Ronald F van Vollenhoven

Karolinska Institutet, Solna, Stockholm, Sweden

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Publications (217)1422.73 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: IntroductionThis study aimed to assess the utility of musculoskeletal ultrasound (MSUS) in patients with joint symptoms using a probabilistic approach.Methods One hundred and three patients without prior rheumatologic diagnosis and referred to our clinic for evaluation of inflammatory arthritis were included. Patients were assessed clinically including joint examination, laboratory testing including acute-phase reactants, rheumatoid factor (RF) and anti citrulinated protein antibody (ACPA), and radiographs of hands and feet if clinically indicated. A diagnostic assessment was then performed by the responsible rheumatologist where the probability of a) any inflammatory arthritis and b) rheumatoid arthritis was given on a 5-point scale ranging from 0 to 20% up to 80 to 100% probability. Subsequently, an ultrasound examination of the wrist, metacarpophalangeal (MCP), proximal interphalangeal (PIP) joints 2 to 5 in both hands, metatarsophalangeal (MTP) joints 2 to 5 in both feet and any symptomatic joints was performed and the results presented to the same rheumatologist. The latter then assessed the diagnostic probabilities again, using the same scale.ResultsThe rheumatologists¿ certainty for presence/absence of inflammatory arthritis and rheumatoid arthritis was increased significantly following ultrasound performance. The proportion of patient for whom diagnostic certainty for inflammatory arthritis was maximal was 33.0% before and 71.8% after musculoskeletal ultrasound (P <0.001). With regard to a diagnosis of RA, the proportions were 31.1% pre-test and 61.2% post-test (P <0.001). MSUS findings agreed with the final diagnosis in 95% of patients.Conclusion Musculoskeletal ultrasound, when added to routine rheumatologic investigation, greatly increases the diagnostic certainty in patients referred for the evaluation of inflammatory arthritis. The changes from pre-test to post-test probability quantify the diagnostic utility of musculoskeletal ultrasound in probabilistic terms.
    Arthritis research & therapy. 10/2014; 16(5):448.
  • Sara Linder Ekö, Ronald F van Vollenhoven
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    ABSTRACT: Systemic lupus erythematosus (SLE) is a clinically diverse and potentially life-threatening auto-immune disease that can affect almost any organ system. Although much is still unknown regarding its pathogenesis, B cell abnormalities are thought to be central. A high relapse rate along with the toxicity associated with conventional treatments signify the need for more tailored approaches in this very heterogeneous disease. Both its mechanism targeting B cells and a relatively large number of case series and observational studies have suggested that the B cell-depleting agent rituximab could be a potent SLE drug. However, two randomized controlled trials failed to meet efficacy endpoints. Nevertheless, rituximab has continued to be used as an off-label alternative mainly in patients refractory to conventional immunosuppressive treatment. This article will review the current role of rituximab in SLE.
    Current Rheumatology Reports 09/2014; 16(9):444.
