Rheumatoid Arthritis: van Vollenhoven RF

van Vollenhoven RF. · No affiliation provided · Ann Rheum Dis. · Pubmed #19605741 No free full text.

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van Vollenhoven RF. · No affiliation provided · Arthritis Res Ther. · Pubmed #18341711 links to  free full text

Abstract: In the present issue of Arthritis Research & Therapy data are presented suggesting that antirheumatic therapies decrease the risk of cardiovascular disease in patients with rheumatoid arthritis. The QUEST-RA group, a large international collaboration, analyzed data on 4,363 patients in a cross-sectional manner. Traditional risk factors were all significantly associated with cardiovascular events, and the presence of extraarticular disease significantly increased the risk, confirming a previous publication. The most interesting analysis in this study suggests that effective antirheumatic treatment, with traditional disease-modifying antirheumatic drugs (DMARDs), glucocorticoids, or anti-TNF biologics, reduces the risk of cardiovascular disease in rheumatoid arthritis. Some methodological issues are discussed, however, and confirmatory studies are suggested.

van Vollenhoven RF. · No affiliation provided · Ann Rheum Dis. · Pubmed #17576784 No free full text.

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van Vollenhoven RF, Klareskog L. · No affiliation provided · Arthritis Rheum. · Pubmed #15818687 links to  free full text

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van Vollenhoven RF. · Department of Rheumatology D1-2, Karolinska University Hospital and Karolinska Institute, 17176 Stockholm, Sweden. · Clin Exp Rheumatol. · Pubmed #15552525 No free full text.

Abstract: Lymphomas are uncommon malignancies of unknown aetiology. Rheumatoid arthritis is a known risk factor for lymphoma, and some studies show that this risk is higher in patients with more severe disease. The causes of the association between RA and lymphoma are not understood. Conventional anti-rheumatic agents may increase the risk for lymphoma, but these associations are relatively weak at most. For the currently available TNF-alpha antagonists, available data include the possibility of a somewhat higher risk for lymphoma than for patients not treated with such agents, but also point to several sources of bias that could explain a possible association. Current practice recommendations should probably not go further than an awareness of the possibility of lymphoma in any patient with RA exhibiting unexplained systemic symptoms.

Smolen J, Landewé RB, Mease P, Brzezicki J, Mason D, Luijtens K, van Vollenhoven RF, Kavanaugh A, Schiff M, Burmester GR, Strand V, Vencovsky J, van der Heijde D. · Department of Internal Medicine III, Medical University of Vienna and 2nd Department of Medicine, Hietzing Hospital, Austria. · Ann Rheum Dis. · Pubmed #19015207 links to  free full text

Abstract: BACKGROUND: Certolizumab pegol is a PEGylated tumour necrosis factor inhibitor. OBJECTIVE: To evaluate the efficacy and safety of certolizumab pegol versus placebo, plus methotrexate (MTX), in patients with active rheumatoid arthritis (RA). METHODS: An international, multicentre, phase 3, randomised, double-blind, placebo-controlled study in active adult-onset RA. Patients (n = 619) were randomised 2:2:1 to subcutaneous certolizumab pegol (liquid formulation) 400 mg at weeks 0, 2 and 4 followed by 200 mg or 400 mg plus MTX, or placebo plus MTX, every 2 weeks for 24 weeks. The primary end point was ACR20 response at week 24. Secondary end points included ACR50 and ACR70 responses, change from baseline in modified Total Sharp Score, ACR core set variables and physical function. RESULTS: Significantly more patients in the certolizumab pegol 200 mg and 400 mg groups achieved an ACR20 response versus placebo (p< or =0.001); rates were 57.3%, 57.6% and 8.7%, respectively. Certolizumab pegol 200 and 400 mg also significantly inhibited radiographic progression; mean changes from baseline in mTSS at week 24 were 0.2 and -0.4, respectively, versus 1.2 for placebo (rank analysis p< or =0.01). Certolizumab pegol-treated patients reported rapid and significant improvements in physical function versus placebo; mean changes from baseline in HAQ-DI at week 24 were -0.50 and -0.50, respectively, versus -0.14 for placebo (p< or =0.001). Most adverse events were mild or moderate, with low incidence of withdrawals due to adverse events. Five patients developed tuberculosis. CONCLUSION: Certolizumab pegol plus MTX was more efficacious than placebo plus MTX, rapidly and significantly improving signs and symptoms of RA and physical function and inhibiting radiographic progression. Trial registration number: NCT00175877.

Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh A, Racewicz AJ, van Vollenhoven RF, Li NF, Agarwal S, Hessey EW, Shaw TM, Anonymous00344. · Academic Unit of Musculoskeletal Disease, Chapel Allerton Hospital, Leeds, UK. · Arthritis Rheum. · Pubmed #16649186 links to  free full text

Abstract: OBJECTIVE: To examine the efficacy and safety of different rituximab doses plus methotrexate (MTX), with or without glucocorticoids, in patients with active rheumatoid arthritis (RA) resistant to disease-modifying antirheumatic drugs (DMARDs), including biologic agents. METHODS: A total of 465 patients were randomized into 9 treatment groups: 3 rituximab groups (placebo [n = 149], 500 mg [n = 124], or 1,000 mg [n = 192] on days 1 and 15) each also taking either placebo glucocorticoids, intravenous methylprednisolone premedication, or intravenous methylprednisolone premedication plus oral prednisone for 2 weeks. All patients received MTX (10-25 mg/week); no other DMARDs were permitted. RESULTS: Significantly more patients who received 2 500-mg or 2 1,000-mg infusions of rituximab met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 24 (55% and 54%, respectively) compared with placebo (28%; P < 0.0001). ACR50 responses were achieved by 33%, 34%, and 13% of patients, respectively (P < 0.001), and ACR70 responses were achieved by 13%, 20%, and 5% of patients (P < 0.05). Changes in the Disease Activity Score in 28 joints (-1.79, -2.05, -0.67; P < 0.0001) and moderate to good responses on the European League Against Rheumatism criteria (P < 0.0001) reflected the ACR criteria responses. Glucocorticoids did not contribute significantly to the primary efficacy end point, ACR20 response at 24 weeks. Intravenous glucocorticoid premedication reduced the frequency and intensity of first infusion-associated events; oral glucocorticoids conferred no additional safety benefit. Rituximab was well tolerated; the type and severity of infections was similar to those for placebo. CONCLUSION: Both rituximab doses were effective and well tolerated when added to MTX therapy in patients with active RA. The primary end point (ACR20 response) was independent of glucocorticoids, although intravenous glucocorticoid premedication improved tolerability during the first rituximab infusion.

van Vollenhoven RF. · Department of Rheumatology, Karolinska University Hospital, 17176 Stockholm, Sweden. · BMC Med. · Pubmed #19331649 links to  free full text

Abstract: ABSTRACT: Sex differences in the prevalence of autoimmune diseases such as rheumatoid arthritis (RA) are well described, but the literature is not as clear about sex differences in RA disease course and prognosis. A recent study from a very large cross-sectional international cohort demonstrated slightly worse levels of disease activity and function in female patients with RA, compared with men. These findings are discussed in the context of our evolving knowledge of sex differences in the expression of this prototypic autoimmune disease, both in terms of the actual disease activity level, the effects that the disease has on physical function, and our ability accurately to measure these aspects.

Sundaramurthy SG, Karsevar MP, van Vollenhoven RF. · Division of Immunology & Rheumatology, Stanford University Medical Center, Stanford, California. · J Clin Rheumatol. · Pubmed #19078342 No free full text.

Abstract: The concurrent presence of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) ("rhupus" or "rufus") has been described in the literature. However, it has not been clear to what extent and under what circumstances clinical disease expresssion can undergo transitions from one disease to the other. We postulated that major hormonal events might have an influence on disease expression in such patients and conducted a retrospective study of 1507 patients with RA and 893 with SLE. In this population, 13 patients were identified as having convincing clinical diagnoses of both RA and SLE. Although 6 of these 13 patients had symptoms and signs of RA and SLE concurrently during their entire illness, 7 patients had clearly identifiable transitions from SLE to RA, and in one of these patients the reverse occurred as well. Of the 7 transitions from SLE to RA, 5 were associated with menopause (3 of these patients were receiving hormone replacement therapy) and the other 2 occurred in the postpartum period. The one change from RA to SLE in this series occurred during pregnancy. Thus, pregnancy, the postpartum period, and menopause can modulate disease expression in patients with both SLE and RA. It is speculated that, in patients with an autoimmune predilection, a high-estrogen environment (premenopause, pregnancy) favors the clinical expression of SLE, whereas a low-estrogen environment favors more RA-like disease, possibly because of the immunomodulatory effects of sex-steroids. The clinical implication is that in the management of patients with autoimmune diseases such as SLE and RA, hormonal alterations could result in changes in disease expression that might necessitate changes in treatment.

