Ronald F van Vollenhoven

Karolinska Institutet, Сольна, Stockholm, Sweden

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Publications (359)2676.39 Total impact

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    Adrian Levitsky · Malin C. Erlandsson · Ronald F van Vollenhoven · Maria I. Bokarewa
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    ABSTRACT: Background: The identification of biomarkers that predict optimal and individual choices of treatment for patients with rheumatoid arthritis gains increasing attention. The purpose of this study was to investigate if the proto-oncogene survivin might aid in treatment decisions in early rheumatoid arthritis. Methods: Serum survivin levels were measured in 302 patients who completed the Swedish pharmacotherapy (SWEFOT) trial at baseline, 3, 12, and 24 months. Survivin levels > 0.45 ng/mL were considered positive. Based on the survivin status, core set outcomes measuring disease activity, functional disability, as well as global health and pain were evaluated after methotrexate (MTX) monotherapy at 3 months, and at 12 and 24 months of follow-up. Treatment of non-responders was randomly intensified with either a combination of disease-modifying antirheumatic drugs (triple therapy: MTX, sulfasalazine, and hydroxychloroquine) or by adding antibodies against tumor necrosis factor (anti-TNF). Results: Antirheumatic treatment resulted in an overall decrease of serum survivin levels. Survivin-positive patients at baseline who initially responded to MTX had a higher risk of disease re-activation (OR 3.21 (95 % CI 1.12–9.24), P = 0.032) and failed to improve in their functional disability (P = 0.018) if having continued on MTX monotherapy compared to survivin-negative patients. Ever-smokers who were survivin-positive were less likely to respond to MTX than those who were survivin-negative (OR 1.91 (1.01–3.62), P = 0.045). In survivin-positive patients, triple therapy led to better improvements in disease activity than did MTX + anti-TNF. At 24 months, survivin-positive patients randomized to anti-TNF had a higher risk of active disease than those randomized to triple therapy (OR 3.15 (1.09–9.10), P = 0.037). Discussion: We demonstrate for the first time that survivin is a valuable serologic marker that can distinguish drug-specific clinical responses in early rheumatoid arthritis through the pragmatic clinical setting of the care-based SWEFOT trial. Although treatment response cannot solely be attributable to survivin status, per protocol sensitivity analyses confirmed the superior effect of triple therapy on survivin-positive patients. Conclusions: Survivin-positive patients have poor outcomes if treated with MTX monotherapy. A decrease of survivin levels during treatment is associated with better clinical responses. For survivin-positive patients who fail MTX, triple therapy is associated with better outcomes than anti-TNF therapy.
    BMC Medicine 09/2015; 13(1):247. DOI:10.1186/s12916-015-0485-2 · 7.25 Impact Factor
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    ABSTRACT: Objectives: To examine the effectiveness of tocilizumab (TCZ) with and without synthetic disease-modifying antirheumatic drugs (sDMARDs) in a large observational study. Methods: Patients with rheumatoid arthritis treated with TCZ who had a baseline visit and information on concomitant sDMARDs were included. According to baseline data, patients were considered as taking TCZ as monotherapy or combination with sDMARDs. Main study outcomes were the change of Clinical Disease Activity Index (CDAI) and TCZ retention. The prescription of TCZ as monotherapy was analysed using logistic regression. CDAI change was analysed with a mixed-effects model for longitudinal data. TCZ retention was analysed with a stratified extended Cox model. Results: Multiple-adjusted analysis suggests that prescription of TCZ as monotherapy varied according to age, corticosteroid use, country of the registry and year of treatment initiation. The change of disease activity assessed by CDAI as well as the likelihood to be in remission were not significantly different whether TCZ was used as monotherapy or in combination with sDMARDs in a covariate-adjusted analysis. Estimates for unadjusted median TCZ retention were 2.3 years (95% CI 1.8 to 2.7) for monotherapy and 3.7 years (lower 95% CI limit 3.1, upper limit not estimable) for combination therapies. In a covariate-adjusted analysis, TCZ retention was also reduced when used as monotherapy, with an increasing difference between mono and combination therapy over time after 1.5 years (p=0.002). Conclusions: TCZ with or without concomitant sDMARDs resulted in comparable clinical response as assessed by CDAI change, but TCZ retention was shorter under monotherapy of TCZ.