  • Annals of the rheumatic diseases. 08/2014;
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    ABSTRACT: Background Methotrexate is the most frequently used first-line antirheumatic drug. We report the findings of a phase 3 study of monotherapy with tofacitinib, an oral Janus kinase inhibitor, as compared with methotrexate monotherapy in patients with rheumatoid arthritis who had not previously received methotrexate or therapeutic doses of methotrexate. Methods We randomly assigned 958 patients to receive 5 mg or 10 mg of tofacitinib twice daily or methotrexate at a dose that was incrementally increased to 20 mg per week over 8 weeks; 956 patients received a study drug. The coprimary end points at month 6 were the mean change from baseline in the van der Heijde modified total Sharp score (which ranges from 0 to 448, with higher scores indicating greater structural joint damage) and the proportion of patients with an American College of Rheumatology (ACR) 70 response (≥70% reduction in the number of both tender and swollen joints and ≥70% improvement in three of five other criteria: the patient's assessment of pain, level of disability, C-reactive protein level or erythrocyte sedimentation rate, global assessment of disease by the patient, and global assessment of disease by the physician). Results Mean changes in the modified total Sharp score from baseline to month 6 were significantly smaller in the tofacitinib groups than in the methotrexate group, but changes were modest in all three groups (0.2 points in the 5-mg tofacitinib group and <0.1 point in the 10-mg tofacitinib group, as compared with 0.8 points in the methotrexate group [P<0.001 for both comparisons]). Among the patients receiving tofacitinib, 25.5% in the 5-mg group and 37.7% in the 10-mg group had an ACR 70 response at month 6, as compared with 12.0% of patients in the methotrexate group (P<0.001 for both comparisons). Herpes zoster developed in 31 of 770 patients who received tofacitinib (4.0%) and in 2 of 186 patients who received methotrexate (1.1%). Confirmed cases of cancer (including three cases of lymphoma) developed in 5 patients who received tofacitinib and in 1 patient who received methotrexate. Tofacitinib was associated with increases in creatinine levels and in low-density and high-density lipoprotein cholesterol levels. Conclusions In patients who had not previously received methotrexate or therapeutic doses of methotrexate, tofacitinib monotherapy was superior to methotrexate in reducing signs and symptoms of rheumatoid arthritis and inhibiting the progression of structural joint damage. The benefits of tofacitinib need to be considered in the context of the risks of adverse events. (Funded by Pfizer; ORAL Start number, NCT01039688 .).
    New England Journal of Medicine 06/2014; 370(25):2377-2386. · 54.42 Impact Factor
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    ABSTRACT: Prediction of radiographic progression (RP) in early rheumatoid arthritis (eRA) would be very useful for optimal choice among available therapies. We evaluated a multi-biomarker disease activity (MBDA) score, based on 12 serum biomarkers as a baseline predictor for 1-year RP in eRA. Baseline disease activity score based on erythrocyte sedimentation rate (DAS28-ESR), disease activity score based on C-reactive protein (DAS28-CRP), CRP, MBDA scores and DAS28-ESR at 3 months were analysed for 235 patients with eRA from the Swedish Farmacotherapy (SWEFOT) clinical trial. RP was defined as an increase in the Van der Heijde-modified Sharp score by more than five points over 1 year. Associations between baseline disease activity measures, the MBDA score, and 1-year RP were evaluated using univariate and multivariate logistic regression, adjusted for potential confounders. Among 235 patients with eRA, 5 had low and 29 moderate MBDA scores at baseline. None of the former and only one of the latter group (3.4%) had RP during 1 year, while the proportion of patients with RP among those with high MBDA score was 20.9% (p=0.021). Among patients with low/moderate CRP, moderate DAS28-CRP or moderate DAS28-ESR at baseline, progression occurred in 14%, 15%, 14% and 15%, respectively. MBDA score was an independent predictor of RP as a continuous (OR=1.0, 95% CI 1.02 to 1.08) and dichotomised variable (high/low, OR=3.86, 95% CI 1.04 to 14.26). In patients with eRA, the MBDA score at baseline was a strong independent predictor of 1-year RP. These results suggest that when choosing initial treatment in eRA the MBDA test may be clinically useful to identify a subgroup of patients at low risk of RP. WHO database at the Karolinska Institute: CT20080004; and NCT00764725.
    Annals of the rheumatic diseases 05/2014; · 8.11 Impact Factor
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    ABSTRACT: Tocilizumab is effective in the treatment of rheumatoid arthritis (RA). A proportion of patients achieve low disease activity using a lower than registered starting dose. We investigated the feasibility of dose reduction to 4 mg/kg in patients who reached low disease activity at the registered dose of 8 mg/kg. In this retrospective study, data were collected of 22 patients successfully treated with tocilizumab 8 mg/kg for about 6 months and tapered to 4 mg/kg because of low disease activity. In case of loss of disease control, the dose could be increased again to 8 mg/kg. The percentage of patients with successful dose reduction and difference in DAS28 was described. Mean DAS28 at time of dose reduction was 2.3 (SD 0.9). After 3 and 6 months follow-up, 77% (95% CI 54-91) and 55% (95% CI 32-76) of patients had successfully reduced the dose without losing disease control, respectively. DAS28 at 3 and 6 months was somewhat higher than baseline, 2.7 (SD 1.2) and 2.5 (SD 1.0) respectively. All patients who experienced worsening of disease activity after dose reduction regained low disease activity after dose escalation. Dose reduction of tocilizumab seems feasible in a substantial proportion of patients. Dose escalation after flare was effective in all patients.
