 observed cancers, the prevalent RA cohort was at marginally increased overall risk of solid cancer, with 20-50% increased risks for smoke related cancers and +70% increased risk for non-melanoma skin cancer, but decreased risk for breast (-20%) and colorectal cancer (-25%). With 138 cancers, the incident RA cohort displayed a similar cancer pattern apart from non-decreased risks for colorectal cancer. TNF antagonist treated patients displayed solid cancer (n = 67) risks largely similar to those of other patients with RA.CONCLUSION:The cancer pattern in patients treated with TNF antagonists mirrors those of other contemporary as well as historic RA cohorts. The consistent increase in smoking associated cancers in patients with RA emphasises the potential for smoking cessation as a cancer preventive measure in RA.
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10.
  • Askling, J, et al. (author)
  • Swedish registers to examine drug safety and clinical issues in RA
  • 2006
  • In: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 65:6, s. 707-712
  • Research review (peer-reviewed)abstract
    • Data from several different monitoring systems are examined. The potential for registers based on data obtained from clinical practice, and linkage of such data to national health and population registers, is discussed. The approach described is a possible prototype for long term surveillance systems needed for the safe introduction of new treatments.
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11.
  • Askling, Johan, et al. (author)
  • Time-dependent increase in risk of hospitalisation with infection among Swedish RA patients treated with TNF antagonists
  • 2007
  • In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 66:10, s. 1339-1344
  • Journal article (peer-reviewed)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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13.
  • Bendtzen, Klaus, et al. (author)
  • Behandling af reumatoid artrit med anti-tumornekrosefaktor-alpha-antistof. Individuel monitorering af biotilgaengelighed og immunogenicitet-- sekundaerpublikation
  • 2007
  • In: Ugeskrift for Laeger. - 0041-5782. ; 169:5, s. 420-423
  • Journal article (peer-reviewed)abstract
    • Remicade/infliximab is effective in rheumatoid arthritis (RA), but response failure is frequent. Sera from 106 RA patients were monitored using an RIA for functional infliximab and an RIA for anti-infliximab antibody (Ab). S-infliximab varied considerably, e.g. 0-22 microg/ml before the 3rd infusion, and 44% were Ab-positive after 6 months. Low s-infliximab was associated with Ab development and later therapeutic failure, and high Ab levels could be related to dose increases, side-effects and cessation of therapy. Pharmacological monitoring should help optimize anti-TNF therapies.
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14.
  • Bendtzen, Klaus, et al. (author)
  • Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab
  • 2006
  • In: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 54:12, s. 3782-3789
  • Journal article (peer-reviewed)abstract
    • Objective. Infliximab, an anti-tumor necrosis factor alpha (anti-TNF alpha) antibody, is effective in the treatment of several immunoinflammatory diseases. However, many patients experience primary or secondary response failure, suggesting that individualization of treatment regimens may be beneficial. This study was undertaken to investigate whether serologic monitoring of infliximab bioavailability and immunogenicity in individual patients would be useful in optimizing treatment regimens to improve efficacy and tolerability. Methods. To avoid the use of solid-phase assays, two radioimmunoassays were developed: one for measurement of levels of anti-infliximab antibody, and a functional one for measurement of TNF alpha binding due to infliximab. Sera from 106 randomly selected rheumatoid arthritis patients were tested within 6 months of therapy initiation, and associations between findings of serum assays and disease activity, infusion reactions, and treatment failure occurring within 18 months were assessed. Results. Trough serum infliximab levels after the first 2 intravenous infusions of infliximab at 3 mg/kg varied considerably between patients (range 0-22 mu g/ml). At this stage, only 13% of the patients were anti-infliximab antibody positive. With subsequent infusions, the frequency of antibody positivity rose to 30% and 44% (at 3 months and 6 months, respectively), accompanied by diminished trough levels of infliximab. Indeed, low infliximab levels at 1.5 months predicted antibody development and later treatment failure. There were highly significant correlations between high levels of antibodies and later dose increases, side effects, and cessation of therapy. High baseline disease activity, judged by C-reactive protein level and Disease Activity Score, was associated with low levels of infliximab at the early stage of treatment and later development of anti-infliximab antibodies. Cotreatment with methotrexate resulted in slightly reduced antibody levels after 6 months; other disease-modifying antirheumatic drugs and prednisolone had no effect. Conclusion. Development of anti-infliximab antibodies, heralded by low preinfusion serum infliximab levels, is associated with increased risk of infusion reaction and treatment failure. Early monitoring may help optimize dosing regimens for individual patients, diminish side effects, and prevent prolonged use of inadequate infliximab therapy.
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15.
  • Berthold, Elisabet, et al. (author)
  • Continuation of TNF blockade in patients with inflammatory rheumatic disease. An observational study on surgical site infections in 1,596 elective orthopedic and hand surgery procedures
  • 2013
  • In: Acta Orthopaedica. - : Medical Journals Sweden AB. - 1745-3682 .- 1745-3674. ; 84:5, s. 495-501
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Increased infection risk in inflammatory rheumatic diseases may be due to inflammation or immunosuppressive treatment. The influence of tumor necrosis factor (TNF) inhibitors on the risk of developing surgical site infections (SSIs) is not fully known. We compared the incidence of SSI after elective orthopedic surgery or hand surgery in patients with a rheumatic disease when TNF inhibitors were continued or discontinued perioperatively.PATIENTS AND METHODS: We included 1,551 patients admitted for elective orthopedic surgery or hand surgery between January 1, 2003 and September 30, 2009. Patient demographic data, previous and current treatment, and factors related to disease severity were collected. Surgical procedures were grouped as hand surgery, foot surgery, implant-related surgery, and other surgery. Infections were recorded and defined according to the 1992 Centers for Disease Control definitions for SSI. In 2003-2005, TNF inhibitors were discontinued perioperatively (group A) but not during 2006-2009 (group B).RESULTS: In group A, there were 28 cases of infection in 870 procedures (3.2%) and in group B, there were 35 infections in 681 procedures (5.1%) (p = < 0.05). Only foot surgery had significantly more SSIs in group B, with very low rates in group A. In multivariable analysis with groups A and B merged, only age was predictive of SSI in a statistically significant manner.INTERPRETATION: Overall, the SSI rates were higher after abolishing the discontinuation of anti-TNF perioperatively, possibly due to unusually low rates in the comparator group. None of the medical treatments analyzed, e.g. methotrexate or TNF inhibitors, were significant risk factors for SSI. Continuation of TNF blockade perioperatively remains a routine at our center.
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16.