    Annals of the rheumatic diseases 09/2015; DOI:10.1136/annrheumdis-2015-207760 · 10.38 Impact Factor
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    ABSTRACT: As patients with rheumatoid arthritis (RA) receive treatment with anti-tumour necrosis factors over several years, it is important to evaluate their long-term safety and efficacy. The objective of this study was to examine the safety and benefits of certolizumab pegol (CZP)+methotrexate (MTX) treatment for almost 5 years in patients with RA. Patients who completed the 24-week Rheumatoid Arthritis Prevention of Structural Damage (RAPID) 2 randomized controlled trial (RCT; NCT00160602), or who were American College of Rheumatology (ACR) 20 non-responders at Week 16, entered the open-label extension (OLE; NCT00160641). After ≥6 months treatment with CZP 400 mg every two weeks (Q2W), dose was reduced to 200 mg Q2W, the approved maintenance dose. Safety data are presented from all patients who received ≥1 dose CZP (Safety population, n=612). Efficacy data are presented to Week 232 for the intent-to-treat (ITT, n=492) and Week 24 CZP RCT Completer (n=342) populations, and through 192 weeks of dose-reduction for the Dose-reduction population (patients whose CZP dose was reduced to 200 mg, n=369). Radiographic progression (modified total Sharp score change from RCT baseline >0.5) to Week 128 is reported for the Week 24 CZP Completers. In the RCT, 619 patients were randomized to CZP+MTX (n=492) or placebo+MTX (n=127). Overall, 567 patients (91.6%) entered the OLE: 447 CZP and 120 placebo patients. Of all randomized patients, 358 (57.8%) were ongoing at Week 232. Annual drop-out rates during the first four years ranged from 8.4–15.0%. Event rates per 100 patient-years were 163.0 for adverse events (AEs) and 15.7 for serious AEs. Nineteen patients (3.1%) had fatal AEs (incidence rate=0.8). Clinical improvements in the RCT were maintained to Week 232 in the CZP Completers: mean Disease Activity Score 28 (Erythrocyte Sedimentation Rate) change from baseline was −3.4 and ACR20/50/70 responses 68.4%/47.1%/25.1% (non-responder imputation). Similar improvements observed in the ITT were maintained following dose-reduction. 73.2% of CZP Completers had no radiographic progression at Week 128. In patients with active RA despite MTX therapy, CZP was well tolerated, with no new safety signals identified. CZP provided sustained improvements in clinical outcomes for almost 5 years. Trial registration, NCT00160602 and NCT00160641. Registered 8 September 2005.
    Arthritis Research & Therapy 09/2015; 17(1). DOI:10.1186/s13075-015-0767-2 · 3.75 Impact Factor
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    ABSTRACT: To determine nephritis outcomes in a prospective multi-ethnic/racial SLE inception cohort. Patients in the Systemic Lupus International Collaborating Clinics inception cohort (≤15 months of SLE diagnosis) were assessed annually for estimated glomerular filtration rate (eGFR), proteinuria and end-stage renal disease (ESRD). Health-related quality of life was measured by the Short Form (36 questions) health survey questionnaire (SF-36) subscales, mental and physical component summary scores. There were 1827 patients, 89% females, mean (s.d.) age 35.1 (13.3) years. The mean (s.d.) SLE duration at enrolment was 0.5 (0.3) years and follow-up 4.6 (3.4) years. LN occurred in 700 (38.3%) patients: 566/700 (80.9%) at enrolment and 134/700 (19.1%) during follow-up. Patients with nephritis were younger, more frequently men and of African, Asian and Hispanic race/ethnicity. The estimated overall 10-year incidence of ESRD was 4.3% (95% CI: 2.8%, 5.8%), and with nephritis was 10.1% (95% CI: 6.6%, 13.6%). Patients with nephritis had a higher risk of death (HR = 2.98, 95% CI: 1.48, 5.99; P = 0.002) and those with eGFR <30 ml/min at diagnosis had lower SF-36 physical component summary scores (P < 0.01) and lower Physical function, Physical role and Bodily pain scores. Over time, patients with abnormal eGFR and proteinuria had lower SF-36 mental component summary (P ≤ 0.02) scores compared to patients with normal values. LN occurred in 38.3% of SLE patients, frequently as the initial presentation, in a large multi-ethnic inception cohort. Despite current standard of care, nephritis was associated with ESRD and death, and renal insufficiency was linked to lower health-related quality of life. Further advances are required for the optimal treatment of LN. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email:
    Rheumatology (Oxford, England) 09/2015; DOI:10.1093/rheumatology/kev311 · 4.48 Impact Factor
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    Annals of the rheumatic diseases 09/2015; DOI:10.1136/annrheumdis-2015-207814 · 10.38 Impact Factor
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    ABSTRACT: Background and aims: We studied damage accrual and factors determining development and progression of damage in an international cohort of systemic lupus erythematosus (SLE) patients. Methods: The Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort recruited patients within 15 months of developing four or more 1997 American College of Rheumatology (ACR) criteria for SLE; the SLICC/ACR damage index (SDI) was measured annually. We assessed relative rates of transition using maximum likelihood estimation in a multistate model. The Kaplan-Meier method estimated the probabilities for time to first increase in SDI score and Cox regression analysis was used to assess mortality. Results: We recruited 1722 patients; mean (SD) age 35.0 (13.4) years at cohort entry. Patients with damage at enrolment were more likely to have further worsening of SDI (SDI 0 vs ≥1; p<0.001). Age, USA African race/ethnicity, SLEDAI-2K score, steroid use and hypertension were associated with transition from no damage to damage, and increase(s) in pre-existing damage. Male gender (relative transition rates (95% CI) 1.48 (1.06 to 2.08)) and USA Caucasian race/ethnicity (1.63 (1.08 to 2.47)) were associated with SDI 0 to ≥1 transitions; Asian race/ethnicity patients had lower rates of new damage (0.60 (0.39 to 0.93)). Antimalarial use was associated with lower rates of increases in pre-existing damage (0.63 (0.44 to 0.89)). Damage was associated with future mortality (HR (95% CI) 1.46 (1.18 to 1.81) per SDI point). Conclusions: Damage in SLE predicts future damage accrual and mortality. We identified several potentially modifiable risk factors for damage accrual; an integrated strategy to address these may improve long-term outcomes.