    Clinical and experimental rheumatology 04/2014; · 2.66 Impact Factor
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    ABSTRACT: The principle of treating-to-target has been successfully applied to many diseases outside rheumatology and more recently to rheumatoid arthritis. Identifying appropriate therapeutic targets and pursuing these systematically has led to improved care for patients with these diseases and useful guidance for healthcare providers and administrators. Thus, an initiative to evaluate possible therapeutic targets and develop treat-to-target guidance was believed to be highly appropriate in the management of systemic lupus erythematosus (SLE) patients as well. Specialists in rheumatology, nephrology, dermatology, internal medicine and clinical immunology, and a patient representative, contributed to this initiative. The majority convened on three occasions in 2012-2013. Twelve topics of critical importance were identified and a systematic literature review was performed. The results were condensed and reformulated as recommendations, discussed, modified and voted upon. The finalised bullet points were analysed for degree of agreement among the task force. The Oxford Centre level of evidence (LoE, corresponding to the research questions) and grade of recommendation (GoR) were determined for each recommendation. The 12 systematic literature searches and their summaries led to 11 recommendations. Prominent features of these recommendations are targeting remission, preventing damage and improving quality of life. LoE and GoR of the recommendations were variable but agreement was >0.9 in each case. An extensive research agenda was identified, and four overarching principles were also agreed upon. Treat-to-target-in-SLE (T2T/SLE) recommendations were developed by a large task force of multispecialty experts and a patient representative. It is anticipated that 'treating-to-target' can and will be applicable to the care of patients with SLE.
    Annals of the rheumatic diseases 04/2014; · 8.11 Impact Factor
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    ABSTRACT: To estimate the incremental cost-effectiveness of infliximab versus conventional combination treatment over 21 months in patients with methotrexate-refractory early rheumatoid arthritis. 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. 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. 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. NCT00764725.
    Annals of the rheumatic diseases 04/2014; · 8.11 Impact Factor
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    ABSTRACT: To study clinical predictors for radiographic progression after 1 year in an early rheumatoid arthritis (RA) trial. In the SWEFOT trial population, disease modifying antirheumatic drug (DMARD) naïve RA patients started methotrexate; 3-month responders (DAS28 <3.2) continued (n=147), while non-responders were randomised to addition of sulfasalazine+hydroxychloroquine (n=130) or infliximab (n=128). X-rays were scored by the Sharp-van der Hejde score (SHS) method and radiographic progression was defined as a ≥5 increase after 1 year. Potential baseline predictors of radiographic progression were tested using multivariable logistic regression, adjusted for potential confounders. 79 of 311 patients with available radiographs at baseline and follow-up had radiographic progression. The following baseline parameters were independent predictors of radiographic progression at 1 year: baseline erosions (adjusted OR=2.29, 95% CI 1.24 to 4.24), erythrocyte sedimentation rate (adjusted OR per tertile increase=1.72, 95% CI 1.12 to 2.65) and C-reactive protein (adjusted OR per tertile increase=1.52, 95% CI 1.03 to 2.26). Current smoking was an independent predictor of radiographic progression (adjusted OR=2.17, 95% CI 1.06 to 4.45). These results remained after further adjustment for treatment strategy. Three-dimensional matrix including current smoking status, erosions and C-reactive protein tertiles showed a 12-63% risk gradient from patients carrying none compared with all predictors. Rheumatoid factor (RF)/anti-cyclic citrullinated peptide (anti-CCP) positivity did not significantly predict radiographic progression using SHS increase ≥5 as cut-off. In a secondary exploratory analysis using cut-off >1, both RF and anti-CCP positivity were significant predictors in the unadjusted, but not the adjusted analyses. The other parameters also remained significant using this lower cut-off. In addition to previously described predictors, we identified smoking as a strong independent risk factor for radiographic progression in early RA. NCT00764725.