Fleischmann R, Vencovsky J, van Vollenhoven RF, Borenstein D, Box J, Coteur G, Goel N, Brezinschek HP, Innes A, Strand V. · University of Texas Southwestern Medical Center, Dallas, 75235, USA. · Ann Rheum Dis. · Pubmed #19015206 links to  free full text

Abstract: BACKGROUND: Tumour necrosis factor alpha (TNFalpha) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis (RA). Treatment with TNFalpha inhibitors reduces disease activity and improves outcomes for patients with RA. This study evaluated the efficacy and safety of certolizumab pegol 400 mg, a novel, poly-(ethylene glycol) (PEG)ylated, Fc-free TNFalpha inhibitor, as monotherapy in patients with active RA. METHODS: In this 24-week, multicentre, randomised, double-blind, placebo-controlled study, 220 patients previously failing > or =1 disease-modifying antirheumatic drug (DMARD) were randomised 1:1 to receive subcutaneous certolizumab pegol 400 mg (n = 111) or placebo (n = 109) every 4 weeks. The primary endpoint was 20% improvement according to the American College of Rheumatology criteria (ACR20) at week 24. Secondary endpoints included ACR50/70 response, ACR component scores, 28-joint Disease Activity Score Erythrocyte Sedimentation Rate 3 (DAS28(ESR)3), patient-reported outcomes (including physical function, health-related quality of life (HRQoL), pain and fatigue) and safety. RESULTS: At week 24, the ACR20 response rates were 45.5% for certolizumab pegol 400 mg every 4 weeks vs 9.3% for placebo (p<0.001). Differences for certolizumab pegol vs placebo in the ACR20 response were statistically significant as early as week 1 through to week 24 (p<0.001). Significant improvements in ACR50, ACR components, DAS28(ESR)3 and all patient-reported outcomes were also observed early with certolizumab pegol and were sustained throughout the study. Most adverse events were mild or moderate and no deaths or cases of tuberculosis were reported. CONCLUSIONS: Treatment with certolizumab pegol 400 mg monotherapy every 4 weeks effectively reduced the signs and symptoms of active RA in patients previously failing > or =1 DMARD compared with placebo, and demonstrated an acceptable safety profile. Trial registration number: NCT00548834.

van Vollenhoven RF, Klareskog L. · Department of Rheumatology, Karolinska University Hospital, Stockholm, Sweden. · Scand J Rheumatol. · Pubmed #18092261 No free full text.

Abstract: OBJECTIVE: To characterize dosages and frequencies of infliximab in a publicly financed health-care system without administrative restrictions on the use of biologics. METHODS: Data from the Stockholm TNFalpha follow-up registry (STURE) were used. Dosages and frequencies of infliximab were adjusted when clinically indicated. Kaplan-Meier survival function was calculated for maintenance of initial infliximab dosage, initial frequency, and both combined; the influence of baseline characteristics on the adjustments and the effects of these adjustments on clinical outcomes were analysed. All analyses were for patients who continued on therapy only. RESULTS: The 1-year survival on initial infliximab frequency was 96.3+/-1.8%, on initial infliximab dose 70.5+/-4.3%, and on the two combined 68.7+/-4.3% (cumulative survival estimate +/- SE). At 2 years, the corresponding values were 88.1+/-3.4%, 53.4+/-5.1%, and 50.3+/-5.1%, and after 3 years 77.4+/-4.9%, 45.9+/-5.4%, and 41.5+/-5.3%. A higher number of prior disease-modifying anti-rheumatic drugs (DMARDs), use of glucocorticoids, and lower baseline swollen joints counts (SJCs) predicted greater likelihood of later adjustments. Efficacy of dosage increases was modest, as reported previously, while frequency increases appeared more efficacious. CONCLUSION: Infliximab dosages and dosing frequencies are increased frequently in clinical practice: after 3 years, only 42% of patients continued on the original schedule. While frequency increases appear to result in better effect persistence between infusions, the gains from dosage increases are small and may not be better than chance. These data suggest that the total amounts of infliximab needed to obtain satisfactory disease control are greater than the amounts suggested by the original dosing recommendations, and may have bearing on pharmaco-economic issues pertaining to treatment with infliximab and other therapeutic agents.