  • Björkengren, Ann G, et al. (author)
  • MR imaging of the knee in acute rheumatoid arthritis: synovial uptake of gadolinium-DOTA
  • 1990
  • In: American Journal of Roentgenology: diagnostic imaging and related sciences. - 1546-3141. ; 155:2, s. 329-332
  • Journal article (peer-reviewed)abstract
    • In patients with rheumatoid arthritis, the presence of acute synovial inflammation is an indication of the activity of the disease. It is an important finding because it often influences therapeutic decisions. However, acute synovitis may be difficult to detect by clinical examination, especially if a joint effusion also is present. As gadolinium tetra-azacyclododecane tetraacetic acid (Gd-DOTA) can be expected to accumulate in areas of acute inflammation, we studied the value of Gd-DOTA-enhanced MR to determine the presence of acute synovitis. Nine patients with current knee symptoms underwent MR examination of the knee. Short and long TR/TE MR images were obtained with a 0.3-T magnet before and immediately after IV administration of Gd-DOTA. A 15-min delayed short TR/TE image also was obtained. Of eight patients with moderate to severe clinical evidence of acute synovitis, six had marked increase and two had moderate increase in signal intensity from synovial tissue on the short TR/TE image obtained immediately after administration of contrast material. In the ninth patient, who had minimal synovitis clinically, the signal from the synovium did not change after administration of contrast material. No difference was seen between the enhancement pattern on the immediate and the 15-min delayed images. These results suggest that Gd-DOTA is taken up by inflamed synovium and that Gd-DOTA-enhanced MR scans may be useful in detecting acute synovitis in patients with rheumatoid arthritis.
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17.
  • C Kapetanovic, Meliha, et al. (author)
  • Antibody response is reduced following vaccination with 7-valent conjugate pneumococcal vaccine in adult methotrexate-treated patients with established arthritis, but not those treated with tumor necrosis factor inhibitors
  • 2011
  • In: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 63:12, s. 3723-3732
  • Journal article (peer-reviewed)abstract
    • Objective To study the influence of antiinflammatory treatments, including methotrexate (MTX) and tumor necrosis factor (TNF) inhibitors, on antibody response following vaccination using a 7-valent conjugate pneumococcal vaccine in adult patients with established arthritis. Methods. Patients with rheumatoid arthritis (RA) or spondylarthropathy (SpA) (including psoriatic arthritis) were vaccinated (n = 505). All patients were stratified into 6 prespecified groups based on diagnosis and treatment (RA patients receiving MTX, RA patients receiving anti-TNF agents and MTX, RA patients receiving TNF inhibitors as monotherapy, SpA patients receiving anti-TNF agents and MTX, SpA patients receiving TNF inhibitors as monotherapy, and SpA patients receiving nonsteroidal antiinflammatory drugs [NSAIDs] and/or analgesics). SpA patients receiving only NSAIDs/analgesics served as a control group. All patients received 1 dose (0.5 ml) of vaccine intramuscu-larly. Levels of IgG antibodies against 23F and 6B serotypes were measured at vaccination and at 4-6 weeks following vaccination, using standardized enzyme-linked immunosorbent assays. Results. Positive antibody response was defined as an antibody response ratio (ARR) (i. e., ratio of post-to prevaccination antibody levels) of > 2. The ARR differed significantly between the groups. A better ARR was seen among patients in the control group compared to those in groups treated with MTX or MTX in combination with TNF inhibitors. Among patients treated with TNF inhibitors as monotherapy, ARRs for both serotypes were lower numerically, but were not significantly different, compared to those in controls. Ongoing MTX treatment was predictive of reduced response (odds ratio 0.41 [95% confidence interval 0.24-0.68], P = 0.001). Higher age was associated with impaired positive antibody response. Concomitant prednisolone treatment elicited better positive antibody response in patients with RA. Conclusion. Treatment with MTX and higher age were predictive of an impaired antibody response to the 7-valent conjugate pneumococcal vaccine in this cohort of patients with chronic arthritis. TNF inhibitors did not significantly affect antibody responses.
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18.
  • C Kapetanovic, Meliha, et al. (author)
  • Development of functional impairment and disability in rheumatoid arthritis patients followed for 20 years - relation to disease activity, joint damage and comorbidity.
  • 2015
  • In: Arthritis Care and Research. - : Wiley. - 2151-4658 .- 2151-464X. ; 67:3, s. 340-348
  • Journal article (peer-reviewed)abstract
    • Objectives. To study the course of impairment measured by signals of functional impairment (SOFI) and disability measured by health assessment questionnaire (HAQ) over 20 years in rheumatoid arthritis (RA) patients followed from diagnosis. To explore the contribution of disease activity, joint damage and comorbidity to variation of SOFI and HAQ over time. Methods. RA patients diagnosed 1985-1989 were prospectively monitored. There were 183 patients, 63 % were women, mean (SD) age was 52 (12) years. Disease activity was measured by 44-joint DAS, joint damage by Larsen score and comorbidity by Charlson Comorbidity Index. Contribution of comorbidity, DAS and joint damage on development of SOFI and HAQ was studied at 0,5,10, 15 and 20 years follow up (hierarchical regression model) and over the total study period using (longitudinal regression model). Results. SOFI progressed over 20 years while progression of HAQ levelled off after 10 years. For SOFI, DAS and joint damage contributed the most (2-28 % and 3-31%, respectively). Over 20 years, SOFI was explained by DAS (20%), joint damage (20%), age (7%) and comorbidity (4%). For HAQ, DAS contributed the most (4-24%). Over 20 years, HAQ was explained by DAS (20%), joint damage (2%), gender (7%), comorbidity (6%) and age (4%). Conclusion. Over 20 years, 51% of the variation of SOFI and 39% of the variation of HAQ could be explained by age, gender and variations in comorbidity, disease activity and joint damage. Over time, disease activity contributed significantly to both SOFI and HAQ. Joint damage contributed predominantly to SOFI. © 2014 American College of Rheumatology.
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19.
  • C Kapetanovic, Meliha, et al. (author)
  • Early changes in bone mineral density measured by digital X-ray radiogrammetry predict up to 20 years radiological outcome in rheumatoid arthritis.