    Annals of the rheumatic diseases 04/2014; · 8.11 Impact Factor
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    ABSTRACT: To determine the frequency of each American College of Rheumatology (ACR) criterion met at time of enrollment, and the increase in each of the criteria over 5 years. In 2000 the Systemic Lupus International Collaborating Clinics (SLICC) recruited an international inception cohort of patients with systemic lupus erythematosus (SLE; ≥ 4 ACR criteria) who were followed at yearly intervals according to a standard protocol. Descriptive statistics were used to assess the total and cumulative number of ACR criteria met at each visit. Regression models were done to compare the increase of individual and cumulative criteria as a function of race/ethnicity group, and sex. In all, 768 patients have been followed for a minimum of 5 years. Overall, 59.1% of the patients had an increase in the number of ACR criteria they met over the 5-year period. The mean number of ACR criteria met at enrollment was 5.04 ± 1.13 and at year 5 was 6.03 ± 1.42. At enrollment, nonwhite patients had a higher number of ACR criteria (5.19 ± 1.23) than white patients. The total number of criteria increased in both white and nonwhite ethnicities, but increased more among whites. Males had a slightly lower number of criteria at enrollment compared to females and males accrued fewer criteria at 5 years. In this international inception cohort of SLE patients with at least 4 ACR criteria at entry, there was an accumulation of ACR criteria over the following 5 years. The distribution of criteria both at inception and over 5 years is affected by sex and ethnicity.
    The Journal of Rheumatology 04/2014; · 3.26 Impact Factor
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    ABSTRACT: The metabolic syndrome (MetS) may contribute to the increased cardiovascular risk in systemic lupus erythematosus (SLE). We examined the association between MetS and disease activity, disease phenotype and corticosteroid exposure over time in patients with SLE. Recently diagnosed (<15 months) patients with SLE from 30 centres across 11 countries were enrolled into the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort from 2000 onwards. Baseline and annual assessments recorded clinical, laboratory and therapeutic data. A longitudinal analysis of factors associated with MetS in the first 2 years of follow-up was performed using random effects logistic regression. We studied 1150 patients with a mean (SD) age of 34.9 (13.6) years and disease duration at enrolment of 24.2 (18.0) weeks. In those with complete data, MetS prevalence was 38.2% at enrolment, 34.8% at year 1 and 35.4% at year 2. In a multivariable random effects model that included data from all visits, prior MetS status, baseline renal disease, SLICC Damage Index >1, higher disease activity, increasing age and Hispanic or Black African race/ethnicity were independently associated with MetS over the first 2 years of follow-up in the cohort. MetS is a persistent phenotype in a significant proportion of patients with SLE. Renal lupus, active inflammatory disease and damage are SLE-related factors that drive MetS development while antimalarial agents appear to be protective from early in the disease course.
    Annals of the rheumatic diseases 04/2014; · 8.11 Impact Factor
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    ABSTRACT: We aimed to describe patterns of disease activity during infliximab plus methotrexate (MTX) treatment and explore C-reactive protein (CRP) as a potential marker of early response. REMARK was a phase IV, open-label, observational study of infliximab-naïve adults with rheumatoid arthritis (RA) who received infliximab 3 mg/kg plus MTX for 14 weeks. Treatment response was evaluated in 3 subgroups: patients with <1 year disease duration who were TNF-inhibitor (TNFi)-naïve, patients with ≥1 year disease duration who were TNFi-naïve, and patients who had previous TNFi failure or intolerance. In post hoc analyses, CRP kinetic profiles were analysed by EULAR response (good, moderate, non-response) in REMARK and in an independent replication with data from the ASPIRE study. In the efficacy-evaluable population (n=662), median 28-joint disease activity score (DAS28) improved from baseline to Week 14 (5.2 vs. 3.6, p<0.0001). Regardless of disease history subgroup, most patients had good or moderate EULAR responses at Weeks 2 (64.9%), 6 (74.1%), and 14 (73.6%). DAS28 and its components did not differ across patient subgroups. Disease flare occurred in 16.2% of patients. CRP levels declined markedly at Week 2, but patients who were EULAR non-responders at Week 14 showed a CRP rebound at Weeks 6 and 14. This CRP pattern was independently replicated in data from ASPIRE. Adverse events were consistent with the known risk profile of infliximab. Infliximab plus MTX treatment in patients with RA rapidly diminished disease activity. A unique pattern of CRP rebound was found in non-responders early in treatment.