Fasth AE, Snir O, Johansson AA, Nordmark B, Rahbar A, Af Klint E, Björkström NK, Ulfgren AK, van Vollenhoven RF, Malmström V, Trollmo C. · Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. · Arthritis Res Ther. · Pubmed #17825098 links to  free full text

Abstract: Expanded populations of CD4+ T cells lacking the co-stimulatory molecule CD28 (CD4+CD28null T cells) have been reported in several inflammatory disorders. In rheumatoid arthritis, increased frequencies of CD4+CD28null T cells in peripheral blood have previously been associated with extra-articular manifestations and human cytomegalovirus (HCMV) infection, but their presence in and contribution to joint manifestations is not clear. In the present article we investigated the distribution of CD4+CD28null T cells in the synovial membrane, synovial fluid and peripheral blood of RA patients, and analysed the association with erosive disease and anti-citrullinated protein antibodies. CD4+CD28null T cells were infrequent in the synovial membrane and synovial fluid, despite significant frequencies in the circulation. Strikingly, the dominant TCR-Vbeta subsets of CD4+CD28null T cells in peripheral blood were often absent in synovial fluid. CD4+CD28null T cells in blood and synovial fluid showed specificity for HCMV antigens, and their presence was clearly associated with HCMV seropositivity but not with anti-citrullinated protein antibodies in the serum or synovial fluid, nor with erosive disease. Together these data imply a primary role for CD4+CD28null T cells in manifestations elsewhere than in the joints of patients with HCMV-seropositive rheumatoid arthritis.

Askling J, Fored CM, Brandt L, Baecklund E, Bertilsson L, Feltelius N, Cöster L, Geborek P, Jacobsson LT, Lindblad S, Lysholm J, Rantapää-Dahlqvist S, Saxne T, van Vollenhoven RF, Klareskog L. · Clinical Epidemiology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden. · Ann Rheum Dis. · Pubmed #17261532 No free full text.

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.

van Vollenhoven RF, Askling J. · Rheumatology Unit, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden. · Clin Exp Rheumatol. · Pubmed #16273807 No free full text.

Abstract: Patient registries provide valuable contributions to the field of rheumatology for both quality control and scientific purposes. With respect to the latter, patient registries are among the most important datasets used for longitudinal observational studies in rheumatic diseases, which are in turn an essential complement to data obtained from randomized, controlled trials. In Sweden a number of registries are available for such studies, ranging from general medical registries such as the in-patient registry, to rheumatoid arthritis (RA)-specific inception cohorts and biologics registries focusing on a specific patient population defined by a group of treatments. In recent years it has become particularly clear that questions regarding new therapies, their use in practice and their long-term safety, as well as aspects such as pharmacoeconomics, cannot fully be assessed using the data from clinical trials, and that registries are indispensible to obtain accurate answers to such questions. In this review we describe the Swedish rheumatology registries, including the Swedish RA registry and the Swedish biologics registries ARTIS (Antirheumatic Therapies Iin Sweden), SSATG (Southern Sweden Antirheumatic Therapy Group), and STURE (Stockholm Tumor Necrosis Factor-a Follow-up Registry). Data obtained from analyses based on these registries are reviewed. It is concluded that rheumatology registries are excellent tools for improving our knowledge base regarding rheumatic diseases.

Wick MC, Ernestam S, Lindblad S, Bratt J, Klareskog L, van Vollenhoven RF. · Department of Rheumatology, Karolinska University Hospital, Solna, Sweden. · Scand J Rheumatol. · Pubmed #16234182 No free full text.