    Annals of the rheumatic diseases 09/2015; 74(9). DOI:10.1136/annrheumdis-2013-205171 · 10.38 Impact Factor
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    ABSTRACT: Objective To assess the effect of a simple intervention on Anti-Nuclear Antibody (ANA) test overuse by rheumatologists. Methods This was an explorative, pragmatic before and after controlled implementation study among rheumatologists working at three rheumatology departments of secondary and tertiary care centers in the Netherlands. The intervention was given in all study centers separately and combined education with feedback. Six outcome measures describe the intervention effects: the ANA/new patient ratio (APR), difference with the target APR, percentage of positive ANA tests, percentage of repeated ANA testing, percentage of ANA associated diseases and APR variation between rheumatologists. Outcomes were compared between the pre- and post-intervention period (both 12 months) using (multilevel) logistic regression or F-testing. Results are reported together for center 1 and 2, and separately for center 3 because ANA tests could not be linked to an individual rheumatologist in center 3. Results The APR decreased from 0.37 to 0.11 after the intervention in center 1 and 2 (odds ratio (OR) 0.19, 95%-confidence interval (95%-CI) 0.17 to 0.22, p-value <0.001) and from 0.45 to 0.30 in center 3 (OR 0.53, 95% CI 0.45 to 0.62, p <0.001). The percentage of repeated ANA requests in all centers and the APR variation center 1 and 2 decreased significantly. Only in center 3 the percentage of ANA associated diseases increased significantly. Conclusion A simple intervention resulted in a relevant and significant decrease in the numbers of ANA tests requested by rheumatologists, together with an improvement on three other outcome measures. This article is protected by copyright. All rights reserved.
    09/2015; DOI:10.1002/acr.22725
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    ABSTRACT: Objective. To compare the effectiveness of biologics after rituximab (RTX) treatment in RA. Methods. The effectiveness of TNF-α inhibitors (TNFi), abatacept (ABA) or tocilizumab (TCZ) was examined in patients previously treated with RTX using clinical data collected in the Collaborative Registries for the Evaluation of Rituximab in RA Collaborative registry. Patients had stopped RTX 6 months or less prior to the new biologic and had a baseline visit within 21 days of starting the new biologic. Results. Two hundred and sixty-five patients were analysed after 6 months of treatment. Patients on TCZ (n = 86) had a greater decline of DAS28-ESR and clinical disease activity index than patients on TNFi (n = 89) or ABA (n = 90). This effect was also seen after adjusting for baseline prednisone use and the number of previous biologics. The mean DAS28-ESR scores in patients on TCZ were 1.0 (95% CI: 0.2, 1.7) and 1.8 (95% CI: 1.0, 2.5) points lower than in patients on TNFi or ABA, respectively. In patients on TCZ, the clinical disease activity index was 9.4 (95% CI: 1.7, 16.1) and 8.1 (95% CI: 0.9, 15.3) points lower than on TNFi and ABA, respectively. Patients on TCZ more frequently had good EULAR responses than patients on TNFi or ABA (66 vs 31 vs 14%, P < 0.001). The HAQ disability index improved in all treatment groups (P < 0.001), but did not differ between biologics, as did drug retention rates. The reasons for discontinuation of RTX and the number of previous biologics had no influence on outcomes. Conclusion. In this observational cohort of patients who discontinued RTX, TCZ provided a better control of RA than ABA or TNFi.