    Clinical and experimental rheumatology 02/2014; · 2.66 Impact Factor
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    ABSTRACT: Purpose: The Medical Outcome Survey Short Form 36 (SF-36) is recommended to assess quality of life (QoL) in SLE. The aim of the current study was to assess QoL over time in the first 5 years of a multi-centered inception cohort of patients with SLE.. Methods: An inception SLE cohort has been assembled according to a standardized protocol between 2000 and 2012. In addition to clinical and laboratory assessments, patients completed the SF-36 at yearly intervals. Only patients who had at least 5 completed QoL questionnaires were included in these analyses. GEE models were run separately for each of the 8 subscales and for the physical and mental component summary scores (PCS and MCS), adjusting for repeated measures by patients. Results: 495 patients were included. The mean (± SD) disease duration at first visit was 5.3± 4.1 months. The mean age at enrolment was 35.8 ± 13.2 years. All 8 subscales and 2 summary scores showed improvement in the first 2 years from enrolment. Between years 2 and 5 none of the subscales or summary scores showed any change. Minimal clinically important improvement was achieved by 35-55% of the patients and was influenced by demographic and disease factors. Conclusion: Unlike late stage lupus where QoL is stable over time, in patients with early disease all subscales improve in early follow-up up to 2 years. Therefore the SF-36 may be a sensitive outcome measure in early disease in patients with SLE. © 2014 American College of Rheumatology.
    Arthritis care & research. 02/2014;
  • Article: Reply.
    Arthritis & rheumatology (Hoboken, N.J.). 02/2014; 66(2):480.
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    ABSTRACT: Objective. An association between 25-hydroxyvitamin D [25(OH)D, vitamin D] deficiency and increased cardiovascular risk factors (CVRF) and cardiovascular disease (CVD) has been shown in general population studies. Vitamin D deficiency has been noted in systemic lupus erythematosus (SLE), and cardiovascular disease is a major cause of morbidity and mortality in SLE. The objectives of this study are to estimate the associations of 25(OH)D levels with CVRF and determine whether low baseline 25(OH)D levels predict future cardiovascular events in patients participating in an international inception cohort. Methods. Data were collected on 890 participants including demographics, SLE activity and damage assessments, CVRF and events, medications, laboratory assessments of 25(OH)D levels and inflammatory markers. Multiple logistic and Cox regressions were used to estimate the associations of baseline 25(OH)D levels with baseline CVRF, and CVD events. The models were adjusted for age, sex, race, season, country, with and without body mass index. Results. Patients in the higher quartiles of 25(OH)D were less likely to have hypertension and hyperlipidemia, were more likely to have lower C-reactive protein, and lower Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) at baseline when compared with the first quartile. Vitamin D levels were not independently associated with CVD event incidence, however hazard ratios for CVD event incidence decreased with successively higher quartiles. Conclusion. Lower baseline 25(OH)D levels are associated with higher risk for CVRF and more active SLE at baseline. There may be a trend towards a lower likelihood of CVD events in those with higher baseline 25(OH)D levels. © 2014 American College of Rheumatology.