Abstract: OBJECTIVES: To determine whether the tumour necrosis factor-alpha (TNF-alpha) antagonist adalimumab (Humira) can be efficacious after secondary loss of efficacy (i.e. loss of clinical response in patients who had initially demonstrated clinical response) to infliximab (Remicade) or etanercept (Enbrel). PATIENTS AND METHODS: We studied 36 patients from the Stockholm TNF-alpha follow-up registry (STURE) who received adalimumab after secondary loss of efficacy to infliximab (group A, n = 27) or etanercept (group B, n = 9), and 26 patients who were started on adalimumab as the first TNF-alpha antagonist (group C). RESULTS: In group A, the baseline disease activity score 28 (DAS28) at infliximab institution was 5.5+/-0.2. During infliximab treatment, the mean best DAS28 was 3.7+/-0.2 (p<0.001), but increased to 5.2+/-0.3 when infliximab was stopped. After 3 months on adalimumab, the mean DAS28 decreased to 4.5+/-0.3 (p<0.003), and then to 4.2+/-0.2 at 6 months (p<0.001). In group B, the baseline DAS28 at etanercept institution was 6.6+/-0.5. During etanercept treatment, the mean best DAS28 was 4.6+/-0.5 (p<0.01), but increased to 5.7+/-0.4 by the time etanercept was stopped. After 3 months on adalimumab, the mean DAS28 decreased to 4.8+/-0.3 (p<0.005), and to 4.1+/-0.2 at 6 months (p<0.001). In group C, the mean baseline DAS28 was 5.6+/-0.3. After 6 months of adalimumab therapy, the DAS28 decreased to 3.5+/-0.4 (p<0.001). ACR20 responses with adalimumab in groups A, B, and C were similar (70-78%). CONCLUSIONS: For patients with secondary loss of efficacy from infliximab or etanercept, switching to adalimumab can restore a good clinical response.

Rönnelid J, Wick MC, Lampa J, Lindblad S, Nordmark B, Klareskog L, van Vollenhoven RF. · Unit of Clinical Immunology, Rudbeck Laboratory C5, SE-75185 Uppsala, Sweden. · Ann Rheum Dis. · Pubmed #15843452 links to  free full text

Abstract: OBJECTIVE: To study serum levels of citrullinated protein/peptide antibodies (anti-CP) during up to 5 years' follow up of patients with early rheumatoid arthritis (RA), and to relate serum levels to disease course and to treatments in clinical practice. METHODS: 279 patients with early RA were followed up with clinical investigations, radiographs, and measurement of anti-CP at baseline and after 3 months, 1, 2, 3, and 5 years. RESULTS: 160/279 (57.3%) patients were anti-CP positive at the first visit (mean 5 months after first symptoms). During follow up only 11/279 (3.9%) of the patients changed their anti-CP status. Anti-CP levels fell significantly during the first year, and this drop correlated with the extent of sulfasalazine treatment but not with other drugs or clinical indices. Anti-CP positive and negative patients had similar disease activities at baseline, but during follow up the anti-CP positive patients had worse clinical disease and greater radiological progression, despite at least equally intensive antirheumatic treatment. CONCLUSIONS: Anti-CP are stable during the first 5 years of RA, suggesting that events before rather than after onset of clinical manifestations of disease determine this phenotype. The presence of anti-CP at diagnosis predicts a less favourable disease course and greater radiological progression despite antirheumatic treatment, but subsequent changes in antibody levels do not reflect changes in disease activity. Taken together, these observations suggest that anti-CP positive RA is a distinct clinical and pathophysiological entity.

Wick MC, Lindblad S, Weiss RJ, Klareskog L, van Vollenhoven RF. · Department of Medicine at Karolinska University Hospital, Stockholm, Sweden. · Scand J Rheumatol. · Pubmed #15794195 No free full text.

Abstract: OBJECTIVES: Disease-modifying anti-rheumatic drugs (DMARDs) decrease clinical signs and symptoms in rheumatoid arthritis (RA). However, radiographic changes sometimes continue to accrue despite effective suppression of clinical symptoms by therapy. The objective of this study was to identify whether successful clinical disease-control in a Swedish early RA-inception cohort of patients led to an attenuation of radiological progression. PATIENTS AND METHODS: We analysed clinical data and radiographs of 95 patients who were on a stable treatment regimen [methotrexate (MTX), sulfasalazine (SSZ), oral gold (AUR)] or who had changed between different DMARDs during the 2-year observation period [multiple therapy failures (mTF)]. Radiographs were quantified using the modified Larsen score and 'X-Ray RheumaCoach' software. RESULTS: Clinical measures improved markedly (p <0.001) from baseline to year 2 under AUR, MTX, and SSZ therapy but not in the mTF group. Similar levels of disease control were seen for each DMARD. During this period, patients treated with AUR had a deltaLarsen score (+ 14.5+/-1.3) similar to mTF patients (+ 15.8+/-1.1) but greater than patients on MTX (+8.6+/-0.8) or SSZ (+9.1+/-0.8). CONCLUSIONS: This study confirms that radiological progression occurs despite a clinically acceptable disease control, but also shows that, given the same degree of clinical disease control, radiological progression can be different for different DMARDs.