  • 2011
  • In: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362. ; 13:1
  • Journal article (peer-reviewed)abstract
    • ABSTRACT: INTRODUCTION: Change in bone mineral density (BMD) in the hand, as evaluated by digital X-ray radiogrammetry (DXR) of the II-IV metacarpal bones, has been suggested to predict future joint damage in rheumatoid arthritis (RA). This study's objective was to investigate if DXR-BMD loss early in the disease predicts development of joint damage in RA patients followed for up to 20 years. METHODS: 183 patients (115 women and 68 men) with early RA (mean disease duration 11 months) included from 1985 to 1989 were followed prospectively (the Lund early RA cohort). Clinical and functional measures were assessed yearly. Joint damage was evaluated according to the Larsen score on radiographs of hands and feet taken in years 0 to 5, 10, 15 and 20. These radiographs were digitized and BMD of the II-IV metacarpal bones was evaluated by DXR (Sectra, Linkoping. Sweden). Early DXR-BMD change rate (bone loss) per year calculated from the first 2 radiographs taken on average 9 months apart (SD 4.8) were available for 135 patients. Mean values of right and left hand were used. RESULTS: Mean early DXR-BMD loss during the first year calculated was -0.023 g/cm2 (SD 0.025). Patients with marked bone loss, i.e. early DXR-BMD loss above the median for the group, had significantly worse progression of joint damage at all examinations during the 20-year period. CONCLUSIONS: Early DXR-BMD progression rate predicted development of joint damage evaluated according to Larsen at year one and further onwards up to 20 years in this cohort of early RA patients.
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20.
  • C Kapetanovic, Meliha, et al. (author)
  • Impact of anti-rheumatic treatment on immunogenicity of pandemic H1N1 influenza vaccine in patients with arthritis.
  • 2014
  • In: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 16:1
  • Journal article (peer-reviewed)abstract
    • An adjuvanted pandemic H1N1 influenza (pH1N1) vaccine (Pandemrix®) was reported as highly immunogenic resulting in seroconversion in 77 to 94% of adults after administration of a single dose. The aim of the study was to investigate the impact of different anti-rheumatic treatments on antibody response to pH1N1 vaccination in patients with rheumatoid arthritis (RA) and spondylarthropathy (SpA).
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21.
  • C Kapetanovic, Meliha, et al. (author)
  • Influence of methotrexate, TNF blockers and prednisolone on antibody responses to pneumococcal polysaccharide vaccine in patients with rheumatoid arthritis.
  • 2006
  • In: Rheumatology. - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 45:1, s. 106-111
  • Journal article (peer-reviewed)abstract
    • Objective. To compare antibody responses to 23-valent pneumococcal vaccine (Pneumovax (R)) in controls and patients with established rheumatoid arthritis (RA) treated with TNF blockers, methotrexate (MTX) or a combination of both. Methods. Patients with RA (n = 149) and healthy controls (n = 47) were vaccinated. Treatment with TNF blockers (etanercept or infliximab) and MTX was given to 50 patients, and 62 patients were treated with TNF blockers alone or with other DMARDs. MTX alone was given to 37 patients. Concentrations of immunoglobulin G (IgG) antibodies against pneumococcal capsular polysaccharides 23F and 6B were measured by enzyme-linked immunoassay before and 4-6 weeks after vaccination. An immune response was defined as a twofold or higher increase in antibody concentration following vaccination. Results. Prevaccination antibody levels for both 23F and 6B were similar in the patient groups. Antibody concentrations after vaccination increased significantly in all groups. Patients treated with TNF blockers without MTX showed better immune responses than those treated with TNF blockers in combination with MTX (P = 0.037 for 23F and P = 0.004 for 6B) or MTX alone (P < 0.001 for both 23F and 6B). RA patients given MTX alone had the lowest immune responses. Prednisolone treatment did not influence the responses. Conclusions. Patients treated with TNF blockers and controls showed similar responses to vaccination. In contrast, patients treated with MTX had reduced responses regardless of anti-TNF treatment. The findings do not argue against the use of pneumococcal vaccination in RA patients undergoing treatment with TNF blockers.
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22.
  •  
23.
  • C Kapetanovic, Meliha, et al. (author)
  • Long-term mortality rate in rheumatoid arthritis patients with disease onset in the 1980s.
  • 2011
  • In: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 1502-7732 .- 0300-9742. ; 40, s. 433-438
  • Journal article (peer-reviewed)abstract
    • Objective: To investigate the mortality rate and possible early predictive factors of mortality after 19-23 years in a cohort of patients with rheumatoid arthritis (RA) followed prospectively from disease onset. Patients and methods: A community-based cohort of 183 patients (63% female) with RA and disease duration < 2 years was recruited 1985-1989. The patients were followed yearly from diagnosis until death or 31 December 2008. Mean age and mean duration of symptoms (range) at diagnosis were 52 (18-78) years and 11 (0-24) months, respectively. Death certificates were obtained from the Swedish Cause of Death Register and causes of death were coded by the International Classification of Diseases (ICD-10). Death rates of RA patients were compared to those of age- and sex-matched controls. Possible predictors of mortality were analysed using a Cox regression model. Results: By 31 December 2008, 69 patients (37 women and 32 men) had died. The standardized mortality ratio (SMR) was 1.23 [95% confidence interval (CI) 0.97-1.55] and p < 0.09. Older age, male sex, smoking, and the presence of cardiovascular disease (CVD) at RA diagnosis were identified as early predictors of mortality. CVD was the most common cause of death (46%), followed by malignancies (29%) and infections (13%). RA was not stated as the direct cause of death in any patient and was mentioned among underlying causes in only 16/69 (23%) patients. Conclusion: Mortality rate after 19-23 years of disease duration in this cohort of patients with disease onset in the 1980s was not significantly increased compared to age- and sex-matched controls. No RA disease-related factor predicted mortality.
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24.