    Arthritis care & research. 01/2014;
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    ABSTRACT: Switching to a second tumour necrosis factor inhibitor (TNFi) after discontinuation of a first in rheumatoid arthritis (RA) is a common strategy. The reason for the switch from the first TNFi could potentially influence the response to therapy. Data on direct comparisons between TNFi after switching are limited. The national Swedish register was used. RA patients who switched to a second TNFi (infliximab, etanercept or adalimumab) after failure of a TNFi as first-ever biologic were identified. Effectiveness of treatment was compared across the three drugs according to the first TNFi used, the reason for discontinuing and the drug survival. Drug survival across TNFi used as second biologic was compared. Half of all patients starting infliximab, adalimumab or etanercept during the period 2005-2012 discontinued treatment for various reasons. Of these patients, a third switched within 2 months to a second TNFi (infliximab, etanercept or adalimumab). Around 35% of all patients achieved low disease activity or remission at 6 months. Regarding the switching strategy, best results were observed among patients who switched from infliximab to etanercept because of (secondary) inefficacy. Etanercept as second TNFi was associated with longer drug survival compared with infliximab. Switching to a second TNFi after the failure of the first may lead to good clinical results. The inter-drug differences in drug survival on the second TNFi mirror those reported previously for the first TNFi, suggesting that these differences are not solely due to channelling bias.
    Annals of the rheumatic diseases 01/2014; · 8.11 Impact Factor
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    ABSTRACT: Background Hepatitis A vaccine is the most frequently used travel vaccine, yet data are scarce about its ability to induce protection in patients with concurrent immunosuppressive treatment. We assessed the immunogenicity of this vaccine in rheumatoid arthritis (RA) patients treated with tumor necrosis factor-inhibitors (TNFi) and/or methotrexate (MTX). Methods Hepatitis A vaccine was administered to non-immune RA patients at 0 and 6 months. Hepatitis A virus (HAV) antibodies were assessed at 0, 1, 6, 7, 12, and 24 months with a quantitative Chemiluminescent Microparticle Immuno Assay (CMIA) for HAV-IgG. Samples from month 1, 6, and 7 were, in addition, analysed with a microparticle EIA (MEIA) for anti-HAV IgM+IgG. Results The final study population consisted of 53 patients treated with TNFi (n=15), TNFi+MTX (n=21) or MTX (n=17). One and six months after the first dose, 10 % and 33% of the patients had attained seroprotection. One and six months after the second dose 83% and 72% were seroprotected. At month 24, 86% of the vaccinees showed protective levels. Conclusions Two doses of hepatitis A vaccine at a 6-month interval provided protection for most immunosuppressed RA patients. A single dose does not seem to afford sufficient protection to this group of patients.
    Travel Medicine and Infectious Disease 01/2014; · 1.78 Impact Factor
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    Ronald F van Vollenhoven, György Nagy, Paul P Tak
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    ABSTRACT: Despite considerable advances in the management of rheumatoid arthritis, results are still not satisfactory for all patients. The treatment goal in rheumatoid arthritis is remission, and there currently are numerous conventional and biological medications available to reach this aim. There are also different treatment strategies but with only limited comparative evidence about their efficacies. More patients now achieve remission while on treatment, but it remains elusive in the majority of patients. Treatment-free remission, the ultimate goal of therapy, is only achieved in very few patients; even when this happens, it is most likely due to the natural course of the disease rather than to any specific therapies. Modern treatment is based on the initiation of aggressive therapy as soon as the diagnosis is established, and on modifying or intensifying therapy guided by frequent assessment of disease activity. In this commentary we will discuss the current treatment paradigm as well as the possibility of an induction-maintenance regimen with biological disease-modifying antirheumatic drugs in early rheumatoid arthritis.
    BMC Medicine 01/2014; 12(1):25. · 7.28 Impact Factor
  • Nancy Vivar, Ronald F Van Vollenhoven
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    ABSTRACT: The intense pursuit of novel therapies in rheumatoid arthritis has provided physicians with an assorted set of biologic drugs to treat patients with moderate to severe disease activity. Nine different biologic therapies are currently available: seven inhibitors of pro-inflammatory cytokines (five targeting tumor necrosis factor [TNF], one interleukin [IL]-1 and one IL-6), as well as a T- and a B-lymphocyte targeting agent. All these drugs have roughly similar efficacy profiles and are approved as first- or second-line therapy in patients who failed to respond to conventional disease-modifying anti-rheumatic drugs (DMARDs) and in most cases for first line use in rheumatoid arthritis as well. Despite the irrefutable clinical and radiological benefits of biologic therapies, there are still low rates of patients achieving stable remission. Therefore, the quest for new and more effective biologic therapies continues and every year new drugs are tested. Simultaneously, optimal use of established agents is being studied in different ways. Recently, the approval of the first small molecule targeting intracellular pathways has opened a new chapter in the treatment of rheumatoid arthritis. Other emerging treatment strategies include the activation of regulatory T cells as well as new cytokine-targeting therapies.