Wick MC, Lindblad S, Weiss RJ, Klareskog L, van Vollenhoven RF. · Rheumatology Unit, Department of Medicine at Karolinska Hospital, Stockholm, Sweden. · Ann Rheum Dis. · Pubmed #15096329 links to  free full text

Abstract: OBJECTIVE: To determine if intrapatient comparisons between prediagnosis and subsequent radiological progression could be used to assess effects of DMARDs in an RA inception cohort. PATIENTS AND METHODS: 149 non-randomised patients with newly diagnosed RA in four groups were analysed: patients treated with (a) methotrexate (n = 56); (b) sulfasalazine (n = 55); (c) auranofin (n = 19); and (d) controls who were poor treatment responders (n = 19). Radiographs were quantified using the Larsen erosion score. The prediagnosis radiological progression from the onset of RA symptoms to diagnosis was calculated and compared with the observed progression rate during the first year after diagnosis while receiving DMARD treatment. RESULTS: Mean (SD) disease duration from onset of symptoms until diagnosis was 6.7 (4.0) months. Mean (SD) baseline Larsen score was 13.2 (9.3), giving a mean (SD) estimated prediagnosis progression rate of 23.6 (12.4) Larsen score units/year. Control and auranofin groups showed radiological progression after diagnosis similar to the progression predicted by prediagnosis progression rates. Patients receiving methotrexate or sulfasalazine showed a marked reduction (71% and 73%, respectively; p<0.001) in radiographic progression compared with prediagnosis progression. CONCLUSIONS: Prediagnosis rates of radiological progression can be used quantitatively to obtain information on the potential efficacy of DMARDs, and indicate that methotrexate and sulfasalazine, but not auranofin, significantly retard radiographic damage in the first year after diagnosis.

Jonsdottir T, Forslid J, van Vollenhoven A, Harju A, Brannemark S, Klareskog L, van Vollenhoven RF. · Department of Rheumatology, Karolinska University Hospital, Stockholm, Sweden. · Ann Rheum Dis. · Pubmed #15066863 links to  free full text

Abstract: OBJECTIVE: To determine the frequency and clinical impact of anticardiolipin antibodies (aCL) in patients with rheumatoid arthritis treated with infliximab and etanercept. METHODS: 121 patients from the Stockholm tumour necrosis factor alpha (TNFalpha) follow up registry (STURE) treated with infliximab or etanercept were studied. RESULTS: At baseline 9/65 (14%) infliximab and 10/56 (18%) etanercept treated patients had positive aCL. After 3 months the frequencies of aCL positivity were 29% (p<0.05 compared with baseline) and 27%, respectively, and after 6 months 28% and 25%. Increases were seen for both IgG and IgM aCL. Increasing age, a higher number of prior DMARDs, and higher DAS28 were predictors for the development of aCL. In the infliximab treated patients, 26/30 (87%) aCL(-) but only 7/14 (50%) aCL(+) patients met the ACR20 criteria (p<0.05), and the frequency of treatment limiting infusion reactions in the aCL(+) patients was higher than expected (17%). aCL positivity in the etanercept treated patients did not show such a clinical correlate. Four patients had thromboembolic events, of whom two were aCL(+) and two aCL(-). CONCLUSION: Frequencies of both IgM and IgG aCL positivity increase in patients treated with these TNFalpha antagonists for 3 months or longer. Increasing age, a greater number of prior DMARDs and a greater disease activity at baseline are predictors for the development of aCL. The development of aCL during treatment with infliximab, but not etanercept, is associated with worse clinical results and more frequent serious infusion reactions. aCL are an important class of autoantibodies associated with TNFalpha blocking therapy.

van Vollenhoven RF, Brannemark S, Klareskog L. · Department of Rheumatology, Karolinska Hospital, 17176 Stockholm, Sweden. · Ann Rheum Dis. · Pubmed #15020338 links to  free full text