  • C Kapetanovic, Meliha, et al. (author)
  • Persistence of antibody response 1.5 years after vaccination using 7-valent pneumococcal conjugate vaccine in patients with arthritis treated with different antirheumatic drugs
  • 2013
  • In: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 15:1
  • Journal article (peer-reviewed)abstract
    • Introduction: The aim of this study was to explore the persistence of an antibody response 1.5 years after vaccination with 7-valent pneumococcal conjugate vaccine in patients with rheumatoid arthritis (RA) or spondyloarthropathy (SpA) treated with different antirheumatic drugs. Methods: Of 505 patients initially recruited, data on current antirheumatic treatment and blood samples were obtained from 398 (79%) subjects after mean (SD, range) 1.4 (0.5; 1 to 2) years. Antibody levels against pneumococcal serotypes 23F and 6B were analyzed by using enzyme-linked immunosorbent assay (ELISA). Original treatment groups were as follows: (a) RA receiving methotrexate (MTX); (b) RA taking anti-TNF monotherapy; (c) RA taking anti-TNF+MTX; (d) SpA with anti-TNF monotherapy; (e) SpA taking anti-TNF+MTX; and (f) SpA taking NSAID/analgesics. Geometric mean levels (GMLs; 95% CI) and proportion (percentage) of patients with putative protective antibody levels >= 1 mg/L for both serotypes, calculated in different treatment groups, were compared with results 4 to 6 weeks after vaccination. Patients remaining on initial treatment were included in the analysis. Possible predictors of persistence of protective antibody response were analysed by using logistic regression analysis. Results: Of 398 patients participating in the 1.5-year follow up, 302 patients (RA, 163, and SpA, 139) had unchanged medication. Compared with postvaccination levels at 1.5 years, GMLs for each serotype were significantly lower in all groups (P between 0.035 and <0.001; paired-sample t test), as were the proportions of patients with protective antibody levels for both serotypes (P < 0.001; chi(2) test). Higher prevaccination antibody levels for both serotypes 23F and 6B were associated with better persistence of protective antibodies (P < 0.001). Compared with patients with protective antibody levels at 1.5 years, those not having protective antibody levels were older, more often women, had longer disease duration and higher HAQ and DAS, and had a lower proportion of initial responders to both serotypes. Concomitant anti-TNF treatment and MTX were identified as negative predictors of the persistence of protective antibodies among RA patients (P = 0.024 and P = 0.065, respectively). Only age 65 years or older (P = 0.017) and not antirheumatic treatment was found to be a negative predictor of protective antibodies in patients with SpA. Conclusions: After initial increase, 1.5 years after pneumococcal vaccination with 7-valent conjugate vaccine, postvaccination antibody levels decreased significantly, reaching levels before vaccination in this cohort of patients with established arthritis treated with different antirheumatic drugs. MTX and anti-TNF treatment predicted low persistence of protective immunity among patients with RA. To boost antibody response, early revaccination with conjugate vaccine might be needed in patients receiving potent immunosuppressive remedies.
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25.
  •  
26.
  • C Kapetanovic, Meliha, et al. (author)
  • Prevalence and predictive factors of comorbidity in rheumatoid arthritis patients monitored prospectively from disease onset up to 20 years: lack of association between inflammation and cardiovascular disease.
  • 2010
  • In: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 1502-7732 .- 0300-9742. ; 39, s. 353-359
  • Journal article (peer-reviewed)abstract
    • Objectives: To study the prevalence of comorbid conditions at diagnosis and during follow-up in a cohort of patients with early rheumatoid arthritis (RA) followed prospectively over 20 years, and to identify possible early predictive factors for future comorbidities. Methods: A community-based cohort of 183 patients (mean age 52 years, 63% female) with early RA was recruited between 1985 and 1989. The presence of comorbidity at RA diagnosis and the occurrence of additional comorbidities were recorded continuously. Possible predictors of future comorbidities were analysed using the Cox proportional hazards model. Results: At RA diagnosis, at least one comorbid condition was present in 43% of the patients. Cardiovascular diseases (CVDs), including hypertension (16% of patients) and malignancy (6% of patients), were most common. In total, 82% of patients developed additional comorbidities during follow-up. CVD and malignancies remained the most frequent comorbidities. Higher age [p < 0.001, odds ratio (OR) 1.03, 95% confidence interval (CI) 1.01-1.15] and the presence of any comorbidity at diagnosis (p = 0.02; OR 1.64, 95% CI 1.08-2.52) predicted future comorbidity. Measures of inflammation at diagnosis or during follow-up were not predictive for development of CVD. Conclusion: Comorbidity was present in a considerable proportion of patients in this cohort. More than 40% of patients had another disease at inclusion and during follow-up and > 80% developed additional conditions. The pattern of comorbidity remained unchanged, with CVD and malignancy being most common. Older age and the presence of comorbidity at RA diagnosis predicted the development of comorbidities. The degree of inflammation at any time point was not predictive of future CVD.
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27.
  • C Kapetanovic, Meliha, et al. (author)
  • Rituximab and abatacept but not tocilizumab impair antibody response to pneumococcal conjugate vaccine in patients with rheumatoid arthritis
  • 2013
  • In: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 15:5
  • Journal article (peer-reviewed)abstract
    • Introduction: The objective of the study was to investigate the impact of newer biologic treatments including rituximab, abatacept and tocilizumab on antibody response following pneumococcal vaccination using a 7-valent conjugate vaccine in patients with established rheumatoid arthritis (RA). Methods: Patients with RA receiving rituximab, abatacept or tocilizumab as monotherapy or combined with methotrexate (MTX) participated in the study. Specific IgG antibodies against 23F and 6B serotypes were measured at vaccination and 4 to 6 weeks after vaccination using standardised ELISA. Geometric mean antibody levels (GML) were calculated. Antibody response (AR) was defined as the ratio between post-and pre-vaccination antibody levels and a positive antibody response (posAR) was AR >= 2. Results: In total, 88 patients were enrolled in the study. Of 55 patients treated with rituximab, 26 (46%) were on concomitant MTX. Of patients receiving abatacept (n = 17) and tocilizumab (n = 16) biologic treatment was given in combination with MTX in 13 (76%) and 9 (56%) patients, respectively. Patients treated with rituximab had significantly lower AR compared to those on tocilizumab, as well as compared to previously reported RA patients on MTX and controls (spondylarthropathy patients treated with NSAIDs and/or analgesics). In total, 10.3% of patients on rituximab monotherapy and no patient on rituximab + MTX had posAR for both serotypes. For abatacept and tocilizumab the corresponding figures were 17.6% and 50%. Conclusion: In this cohort of patients with established RA, treatment with rituximab and abatacept was associated with diminished antibody response but this was most pronounced for rituximab. Pneumococcal conjugate vaccine administrated during ongoing tocilizumab treatment seems to be associated with sufficient antibody response. Pneumococcal vaccination should preferably be encouraged before initiation of rituximab or abatacept treatment.
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28.
  • C Kapetanovic, Meliha, et al. (author)
  • Serum cartilage oligomeric matrix protein (COMP) decreases in rheumatoid arthritis patients treated with infliximab or etanercept.