    Rheumatology (Oxford, England) 08/2015; DOI:10.1093/rheumatology/kev297 · 4.48 Impact Factor
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    ABSTRACT: Objectives To evaluate the efficacy and safety of tabalumab, a human IgG4 monoclonal antibody that neutralises membrane and soluble B-cell activating factor (BAFF). Methods This randomised, placebo-controlled study enrolled 1124 patients with moderate-to-severe systemic lupus erythematosus (SLE) (Safety of Estrogens in Lupus Erythematosus National Assessment- SLE Disease Activity Index ≥6 at baseline). Patients received standard of care plus subcutaneous study drug, starting with a loading dose (240 mg) at week 0 and followed by 120 mg every 2 weeks (120 Q2W), 120 mg every 4 weeks (120 Q4W) or placebo. Primary endpoint was proportion achieving SLE Responder Index 5 (SRI-5) improvement at week 52. Results Clinical characteristics were balanced across groups. The primary endpoint was met with 120 Q2W (38.4% vs 27.7%, placebo; p=0.002), but not with the less frequent 120 Q4W regimen (34.8%, p=0.051). Although key secondary endpoints (time to severe flare, corticosteroid sparing and fatigue) were not met, patients treated with tabalumab had greater SRI-5 response rates in a serologically active subset and improvements in more stringent SRI cut-offs, SELENA-SLEDAI, Physician's Global Assessment, anti-double-stranded DNA antibodies, complement, total B cells and immunoglobulins. The incidences of deaths, serious adverse events (AEs), and treatment-emergent AEs were similar in the 120 Q2W, 120 Q4W and placebo groups, but depression and suicidal ideation, albeit rare events, were more commonly reported with tabalumab. Conclusion SRI-5 was met with 120 Q2W and although key secondary endpoints were not met, numerous other secondary endpoints significantly improved in addition to pharmacodynamic evidence of BAFF pathway blockade. The safety profile for tabalumab was similar to placebo, except for depression and suicidality, which were uncommon. Trial registration number NCT01205438.
    Annals of the rheumatic diseases 08/2015; DOI:10.1136/annrheumdis-2015-207654 · 10.38 Impact Factor
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    Ronald F van Vollenhoven · Roy M Fleischmann · Daniel E Furst · Stuart Lacey · Patricia B Lehane
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    ABSTRACT: Final evaluation of the longterm safety of rituximab (RTX) in rheumatoid arthritis (RA) up to 11 years. Pooled observed case analysis of data from patients with moderate to severe, active RA in a global clinical trial program. As of September 2012, 3595 patients received a mean of 4 courses (range 1-20) of RTX over 11 years [14,816 patient-years (PY)]. Of these, 1246 patients had > 5 years of followup (8970 PY). A pooled placebo population (n = 818) was included in the analysis. The overall serious infection event (SIE) rate was 3.76/100 PY (2.71/100 PY in patients observed for > 5 yrs) and comparable with rates reported previously at 9.5 years (3.94/100 PY and 3.26/100 PY, respectively). SIE rates continued to be similar before and during/after development of low immunoglobulin levels, and serious opportunistic infections remained rare. Rates of cardiac events remained consistent with previous analysis and with rates in the general RA population. No increased risk of malignancy over time was observed. This final report demonstrates that RTX remains well tolerated over time and multiple courses. No new safety risks were identified and there was no increase in the rate of any types of adverse events with prolonged exposure to RTX during 11 years of observation.
    The Journal of Rheumatology 08/2015; DOI:10.3899/jrheum.150051 · 3.19 Impact Factor
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    György Nagy · Ronald F van Vollenhoven
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    ABSTRACT: The advent of new medications and new treatment strategies for rheumatoid arthritis has made it possible to achieve remission in more patients than before. Furthermore, recent clinical trials and register studies suggest that some patients who initially required aggressive therapy may achieve biologic-free remission or even the ultimate goal of therapy, drug-free remission, resembling recovery. Here, we present a discursive review of the most important studies addressing these issues. Based on the overall results, it remains unclear if achieving biologic-free and drug-free remissions are primarily due to the natural course of the disease or to the early therapeutic intervention according to the ‘window of opportunity’ hypothesis. Although medication-free remission is only achievable in a small subset of patients, characterizing this patient cohort may provide important information about beneficial prognostic factors and the underlying mechanisms. In summary, in a subset of patients biologic-free and even drug-free remission can be achieved; pursuing these possibilities in practice may decrease the risk for long-term side effects and attenuate the economic burden of the disease.
    Arthritis Research & Therapy 08/2015; 17(1). DOI:10.1186/s13075-015-0707-1 · 3.75 Impact Factor
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    ABSTRACT: Objective Rheumatoid arthritis (RA) clinical trials often exclude patients with low C-reactive protein (CRP), slowing trial enrollment. We evaluated whether RA patients with a high multi-biomarker disease activity (MBDA) score (>44) among those with low CRP (≤10 mg/L) could complement patients with CRP >10mg/L to enhance patient recruitment without affecting clinical trial outcomes. Methods We evaluated patients from the Swedish pharmacotherapy (SWEFOT) trial, which had no CRP selection criteria. Clinical outcomes were assessed after 3 months of methotrexate (MTX) monotherapy for MTX-naïve patients (N=220) and after add-on therapy from Months 3 to 12 for MTX-inadequate responder (IR) patients (N=127). Radiographic outcomes were assessed at 1 year for all patients. Within each cohort, outcomes were compared between patients with CRP ≤10 mg/L and MBDA score >44 at the start of the respective treatment interval versus those with CRP >10 mg/L. Results Patients with baseline CRP ≤10 mg/L and MBDA score >44 at baseline had comparable clinical and radiographic outcomes to those for patients with CRP>10 mg/L. This broadened definition of inclusion criteria identified an additional 24% MTX-naïve and 47% MTX-IR patients. Conclusion Patient recruitment of RA clinical trials may be substantially enhanced by using "CRP >10 mg/L and/or MBDA score >44" as an inclusion criterion, without diminishing clinical or radiographic outcomes. This article is protected by copyright. All rights reserved. © 2015, American College of Rheumatology.