Abstract: OBJECTIVE: To determine whether increased infliximab doses result in better clinical outcome in rheumatic diseases. METHODS: Subjects were 124 patients with rheumatoid arthritis treated with biological agents at a single institute. Index cases were 44 patients whose infliximab doses had been increased. Controls were patients treated with infliximab without dose increase (n = 44), and patients treated with etanercept (n = 36). Disease activity score (DAS28), ACR28 swollen joint counts, and numerical ACR responses were compared before and after dose increases. For the controls, the point at which the DAS28 value showed any increase (despite infliximab/etanercept treatment) was used as the reference time point. Comparisons were made between three sets of outcomes: best outcome achieved before the dose increase (cases) or before the reference time point (controls); outcomes at this point; and best outcomes after this point. RESULTS: Following dose increase, disease activity showed modest but statistically significant improvements. The improvement achieved after dosage escalation was equal to, but not better than, the best values before dose escalation. While this finding could be interpreted as "recapturing" the previous response, similar improvements were seen in both control groups. Thus the same pattern of worsening and subsequent improvement was seen with or without the infliximab dose increase. CONCLUSIONS: Clinical improvement with increased infliximab dose, and the impression that a previous response can be "recaptured" with higher doses, cannot be taken at face value, as similar improvements occurred in two control groups. The use of infliximab at doses higher than 3 mg/kg needs to be evaluated further.

van Vollenhoven RF, Ernestam S, Harju A, Bratt J, Klareskog L. · Department of Rheumatology, Karolinska Hospital, Stockholm, Sweden. · Arthritis Res Ther. · Pubmed #14680509 links to  free full text

Abstract: Etanercept can be used both as monotherapy and in combination with methotrexate (MTX), but direct comparisons of these two options have not yet been reported. In order to compare the results seen in actual practice between these two options, clinical data on 97 patients followed in the Stockholm TNFalpha Follow-Up Registry were analysed. In 57 of these patients etanercept was added to previously started MTX while the others were treated with etanercept alone. The two groups had similar levels of disease activity at baseline. After 3 months, a significantly lower mean disease activity score (28-joint count-based disease activity score) was attained by the patients on etanercept plus MTX. In this group, the number of patients achieving European League Against Rheumatism-defined remission was also significantly greater. Other disease outcomes showed non-significant trends in the same direction. These data suggest that the combination of etanercept plus MTX is clinically more efficacious than etanercept alone.

van Vollenhoven RF, Klareskog L. · Karolinska Hospital, Stockholm, Sweden. · Arthritis Rheum. · Pubmed #12794816 links to  free full text

Abstract: OBJECTIVE: To study the distribution of clinical responses to treatment with the tumor necrosis factor alpha (TNFalpha) antagonists etanercept and infliximab, and in particular, to determine whether there is a biologically meaningful distinction between responders and nonresponders. METHODS: Among patients in the Stockholm TNFalpha Followup Registry, we analyzed the clinical responses to etanercept and infliximab, using the American College of Rheumatology (ACR) core set of outcome measures. For each parameter, the absolute change (value at baseline - current value) and the percentage change ([absolute change]/[value at baseline] x 100) from baseline were calculated. The results were plotted as histograms and inspected visually, and the distributions were statistically compared with computer-generated normal distributions. RESULTS: Absolute and relative changes in outcomes on the ACR core set of measures in 406 patients receiving etanercept or infliximab were studied. All but a few of these analyses yielded normal or somewhat skewed distributions. The statistical analyses did not detect any non-normal distributions, and visually, the distributions did not appear to be bimodal. CONCLUSION: The clinical response to TNFalpha blockade displays a normal or skewed, but not bimodal, distribution. The frequently encountered perception that a clear distinction can be made between responders and nonresponders is not borne out. These relatively straightforward findings imply that the biologic mechanisms determining responsiveness to TNFalpha blockade are multifactorial and may also have important implications for regulatory guidelines pertaining to treatment with these biologic agents.

van Vollenhoven RF. · Immunology and Rheumatology Clinic, Stanford University Medical Center, CA 94305, USA. · J Rheumatol. · Pubmed #9918263 No free full text.

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van Vollenhoven RF, Anonymous00425. · No affiliation provided · Rheumatology (Oxford). · Pubmed #18326533 No free full text.

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van Vollenhoven RF, Gullström E, Klareskog L. · No affiliation provided · Ann Rheum Dis. · Pubmed #15769930 links to  free full text

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