  • 2003
  • In: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1465-9905. ; 5:4, s. 181-185
  • Journal article (peer-reviewed)abstract
    • Changes in serum cartilage oligomeric matrix protein (COMP) were studied during a 6-month period from initiation of treatment of rheumatoid arthritis patients with either infliximab or etanercept, to elucidate whether the favourable results of tissue protection reported in clinical trials are corroborated by changing levels of circulating COMP. Rheumatoid arthritis patients commencing treatment with infliximab (N = 32) or etanercept (N = 17) were monitored in accordance with a structured protocol. Only patients who were not receiving glucocorticoids or who were on a stable dose of oral prednisolone (<10 mg daily) were included. Serum COMP was measured by a sandwich immunoassay based on two monoclonal antibodies against human COMP in samples obtained at treatment initiation and at 3 and 6 months. Serum COMP decreased at 3 months in both infliximab- and etanercept-treated patients (P < 0.001 and <0.005, respectively) and remained low at 6 months. There was no significant correlation between changes in or concentrations of serum COMP and serum C-reactive protein at any time point. A decrease in serum COMP was seen both in ACR20 responders (patients meeting the American College of Rheumatology criteria for 20% improvement) and in nonresponders. The pattern of changes of serum COMP, a marker for cartilage turnover, in these patient groups supports the interpretation that infliximab and etanercept have a joint protective effect. Serum COMP has potential as a useful marker for evaluating tissue effects of novel treatment modalities in rheumatoid arthritis.
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29.
  • Eberhardt, Kerstin, et al. (author)
  • Hand function tests are important and sensitive tools for assessment of treatment response in patients with rheumatoid arthritis.
  • 2008
  • In: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 1502-7732 .- 0300-9742. ; 37:2, s. 109-112
  • Journal article (peer-reviewed)abstract
    • Objectives: To assess the usefulness of hand function measurements in a study of treatment effects of tumour necrosis factor (TNF) blockers and to define the relationship between different hand function tests and also relate hand function to general disability and disease activity. Methods: The study group consisted of 49 patients with established rheumatoid arthritis (RA) who were followed for 1 year while on TNF inhibitors. Evaluation of hand function included Signals of Functional Impairment (SOFI), grip and pinch grip force, and the Grip Ability Test (GAT). General disability was assessed by the Health Assessment Questionnaire (HAQ) and disease activity by the 28-joint Disease Activity Score (DAS28). The standardized mean response (SMR) method was used to evaluate sensitivity to change for all hand tests using DAS28 and HAQ as external indicators of change. Results: HAQ, DAS28, grip and pinch grip force, and GAT showed a highly significant improvement over time (p<0.001). The improvement in SOFI was also significant (p<0.01). The correlations between the different hand tests varied between 0.45 and 0.72. All hand function tests were significantly related to HAQ but showed only weak correlations to DAS28. SOFI, grip force, and pinch grip force showed large sensitivity for improvement in DAS28 and HAQ (SMR = 0.8-0.9). GAT showed modest sensitivity (SMR = 0.6-0.7). Conclusions: Patients with advanced RA attained considerable improvement in hand function that was only partly reflected by measures of general disability and disease activity. Focused assessment of hand function is therefore important for optimal evaluation of treatment response.
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30.
  • Eberhardt, Kerstin, et al. (author)
  • Hip involvement in early rheumatoid arthritis
  • 1995
  • In: Annals of the Rheumatic Diseases. - 1468-2060. ; 54:1, s. 45-48
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE--To study early hip involvement in rheumatoid arthritis (RA) and to evaluate the usefulness of ultrasonography in the detection of hip joint synovitis in RA. METHODS--Study I: The number of hip joint replacements was recorded in a cohort of 113 patients with RA of at least five years disease duration followed from an early stage. Study II: Ultrasonography was evaluated as a method to identify hip joint synovitis in 76 patients with RA of shorter disease duration, by relating it to radiograms and clinical findings. RESULTS--Study I: Twenty one hip joint replacements were performed in 15 of the 113 patients. The median disease duration at the time of first arthroplasty was 48 (range 10-76) months; the annual incidence was approximately constant between two and six years. High disease activity at the start of the study was predictive of requirement for hip prosthesis. Study II: Hip ultrasonography was pathological in 13 of the 76 patients studied, bilaterally in nine. Hip joint synovitis could not be confirmed on clinical grounds only as seven of the patients with positive ultrasonographic findings were asymptomatic, and the remaining six patients had only mild symptoms of hip involvement. Also, six of the 63 patients with normal ultrasonography had mild symptoms. There was no difference regarding demographic, clinical, and laboratory findings in patients with and without hip synovitis. CONCLUSIONS--Early hip joint destruction giving symptoms mostly at a very late stage is frequent in RA. Ultrasonography rather than signs or symptoms could identify patients with hip joint involvement and provide a rationale for early treatment.
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31.
  • Einarsson, Jon Thorkell, et al. (author)
  • Prevalence of sustained remission in rheumatoid arthritis: impact of criteria sets and disease duration, a Nationwide Study in Sweden
  • 2019
  • In: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 58:2, s. 227-236
  • Journal article (peer-reviewed)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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32.
  • Einarsson, Jon Thorkell, et al. (author)
  • Rituximab in clinical practice : dosage, drug adherence, Ig levels, infections, and drug antibodies
  • 2017
  • In: Clinical Rheumatology. - : Springer Science and Business Media LLC. - 0770-3198 .- 1434-9949. ; 36:12, s. 2743-2750
  • Journal article (peer-reviewed)abstract
    • The objective of this study is to explore the following: (1) the impact of two different initial doses and cumulative 2-year dose of rituximab (RTX) on drug adherence and predictors of adherence to treatment in rheumatoid arthritis (RA) patients in an observational clinical setting, (2) immunoglobulin levels (IgG/IgM/IgA) during repeated treatment and their relation to infections, and (3) development of anti-rituximab antibodies (ADA). All RA patients receiving RTX from January 2003 to April 2012 at the department were included. The initiating doses were 500 or 1000 mg intravenously days 1 and 15. Drug adherence was estimated using life-table. Baseline predictors of adherence to treatment were analyzed using Cox regression model. Levels of immunoglobulins were measured at treatment initiation and before retreatment. Serum levels of RTX and ADA were measured in 96 patients at 6 months using ELISA. One hundred fifty-three patients were included. Seventy-four (48%) started treatment with 500 and 79 (52%) with 1000 mg. No difference in drug adherence was seen between the different initial or cumulative RTX doses. Methotrexate (MTX) use and low DAS28 at baseline predicted better drug adherence. Ig levels decreased with repeated treatments but low levels were not associated with infections. 11/96 patients had developed ADA at 6 months. Long-term adherence to RTX in RA patient was not influenced by starting- or cumulative 2-year doses. MTX use and low DAS28 at baseline was positively associated with drug adherence. Decreasing Ig levels during treatment were not associated with risk of infections. Development of ADA may influence treatment efficacy and tolerability.
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33.