    Arthritis and Rheumatology 07/2015; DOI:10.1002/art.39274
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  • R F van Vollenhoven · S Wax · Yong Li · P P Tak
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    ABSTRACT: To explore the safety and tolerability of atacicept in combination with rituximab, in patients with active rheumatoid arthritis (RA) receiving rituximab retreatment. In this randomised, double-blind, placebo-controlled pilot trial, two 1000 mg intravenous rituximab infusions, given 2 weeks apart, were followed by once-weekly subcutaneous injections of 150 mg atacicept or placebo for 25 weeks. Primary endpoints were nature, incidence and severity of adverse events (AEs). Secondary endpoints were effect on peripheral blood B cells, biomarkers and American College of Rheumatology (ACR) response rates. Eighteen patients were randomised to atacicept and nine to placebo. AEs occurred in 17 (94.4%) atacicept- and nine (100%) placebo-treated patients. Serious AEs (SAEs) occurred in six (33.3%) atacicept- and two (22.2%) placebo-treated patients. There were no infection-related SAEs. Hypersensitivity and injection site reactions were more common, and more patients withdrew due to AEs, in the atacicept group. Median reductions in immunoglobulins (Ig) were greater with atacicept (IgG -31.2%, IgM -60.9% and IgA -56.4%) than with placebo (IgG -4.4%, IgM -15.9%, IgA -8.2%). Peripheral B-cell numbers in all patients remained low after rituximab-mediated depletion, limiting comparison of time to recovery between treatment groups. There were no between-group differences in ACR-20/50/70 response rates. In this exploratory trial, atacicept in combination with rituximab showed no new safety issues. Peripheral B-cell counts remained too low to determine if atacicept delayed B-cell re-expansion following rituximab-mediated depletion. Despite clear biological effects, adding atacicept to rituximab in patients with active RA was not associated with clinical benefit. This article is protected by copyright. All rights reserved. © 2015, American College of Rheumatology.
    Arthritis and Rheumatology 07/2015; DOI:10.1002/art.39262
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    ABSTRACT: Evidence regarding the efficacy and effectiveness of certolizumab pegol (CZP) in rheumatoid arthritis (RA) patients who have failed to respond to treatment with a tumour necrosis factor inhibitor (TNFi) is limited. The aim of this study was to describe the effectiveness and survival-on-drug of CZP in a real-life setting, both in TNFi-naïve patients and in patients who had previously failed TNFis, and in relation to disease activity at baseline. The national Swedish Rheumatology Quality Register (SRQ) was used to identify patients with RA starting treatment with CZP between 2009 and 2013. The effectiveness of treatment was assessed using the 28-joint Disease Activity Score (DAS28), the Health Assessment Questionnaire (HAQ), measures of remission, the European League Against Rheumatism (EULAR) response during 0-6 months from start of treatment, and survival-on-drug during the first 30 months. A total of 945 RA patients started treatment with CZP. Of these, 540 (57.1%) received CZP as the first biological treatment, 215 (23%) had failed one previous TNFi, and 190 (20%) had failed at least two TNFis. Overall, 71% achieved at least a EULAR moderate response and 38% had a EULAR good response at 6 months from baseline. TNFi-naïve patients achieved significantly better results and had better survival-on-drug compared to patients who had failed previous TNFis. Around 20% of patients who had not responded to two or more prior TNFis achieved EULAR good response to therapy and a similar percentage achieved remission. Patients who had high baseline disease activity had a higher risk of discontinuing treatment compared to those without high disease activity. In this real-life RA cohort, CZP was associated with significant clinical improvement. The effectiveness and survival-on-drug vary markedly depending on the line of treatment.