    F1000prime reports. 01/2014; 6:31.
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    ABSTRACT: Proinflammatory CD4(+) CD28(null) T cells are frequently found in the circulation of RA patients, but are less common in the rheumatic joint. In the present study we sought to identify functional differences between CD4(+) CD28(null) T cells from blood and synovial fluid in comparison to conventional CD28 expressing CD4(+) T cells. 44 RA patients, displaying a distinct CD4(+) CD28(null) T cell population in blood, were recruited for this study and the methylation status of the IFNG locus was examined in isolated T cell subsets, and intracellular cytokine production (IFN-γ, TNF, IL-17) and chemokine receptor expression (CXCR3, CCR6 and CCR7) were assessed by flow cytometry on T cells from the two compartments. Circulating CD4(+) CD28(null) T cells were significantly more hypomethylated in the CNS-1 region of the IFNG locus than conventional CD4(+) CD28(+) T cells and produced higher levels of both IFN-γ and TNF after TCR crosslinking. CD4(+) CD28(null) T cells from the site of inflammation expressed significantly more CXCR3 and CCR6 compared to their counterparts in blood. While IL-17A production could hardly be detected in CD4(+) CD28(null) cells from the blood, a significant production was observed in CD4(+) CD28(null) T cells from synovial fluid. CD4(+) CD28(null) T cells were not only found to differ from conventional CD4(+) CD28(+) T cells in the circulation, but we could also demonstrate that synovial CD4(+) CD28(null) T cells showed additional effector functions (IL-17 co-production) as compared to the same subset in peripheral blood, suggesting an active role for these cells in the perpetuation of inflammation in the subset of patients having a CD28(null) population. This article is protected by copyright. All rights reserved.
    Scandinavian Journal of Immunology 12/2013; · 2.20 Impact Factor

Publication Stats

7k Citations
1,422.73 Total Impact Points


  • 2004–2014
    • Karolinska Institutet
      • Institutionen för medicin, Huddinge
      Solna, Stockholm, Sweden
  • 2013
    • University of Geneva
      Genève, Geneva, Switzerland
    • University of Toronto
      Toronto, Ontario, Canada
  • 2010–2013
    • Medical University of Vienna
      Wien, Vienna, Austria
    • Stockholm University
      Tukholma, Stockholm, Sweden
    • University of Crete
      Retimo, Crete, Greece
  • 2000–2013
    • Karolinska University Hospital
      • Department of Rheumatology
      Tukholma, Stockholm, Sweden
  • 2012
    • Università di Pisa
      Pisa, Tuscany, Italy
    • Radboud University Nijmegen
      Nymegen, Gelderland, Netherlands
    • Mount Sinai Hospital, Toronto
      Toronto, Ontario, Canada
  • 2011
    • North Shore-Long Island Jewish Health System
      New York City, New York, United States
  • 2009–2011
    • Capital District Health Authority of Nova Scotia
      Halifax, Nova Scotia, Canada
    • University of California, San Diego
      • Division of Rheumatology, Allergy and Immunology
      San Diego, CA, United States
  • 2008
    • University of Birmingham
      • School of Immunity and Infection
      Birmingham, ENG, United Kingdom
    • Leiden University Medical Centre
      • Department of Rheumatology
      Leiden, South Holland, Netherlands
  • 2007–2008
    • Dalhousie University
      Halifax, Nova Scotia, Canada
  • 2006
    • Uppsala University
      Uppsala, Uppsala, Sweden
  • 2005
    • University of Innsbruck
      Innsbruck, Tyrol, Austria
  • 1994–2002
    • Stanford Medicine
      • Division of Immunology and Rheumatology
      Stanford, California, United States
  • 1994–1999
    • Stanford University
      • • Division of Rheumatology
      • • Department of Obstetrics and Gynecology
      Palo Alto, CA, United States