  • Einarsson, Jon T., et al. (author)
  • Secular trends of sustained remission in rheumatoid arthritis, a nationwide study in Sweden
  • 2020
  • In: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 59:1, s. 205-212
  • Journal article (peer-reviewed)abstract
    • OBJECTIVES: The aim of this study of patients with RA in Sweden was to investigate secular trends in achieving sustained remission (SR), i.e. DAS28 <2.6 on at least two consecutive occasions and lasting for at least 6 months. METHODS: All adult RA patients registered in the Swedish Rheumatology Quality register through 2012, with at least three registered visits were eligible, a total of 29 084 patients. Year of symptom onset ranged from 1955, but for parts of the analysis only patients with symptom onset between 1994 and 2009 were studied. In total, 95% of patients fulfilled the ACR 1987 classification criteria for RA. Odds of reaching SR for each decade compared with the one before were calculated with logistic regression and individual years of symptom onset were compared with life table analysis. RESULTS: Of patients with symptom onset in the 1980s, 1990s and 2000s, 35.0, 43.0 and 45.6% reached SR, respectively (P < 0.001 for each increment), and the odds of SR were higher in every decade compared with the one before. The hazard ratio for reaching SR was 1.15 (95% CI 1.14, 1.15) for each year from 1994 to 2009 compared with the year before. Five years after symptom onset in 2009, 45.3% of patients had reached SR compared with 15.9% in 1999. CONCLUSION: There is a clear secular trend towards increased incidence of SR in patients with RA in Sweden. This trend most likely reflects earlier diagnosis and treatment start, and adherence to national and international guidelines recommending the treat to target approach.
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34.
  • Einarsson, Jon Thorkell, et al. (author)
  • Sustained Remission Improves Physical Function in Patients with Established Rheumatoid Arthritis, and Should Be a Treatment Goal : A Prospective Observational Cohort Study from Southern Sweden
  • 2016
  • In: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 43:6, s. 1017-1023
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: It has been proposed that remission should be maintained throughout the course of rheumatoid arthritis (RA); however, the evidence supporting this is limited. Physical function measured by the Health Assessment Questionnaire (HAQ) is a major outcome in RA, and HAQ is shown to be one of the strongest predictors of longterm outcomes. The purpose of this study was to investigate the physical function over a long time in patients with RA who achieved sustained remission (SR) compared with that of patients occasionally achieving remission [non-sustained remission (NSR)].METHODS: Patients with RA treated with antitumor necrosis factor and included in the South Swedish Arthritis Treatment Group register were eligible for this study. We identified patients with a Disease Activity Score at 28 joints (DAS28) < 2.6 or Simplified Disease Activity Index (SDAI) ≤ 3.3 at some point and those who achieved SR, i.e., remission during consecutive visits for at least 6 months. The course of functional status was assessed using the HAQ at each visit.RESULTS: Of the 2416 patients, 1177 (48.7%) reached DAS28 remission at some point. SR was achieved by 382 (15.8%) for the DAS28 and 186 (7.7%) for the SDAI criteria. Comparing the SR and NSR groups, HAQ improved during the first 12 months in the DAS28 remission. HAQ continued to improve relatively as long as SR was maintained. A higher proportion of patients in SR reached full physical function.CONCLUSION: In patients with established RA, physical function measured by the HAQ improves in patients reaching SR compared with patients who only occasionally reach remission. The improvement continues while in remission, which supports that maintaining remission should be a treatment goal.
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35.
  • Einarsson, Jon Thorkell, et al. (author)
  • Sustained Remission in Tumor Necrosis Factor Inhibitor-treated Patients with Rheumatoid Arthritis: A Population-based Cohort Study.
  • 2015
  • In: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 42:5, s. 741-748
  • Journal article (peer-reviewed)abstract
    • To study frequency, possible baseline predictors, timing, and duration of sustained remission [SR; defined as 28-joint Disease Activity Score (DAS28) < 2.6 for at least 6 mos] in patients with established rheumatoid arthritis (RA) treated with different tumor necrosis factor (TNF) inhibitors [etanercept (ETN), infliximab (IFX), adalimumab (ADA)]. In addition, the aim was to compare (head-to-head) the effectiveness of individual drugs in patients receiving their first anti-TNF treatment.
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36.
  • Englund, Martin, et al. (author)
  • Prevalence and incidence of rheumatoid arthritis in southern Sweden 2008 and their relation to prescribed biologics.
  • 2010
  • In: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 49, s. 1563-1569
  • Journal article (peer-reviewed)abstract
    • Objectives. To gain updated estimates of prevalence and incidence of RA and proportion on biological treatment in southern Sweden. Methods. Inpatient and outpatient health care provided to residents in the southernmost county of Sweden (1.2 million inhabitants) is registered in the Skåne Health Care Register (SHCR). We identified residents aged >/=20 years who had received a diagnosis of RA at least twice during 2003-08. Valid point prevalence estimates by 31 December 2008 were obtained by linkage to the Swedish population register, and information on biological treatment was obtained from the South Swedish Arthritis Treatment Group register. We also tested our estimates of RA occurrence in a series of sensitivity analyses to investigate the effect of altered case criteria and the uncertainty generated by clinical visits without diagnoses. Results. The prevalence of RA in adults was estimated to 0.66% (women = 0.94%, men = 0.37%). The prevalence peaked at age 70-79 years (women = 2.1%, men = 1.1%) before dropping in those aged >/=80 years. Of prevalent cases, 20% had ongoing biological treatment, a percentage that was highest in women aged 40-49 years (36%). The incidence of RA in 2008 was estimated as 50/100 000 (women = 68/100 000, men = 32/100 000). Conclusions. When compared with a previous report from southern Sweden, the prevalence of RA seems not to have declined in the last decade. The proportion of patients with ongoing biological treatment was slightly higher in women than men. SHCR data are promising additions to other methods to gain frequency estimates of clinically important disease in a timely and cost-efficient manner.
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37.
  • Eriksson, Jonas, et al. (author)
  • Cost-effectiveness of infliximab versus conventional combination treatment in methotrexate-refractory early rheumatoid arthritis: 2-year results of the register-enriched randomised controlled SWEFOT trial.