    Scandinavian journal of rheumatology 06/2015; DOI:10.3109/03009742.2015.1026840 · 2.53 Impact Factor
  • Y. Kisten · N. Györi · E. af Klint · H. Rezaei · A. Levitsky · A. Karlsson · R. van Vollenhoven
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    ABSTRACT: Background The objective detection and quantification of inflammatory disease activity is critical for achieving optimal therapy results. Fluorescence optical imaging (FOI) is a novel modality designed for imaging the hands and wrists, and the automated quantification of the ensuing scans using DACT (Disease ACTivity)-FOI is a novel algorithm for analyzing these images. Objectives To determine the utility of DACT-FOI in the assessment of hand and wrist inflammation. Methods Bilateral finger and wrist joints (n=1360) of 40 patients with inflammatory arthritis were studied. Synovitis was defined as tender and swollen joints on clinical examination, presence of synovial thickening/effusion and intra-articular Doppler signals on ultrasound (MSUS), and abnormal focal optical signal intensities on FOI, respectively. The DACT score used an automatically generated algorithm of the composite images (of 240 frames per second) to achieve a quantified score for each patient. Using dedicated image parameters and size correction, the enhanced pixels were extracted automatically from the image background, and the high signal intensities calculated. The DACT-FOI formula was based on fluorescence intensity curve thresholds that were used to discriminate intensity variations, and then divided by the 95th centile of intensities in normal individuals as the reference value. DACT-FOI ≤1 was referred to as normal digital activity signals. Subclinical synovitis was defined as being clinically non-inflamed but inflamed on MSUS. Results Out of the 1360 joints evaluated, 215 (16%) were inflamed clinically, 329 (24%) by MSUS, and 347 (26%) by FOI. For overall hand and wrist disease activity (n=40), the number (mean ± SD) of active joints detected by clinical, MSUS and semi-quantitative FOI was 5.4±7.0; 8.2±7.8; and 8.7±7.8, respectively. The automated digital activity (±SD) calculation by DACT-FOI was 3.8 (±2.1). Correlations of high statistical significance was denoted as ** when p<0.01. A strong positive correlation (r =0.458**; p=0.003) between clinical synovitis and DACT-FOI was demonstrated. The mean DACT values also correlated significantly with MSUS (r =0.442**; p=0.004) and semi-quantitative FOI (r =0.439**; p=0.005). There was a highly significant correlation of synovitis detection between clinical examination and MSUS (r =0.730**; p=0.000) and between clinical examination and semi-quantitative FOI (r =0.577**; p=0.000). Agreement between MSUS and FOI in synovitis detection was good, and revealed strong correlations (0.816**; p=0.000). Out of the non-inflamed joints by clinical examination, 142/1145 (12%) were inflamed by MSUS, of which 102/142 (72%) were also inflamed by FOI. Thus, for detecting subclinical synovitis, the sensitivity, specificity, and positive and negative predictive values of FOI were 72% (102/142), 93% (934/1003), 77% and 91%, respectively. Conclusions FOI and the automated analysis DACT-FOI were technically feasible with high reproducibility and strong agreement with clinical scoring. Therefore, this objective digitally quantified measurement of inflammatory disease activity in the hands & wrists may be useful both in diagnosis and in monitoring the effects of clinical therapy. Disclosure of Interest None declared
    Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):890-890. DOI:10.1136/annrheumdis-2015-eular.1608 · 10.38 Impact Factor
  • A. Levitsky · Y. Kisten · P. Nordström · S. Lind · N. Vivar · R.F. van Vollenhoven
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    ABSTRACT: Background Pain is an important manifestation of rheumatoid arthritis (RA) and it is imperative to find complementary options for patients experiencing pain despite antirheumatic treatment. Kaltenborn's manual mobilization is a complementary and alternative medicine (CAM) method based on gentle traction and passive motion. It has been tested extensively in osteoarthritic joints and found to provide pain relief, but there are no published studies to date on the use of this method in RA hand joints under ultrasound (Doppler) surveillance. Objectives The aim of this pilot study was to preliminarily assess the effectiveness of the Kaltenborn manual mobilization method in reducing tenderness, pain, and Doppler activity in patients with RA. Methods A total of 110 hand joints (1 wrist, 5 MCPs & PIPs bilaterally) in 5 female patients with RA who did not respond to antirheumatic treatment were clinically examined with patient-reported outcomes (PROs) for joint swelling, tenderness, and pain (VAS). Using Kaltenborn's technique, the MCP2-5 joints in 1 randomized hand (4/5 patients, n=20) were manually mobilized. Synovitis, tenosynovitis and disease activity were evaluated using the ultrasound Doppler quantification method. Three treatment sessions, each with two segments, were carried out every 2nd day for 1 week. Results Out of the 20 MCP joints treated in the test-hand, 75% (15/20) were self-reported as tender. Of these, 67% (10/15) were non-tender after the 3rd treatment session (1 week). In the control-hand, 