  • 2015
  • In: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 74:6, s. 1094-1101
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: To estimate the incremental cost-effectiveness of infliximab versus conventional combination treatment over 21 months in patients with methotrexate-refractory early rheumatoid arthritis. METHODS: In this multicentre, two-arm, parallel, randomised, active-controlled, open-label trial, rheumatoid arthritis patients with <1 year symptom duration were recruited from 15 rheumatology clinics in Sweden between October 2002 and December 2005. After 3-4 months of methotrexate monotherapy, patients not achieving low disease activity were randomised to addition of infliximab or sulfasalazine+hydroxychloroquine (conventional treatment group). Costs of drugs, healthcare use, and productivity losses were retrieved from nationwide registers, while EuroQol 5-Dimensions utility was collected quarterly. RESULTS: Of 487 patients initially enrolled, 128 and 130 were randomised to infliximab and conventional treatment, respectively. The infliximab group accumulated higher drug and healthcare costs (€27 487 vs €10 364; adjusted mean difference €16 956 (95% CI 14 647 to 19 162)), while productivity losses did not differ (€33 804 vs €29 220; €3961 (95% CI -3986 to 11 850)), resulting in higher societal cost compared to the conventional group (€61 291 vs €39 584; €20 916 (95% CI 12 800 to 28 660)). Mean accumulated quality-adjusted life-years (QALYs) did not differ (1.10 vs 1.12; adjusted mean difference favouring infliximab treatment 0.01 (95% CI -0.07 to 0.08)). The incremental cost-effectiveness ratios for the infliximab versus conventional treatment strategy were €2 404 197/QALY from the societal perspective and €1 948 919/QALY from the healthcare perspective. CONCLUSIONS: In early, methotrexate-refractory rheumatoid arthritis, a treatment strategy commencing with addition of infliximab, as compared to sulfasalazine+hydroxychloroquine, was not cost-effective over 21 months at willingness to pay levels generally considered acceptable. TRIAL REGISTRATION NUMBER: NCT00764725.
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38.
  • Eriksson, Jonas K., et al. (author)
  • Biological vs Conventional Combination Treatment and Work Loss in Early Rheumatoid Arthritis A Randomized Trial
  • 2013
  • In: JAMA Internal Medicine. - : American Medical Association (AMA). - 2168-6114 .- 2168-6106. ; 173:15, s. 1407-1414
  • Journal article (peer-reviewed)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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39.
  •  
40.
  • Flouri, Irini, et al. (author)
  • Comparative effectiveness and survival of infliximab, adalimumab, and etanercept for rheumatoid arthritis patients in the Hellenic Registry of Biologics: Low rates of remission and 5-year drug survival
  • 2014
  • In: Seminars in Arthritis and Rheumatism. - : Elsevier BV. - 0049-0172. ; 43:4, s. 447-457
  • Research review (peer-reviewed)abstract
    • Objective: To compare effectiveness, drug survival, and safety between infliximab, adalimumab, and etanercept, in a nationwide cohort of rheumatoid arthritis (RA) patients. Methods: This study is a prospective cohort study of 1208 active RA patients. Effectiveness, drug survival, and serious adverse events during entire follow-up (median 2.9 years) were monitored. Results: EULAR and CDAI responses were comparable between the three agents (EULAR good/moderate responses at 12 months ranged 76-79%). At 12 months, 15-23% achieved remission. For adalimumab and etanercept, adjusted hazard rate (HR) for EULAR/ACR remission (reference: infliximab) was 2.7 and 2.1 (95% confidence interval was 1.7-4.1 and 1.3-3.4, respectively); males (HR 1.6; 1.1-2.4), use of glucocorticoids (HR 2.0; 13-3.0), and swollen joint count > 7 (HR 0.36; 0.24-0.55) were independent predictors. Five-year drug survival was 31%, 43%, and 49% for infliximab, adalimumab, and etanercept, respectively (p = 0.010). Infliximab was associated with significantly more withdrawals due to adverse events. Disease activity, CRP, and use of glucocorticoids predicted efficacy-related drug survival; age, use of methotrexate, and prior DMARDs failures predicted safety-related survival. Risk for serious infections was lower with adalimumab (odds ratio [OR] 0.62; 0.38-1.00) or etanercept (OR 0.39; 0.21-0.72) than infliximab, independent of the effects of age (OR 1.65; 1.37-2.00 per 10 years), tender joint count > 10 (OR 1.86; 1.21-2.86), and glucocorticoids >35 mg/week (OR 1.83; 1.12-2.99). Conclusions: Response rates were comparable among anti-TNF agents. Overall, 5-year drug survival was below 50%, with infliximab demonstrating increased safety-related discontinuations. Remission rates are low in clinical practice. Strategies to increase effectiveness and long-term survival of anti-TNF agents in RA are needed. (C) 2014 Elsevier Inc. All rights reserved.
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41.
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42.
  • Geborek, Pierre, et al. (author)
  • A survey of spinal collateral actions of feline ventral spinocerebellar tract neurons
  • 2013
  • In: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 37:3, s. 380-392
  • Journal article (peer-reviewed)abstract
    • The aim of this study was to identify spinal target cells of spinocerebellar neurons, in particular the ventral spinocerebellar tract (VSCT) neurons, giving off axon collaterals terminating within the lumbosacral enlargement. Axons of spinocerebellar neurons were stimulated within the cerebellum while searching for most direct synaptic actions on intracellularly recorded hindlimb motoneurons and interneurons. In motoneurons the dominating effects were inhibitory [inhibitory postsynaptic potentials (IPSPs) in 67% and excitatory postsynaptic potentials (EPSPs) in 17% of motoneurons]. Latencies of most IPSPs indicated that they were evoked disynaptically and mutual facilitation between these IPSPs and disynaptic IPSPs evoked by group Ia afferents from antagonist muscles and group Ib and II afferents from synergists indicated that they were relayed by premotor interneurons in reflex pathways from muscle afferents. Monosynaptic EPSPs from the cerebellum were accordingly found in Ia inhibitory interneurons and intermediate zone interneurons with input from group I and II afferents but only oligosynaptic EPSPs in motoneurons. Monosynaptic EPSPs following cerebellar stimulation were also found in some VSCT neurons, indicating coupling between various spinocerebellar neurons. The results are in keeping with the previously demonstrated projections of VSCT neurons to the contralateral ventral horn, showing that VSCT neurons might contribute to motor control at a spinal level. They might thus play a role in modulating spinal activity in advance of any control exerted via the cerebellar loop.
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43.
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44.
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45.
  • Geborek, Pierre, et al. (author)
  • Cytidine deaminase and lactoferrin in inflammatory synovial fluids. Indicators of local polymorphonuclear cell function?