60% (12/20) were self-reported as tender. Of these, 50% (6/12) were non-tender after 1 week. Both hands combined yielded highly significant reductions in self-reported tenderness (27/40 vs. 11/40, OR 5.48 [2.10, 14.28], p<0.001). After combining bilateral baseline tenderness with reduced bilateral tenderness after 1 week, patient and physician assessments of both hands demonstrated clinically relevant agreement (0.419, p=0.007). The VAS score (mean ± SD) for the test-hand at baseline was 60.0 (±22.1) vs. 40.0 (±24.2) after the last treatment session (p=0.003). The mean for the control hand was 50.4 (±25.0) at baseline vs. 31.0 (±23.9) after the last treatment session (p=0.036). There was a 14.2% overall reduction in quantitative Doppler activity from the treated joints at baseline (51.5±35.7) vs. all treatment segments within the 1st and 3rd treatment sessions over 1 week (37.3±31.6) (p<0.002). When comparing solely to the final segment of the 3rd treatment session, the treated joints had the largest mean decrease from baseline (21.0%, 51.5±35.7 vs. 30.5±30.8) (p<0.002) (figure). Conclusions An overall pattern of tenderness and pain reduction from baseline to post treatment and even among the control hand was observed, suggesting symmetry behind pain perception in RA. A strong patient-reported effect is present with pain outcomes and quantitative ultrasound helps with identifying changes in inflammation. A highly significant decrease in Doppler activity was observed. The remarkable ultrasound findings may indicate possible physiological microcirculatory changes as a result of joint mobilization therapy. These results support further studies of Kaltenborn's manual mobilization as a relatively safe, complementary treatment option for RA patients with tender hand joints despite antirheumatic therapy. Disclosure of Interest A. Levitsky: None declared, Y. Kisten: None declared, P. Nordström: None declared, S. Lind: None declared, N. Vivar: None declared, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, Roche, UCB, Consultant for: AbbVie, Biotest, BMS, Crescendo, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB, Vertex
    Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):1062.2-1062. DOI:10.1136/annrheumdis-2015-eular.4576 · 10.38 Impact Factor
  • F. Faustini · M.C. Wick · N. Györi · P.T. Larsson · R.F. van Vollenhoven
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    ABSTRACT: Background SI-MRI is essential for diagnosing and monitoring ax-SpA. How the imaging findings relate to clinical characteristics is still poorly understood. Objectives To clarify the relationships between the findings observed on SI-MRI and the clinical characteristics in ax-SpA. Methods We selected 47 SI-MRI performed on ax-SPA patients between 1994 and 2013. An experienced radiologist reviewed and scored the images according to a modified version of the SPARCC1,2 scoring system for SI-MRI. SI joints were assessed for bone marrow edema (BME), erosions, joint space irregularities subchondral cysts, and contrast enhancement after Gadolinium-DTPA administration. Demographic and clinical data at the time of imaging were collected retrospectively. MRI findings were analysed for correlation with clinical parameters. Results At the time of imaging the patients had mean ± SEM age of 37.4±1.7 and mean disease duration of 9.0±1.6 years. Fifty-three percent were male while the prevalence of HLA-B27 positivity was 52%. Mean disease activity as measured by the BASDAI was 5.4±0.6, while mean ASDAS-ESR was 3.0±0.3 and ASDAS-CRP was 3.1±0.3. The mean BASFI was 4.2±0.8. Mean CRP was 10.1±2.6 mg/L and mean ESR was 17.5±2.6 mm. Twenty-eight percent of the patients received TNF blockers and 60% NSAIDs. Imaging analysis revealed a prevalence of BME of 66% with a mean score of 2.4±0.4. Erosions were detected in 53% of the cases (mean score 1.4±0.3). Subchondral cysts were present in 30%, and joint space irregularities in 45% of the cases. Ankylosis was observed in 8 cases. Contrast enhancement had been performed in 15 scans and its mean score accounted for 1.2±0.3. Interestingly, this feature was significantly associated with systemic inflammation (for CRP: R=0.64, p=0.03; for ESR: R=0.84, p=0.003). The score for BME only showed a trend towards an association with ESR (R=0.30, p=0.09), while it did not associate with the CRP levels (R=0.08, p=0.64), nor with the BASDAI score (R=-0.4, p=0.13) or the ASDAS-ESR (R= -0.3, p=0.42) and ASDAS-CRP ASDAS-CRP (R=-0.38, p=0.25). Chronic damage, as expressed by the erosion mean score was not associated with disease duration (R=0.17, p=0.34) nor with the BASFI index (R=-0.03, p=0.94). Carrying the HLA-B27 antigen did not associate with a higher burden of MRI detectable inflammation or damage. Mean scores of BME in carriers compared to non-carriers (3.5±0.8 vs 2.8±0.7, p=0.47) and of erosions (2.0±0.6 vs 1.6±0.7, p=0.53) did not show statistically significant differences. HLA-B27 positivity was instead associated with a trend towards higher clinical activity by ASDAS-ESR and ASDAS-CRP (p=0.08). Conclusions In patients with ax-SpA SI-MRI findings show poor associations with clinical parameters. Although not routinely performed, the degree of contrast enhancement after Gadolinium-DTPA administration is strongly correlated with the degree of systemic inflammation. This association underlines the importance of its use in the clinical evaluation of ax-SpA patients. References Disclosure of Interest None declared
    Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):640.2-640. DOI:10.1136/annrheumdis-2015-eular.4807 · 10.38 Impact Factor
  • R.F. van Vollenhoven
    Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):2.3-2. DOI:10.1136/annrheumdis-2015-eular.6827 · 10.38 Impact Factor
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    ABSTRACT: Background Systemic lupus erythematosus (SLE) is a chronic relapsing and remitting condition in which long-term damage can accrue over time. Objectives To examine long-term organ damage and safety following 5 years of treatment with belimumab plus standard of care (SoC) in patients with SLE. Methods We examined pooled interim data (GSK201223) from two open-label studies that enrolled patients who completed the BLISS-52 and BLISS-76 studies. Patients received belimumab plus SoC every 4 weeks. Baseline was defined as prior to the first dose of belimumab. SLICC Damage Index (SDI) values were assessed every 48 weeks (yearly interval). Results 998 patients comprised the modified intent-to-treat population at baseline: 940 (94.2%) were female, with a mean (SD) age of 38.7 (11.49) years and disease duration of 6.69 (6.24) years. The mean (SD) SELENA-SLEDAI and SDI were 8.2 (4.18) and 0.7 (1.19), respectively. Reasons for study withdrawal included: subject request (16.8%), AEs (8.5%), other (7.0%), and investigator decision (4.8%). 411 (41.2%) patients had damage at baseline (SDI =1: 235 [23.5%]; SDI ≥2: 176 [17.6%]). At Years 5–6 (n=403), 343 (85.1%) patients had no change from baseline in SDI score (SDI +1: 46 [11.4%, SDI +2: 13 [3.2%], SDI +3: 1 [0.2%]). The mean (SD) change in SDI was +0.19 (0.481). Of patients with damage at baseline, 132/162 (81.5%) had no change in SDI (SDI +1: 22/162 [13.6%], SDI +2: 8/162 [4.9%], SDI +3: 0/162 [0%]), mean (SD) change in SDI was +0.23 (0.529). Of patients without baseline damage, 211/241 (87.6%) had no change in SDI (SDI +1: 24/241 [10.0%], SDI +2: 5/241 [2.1%], SDI +3: 1/241 [0.4%]), mean change (SD) in SDI was +0.15 (0.444). Overall, 433 (43.4%) of patients had a drug-related AE. The most common drug-related AEs were infections/infestations, 282 (28%) patients, and gastrointestinal disorders, 139 (14%) patients. 23 (2%) patients had an adjudicated opportunistic infection (OI); 4 (0.4%) patients had a serious OI. 87 (8.7%) patients had herpes zoster. 88 (8.8%) patients had an AE causing belimumab discontinuation. 11 deaths occurred during the study period; 2 deaths occurred after study exit. Conclusions Patients with moderate to severe SLE treated with belimumab plus SoC for 5 years had a low incidence of organ damage accrual and clinically manageable rates of AEs. Importantly, patients with pre-existing organ damage at study entry experienced similar rates of damage accrual compared with those with no baseline damage. As existing damage is a known risk for future damage accrual, our data suggest that belimumab may have a positive effect on risk factors for future damage that requires further evaluation. Acknowledgements Studies funded by GlaxoSmithKline (study #201223) and Human Genome Sciences. Louisa Pettinger, PhD, Fishawack Indicia Ltd, UK, assisted with the abstract submission and was funded by GSK. Disclosure of Interest I. Bruce Grant/research support from: UCB, GSK, Roche, Sanofi, Consultant for: UCB, Eli Lilly, GSK, Medimmune, Pfizer, Employee of: University of Manchester, Speakers bureau: UCB, GSK, Medimmune, M. Urowitz Grant/research support from: GSK, UCB, Eli Lilly, Consultant for: GSK, UCB, Eli Lilly, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, Roche, UCB, Consultant for: AbbVie, Biotest, BMS, Crescendo, Eli Lilly, GSK, Janssen, Merck, Pfizer, Roche, UCB, Vertex, C. Aranow Grant/research support from: GSK, UCB, Eli Lilly, Celgene, Janssen, Consultant for: GSK, UCB, Eli Lilly, Celgene, Janssen, J. Fettiplace Shareholder of: GSK, Employee of: GSK, M. Oldham Shareholder of: GSK, Employee of: GSK, E. Menius Shareholder of: GSK, Employee of: GSK, B. Wilson Shareholder of: GSK, Employee of: GSK, C. Molta Shareholder of: GSK, Employee of: GSK, D. Roth Shareholder of: GSK, Employee of: GSK, D. Gordon Shareholder of: GSK, Employee of: GSK
    Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):142.1-142. DOI:10.1136/annrheumdis-2015-eular.3324 · 10.38 Impact Factor

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12k Citations
2,676.39 Total Impact Points


  • 2003–2015
    • Karolinska Institutet
      • • Clinical Epidemiology Unit
      • • Department of Rheumatology
      • • Department of Medicine, Huddinge
      Сольна, Stockholm, Sweden
  • 2000–2015
    • Karolinska University Hospital
      • Department of Rheumatology
      Tukholma, Stockholm, Sweden
  • 2008
    • University of Birmingham
      • School of Immunity and Infection
      Birmingham, England, United Kingdom
  • 2007–2008
    • Toronto Western Hospital
      Toronto, Ontario, Canada
  • 1994–2002
    • Stanford Medicine
      • Division of Immunology and Rheumatology
      Stanford, California, United States
  • 1998
    • Stanford University
      • Division of Rheumatology
      Palo Alto, CA, United States