  • 1992
  • In: British Journal of Rheumatology. - : Oxford University Press (OUP). - 0263-7103. ; 31:4, s. 235-240
  • Journal article (peer-reviewed)abstract
    • Cytidine deaminase (CD) is a cytoplasmatic enzyme present predominantly in polymorphonuclear cells (PMNC) in inflamed joints. Lactoferrin is situated in the secondary granules of PMNC and is released by secretory/phagocytic stimuli, whereas CD is released mainly upon cell lysis. To study the release of these molecules in arthritic conditions we measured CD and lactoferrin levels in synovial fluid (SF) drawn from patients with rheumatoid arthritis (RA), crystal pyrophosphate disease (CPPD), psoriatic arthropathy, reactive arthritis, spondylarthropathy, and osteoarthrosis. CD activity was highest in SF from RA and CPPD followed by psoriatic arthropathy, reactive arthritis and spondylarthropathy. Lactoferrin concentrations were highest in CPPD followed by RA, reactive arthritis, psoriatic arthropathy, and spondylarthropathy. Both CD and lactoferrin levels were low in osteoarthrosis SF. Although SF CD activity and lactoferrin levels correlated well in all diagnostic groups, the ratio between CD and lactoferrin was higher for RA, psoriatic arthropathy, and spondylarthropathy compared to reactive arthritis and CPPD. This suggests predominant release by PMNC lysis in the more chronic arthritis groups and more degranulation in the more episodic CPPD and reactive arthritis groups. CD activity and lactoferrin levels correlated significantly with SF cell counts in the RA and psoriatic arthropathy groups.
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46.
  • Geborek, Pierre, et al. (author)
  • Direct assessment of synovial blood flow and its relation to induced hydrostatic pressure changes
  • 1989
  • In: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 48:4, s. 281-286
  • Journal article (peer-reviewed)abstract
    • A method for measuring synovial blood flow changes using the laser Doppler technique is described. Mean blood flow and mean pulse amplitude decreased by 50-70% in relation to the reference level when the intra-articular hydrostatic pressure in effusive knee joints of patients with rheumatoid arthritis was increased. As an increase of intra-articular pressure of as little as 20 mmHg decreased synovial blood flow significantly it is suggested that hypoxia may occur in vivo during joint use in the presence of an effusion. This may be of aetiopathogenetic importance for tissue destruction and the persistence of chronic synovitis.
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47.
  • Geborek, Pierre, et al. (author)
  • Etanercept, infliximab, and leflunomide in established rheumatoid arthritis: clinical experience using a structured follow up programme in southern Sweden.
  • 2002
  • In: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 61:9, s. 793-798
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: To explore the feasibility of prospectively monitoring treatment efficacy and tolerability of infliximab, etanercept, and leflunomide over a two year period in patients with established rheumatoid arthritis (RA) in clinical practice using a structured protocol. METHODS: All patients with RA at seven centres in southern Sweden, for whom at least two disease modifying antirheumatic drugs, including methotrexate, had failed or not been tolerated, who started treatment with either infliximab, etanercept, or leflunomide were included. They were evaluated at predefined times using a standardised protocol including items required for evaluating response to the American College of Rheumatology (ACR) or EULAR criteria. All adverse events were recorded using World Health Organisation terminology. Concomitant treatment and survival while receiving a drug were recorded. RESULTS: During the study 166 patients were treated with etanercept, 135 with infliximab, and 103 with leflunomide. Treatment response as determined by the ACR and EULAR response criteria was similar for the tumour necrosis factor (TNF) blockers. The TNF blockers performed significantly better than leflunomide both as determined by the response criteria and by survival on drug analysis. Thus 79% and 75% continued to receive etanercept or infliximab compared with 22% of patients who started leflunomide after 20 months. The spectrum of side effects did not differ from those previously reported in the clinical trials. The initial two year experience of a protocol for postmarketing surveillance of etanercept, infliximab, and leflunomide shows that a structured protocol with central data handling can be used in clinical practice for documenting the performance of newly introduced drugs. CONCLUSIONS: Efficacy data for the TNF blockers comply with results in clinical trials, whereas leflunomide appeared to perform worse than in clinical trials. Prolonged monitoring is required to identify possible rare side effects.
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48.
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49.
  • Geborek, Pierre, et al. (author)
  • Intraarticular corticosteroid injection into rheumatoid arthritis knees improves extensor muscles strength
  • 1990
  • In: Rheumatology International. - 1437-160X. ; 9:6, s. 265-270
  • Journal article (peer-reviewed)abstract
    • Eleven arthritic knee joints in seven patients with rheumatoid arthritis were studied before and after intraarticular injection of a corticosteroid preparation. Extensor muscle torque and quantitative electromyography increased on days 7 and 14 after treatment, indicating that muscle function had been inhibited by synovitis. Clinical signs of synovitis, such as pain, range of motion and knee circumference, also improved. Synovial fluid withdrawal alone improved extensor muscle torque. Joints with instability and/or radiological cartilage involvement also improved.
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50.
  • Geborek, Pierre, et al. (author)
  • Joint capsular stiffness in knee arthritis. Relationship to intraarticular volume, hydrostatic pressures, and extensor muscle function
  • 1989
  • In: Journal of Rheumatology. - 0315-162X. ; 16:10, s. 1351-1358
  • Journal article (peer-reviewed)abstract
    • Increased intraarticular hydrostatic pressure (Pia) may inhibit juxtaarticular muscle function, obstruct blood supply to joint structures and promote anoxic joint destruction in chronic arthritis. Joint capsular stiffness together with synovial fluid volume determines Pia at rest. Seventeen knee joints with effusive arthritis and different degrees of radiological cartilage involvement in 13 patients with chronic arthritis were examined. Since capsular elastance was difficult to standardize, we introduce a measure of joint capsular stiffness where the intraarticular volume yielding a pressure of 50 mm Hg (V50) is used. After normalization of injected volumes according to the V50, pressure volume curves became similar. Intraarticular hydrostatic pressure and maximal voluntary isometric extensor torque were measured simultaneously, while altering the intraarticular fluid volume in 9 knee joints. In 5 of these, quantified electromyography (EMG) of the vastus medialis and lateralis portion of the quadriceps muscle was also monitored. Progressive inhibition of extensor torque and EMG was found as the intraarticular pressure volume was increased in both intact and destroyed joints. No difference in inhibition was found for the 2 portions of quadriceps muscle tested. Increased intraarticular hydrostatic pressure Pia levels between 200 and 1150 mm Hg were observed during maximal voluntary activation of extensor muscles. The reproducibility was good for all variables studied. In a few instances evidence of intraarticular compartmentalization was found at low volumes. We conclude that the V50 is a convenient expression of capsular stiffness. Furthermore, increasing Pia caused by joint effusion inhibits knee extensor muscle function and impairs synovial blood flow. Awareness of these relations will facilitate more rational therapeutic approaches in chronic arthritis.
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