Rheumatoid Arthritis: Breedveld FC

Breedveld FC. · Department of Rheumatology, Leiden Medical Center, Netherlands. · Clin Med. · Pubmed #11333452 No free full text.

This publication has no abstract.

Goekoop YP, Allaart CF, Breedveld FC, Dijkmans BA. · Department of Rheumatology, Vr&OV0451;e Universiteit Medical Center, Amsterdam, The Netherlands. · Curr Opin Rheumatol. · Pubmed #11333345 No free full text.

Abstract: It has become clear that early suppression of rheumatoid arthritis disease activity is important in preventing progressive joint destruction and functional decline. To achieve this goal, many rheumatologists today advocate a more aggressive approach, using combinations of classic disease-modifying antirheumatic drugs-often including methotrexate-or new drugs. During the last 2 years, the combination of methotrexate, sulfasalazine, hydroxychloroquine, and prednisolone has been demonstrated to be more beneficial than monotherapy in patients with early rheumatoid arthritis. In addition, the superior efficacy of the combination of new tumor necrosis factor-alpha blocking agents plus methotrexate to methotrexate alone in patients with chronic disease is very promising. Most studies of combination therapy focus on the efficacy of a combination compared with monotherapy, rather than on the efficacy of a treatment strategy. Although these studies of combination therapy provide useful information about the possible synergistic action of combinations of drugs, many questions remain unanswered, and studies evaluating different treatment strategies are needed before a new approach can be suggested.

Cannon GW, Breedveld FC. · Veterans Affairs Medical Center, and the Division of Rheumatology, Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA. · Am J Med. · Pubmed #11173044 No free full text.

Abstract: Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The clinical efficacy of NSAIDs is primarily related to the inhibition of COX-2 activity, whereas much of the toxicity, particularly gastrointestinal toxicity, is related to COX-1 inhibition. In vitro and in vivo assays indicate that both COX-2-specific inhibitors and conventional NSAIDs are equally effective in inhibiting COX-2, suggesting that the clinical efficacy of COX-2-specific inhibitors should be similar to that of conventional NSAIDs. Multiple studies in patients with osteoarthritis, rheumatoid arthritis, and acute pain have now confirmed that the clinical efficacy of COX-2-specific inhibitors is similar to that of conventional NSAIDs.

Zanelli E, Breedveld FC, de Vries RR. · Department of Immunohematology and Blood Transfusion, University Medical Center, Leiden, The Netherlands. · Hum Immunol. · Pubmed #11163080 No free full text.

Abstract: We have reviewed the literature on the association of HLA class II with rheumatoid arthritis (RA). Strong linkage disequilibrium among DQB1, DQA1 and DRB1 alleles makes it difficult to evaluate the individual contribution of each locus. Nonetheless, there is a strong case for the role of DQB1*03 and *04 combined with DQA1*03 in susceptibility to severe RA while DQB1*0501 combined with DQA1*0101 and *0104 weakly predisposes to a mild form of RA. However, it is also clear that DRB1*0401 has a particular role in predisposition to the most severe form of the disease while other DRB1 alleles might provide protection. We would like to propose that in RA, as in type I diabetes, both DQ and DR loci contribute to predisposition to the disease.

Tak PP, Breedveld FC. · Division of Clinical Immunology and Rheumatology, Academic Medical Center, Amsterdam, The Netherlands. · Arthritis Res. · Pubmed #11094407 links to  free full text

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Furst DE, Breedveld FC, Burmester GR, Crofford JJ, Emery P, Feldmann M, Kalden JR, Kavanaugh AF, Keystone EC, Klareskog LG, Lipsky PE, Maini RN, Russell AS, Scott DL, Smolen JS, Van de Putte LB, Visher TL, Weisman MH. · No affiliation provided · Ann Rheum Dis. · Pubmed #11053077 links to  free full text

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Breedveld FC, Dayer JM. · Academic Ziekenhuis Leiden, Stafcentrum Reumatologie, Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #11053058 links to  free full text

Abstract: Leflunomide is a selective inhibitor of de novo pyrimidine synthesis. In phase II and III clinical trials of active rheumatoid arthritis, leflunomide was shown to improve primary and secondary outcome measures with a satisfactory safety profile. The active metabolite of leflunomide, A77 1726, at low, therapeutically applicable doses, reversibly inhibits dihydroorotate dehydrogenase (DHODH), the rate limiting step in the de novo synthesis of pyrimidines. Unlike other cells, activated lymphocytes expand their pyrimidine pool by approximately eightfold during proliferation; purine pools are increased only twofold. To meet this demand, lymphocytes must use both salvage and de novo synthesis pathways. Thus the inhibition of DHODH by A77 1726 prevents lymphocytes from accumulating sufficient pyrimidines to support DNA synthesis. At higher doses, A77 1726 inhibits tyrosine kinases responsible for early T cell and B cell signalling in the G(0)/G(1) phase of the cell cycle. Because the immunoregulatory effects of A77 1726 occur at doses that inhibit DHODH but not tyrosine kinases, the interruption of de novo pyrimidine synthesis may be the primary mode of action. Recent evidence suggests that the observed anti-inflammatory effects of A77 1726 may relate to its ability to suppress interleukin 1 and tumour necrosis factor alpha selectively over their inhibitors in T lymphocyte/monocyte contact activation. A77 1726 has also been shown to suppress the activation of nuclear factor kappaB, a potent mediator of inflammation when stimulated by inflammatory agents. Continuing research indicates that A77 1726 may downregulate the glycosylation of adhesion molecules, effectively reducing cell-cell contact activation during inflammation.

Zanelli E, Breedveld FC, de Vries RR. · Department of Immunohaematology and Blood Bank, Leiden University Medical Centre, Leiden, The Netherlands. · Rheumatology (Oxford). · Pubmed #11035123 links to  free full text

Abstract: That certain HLA specificities are associated with predisposition to autoimmune disease does not necessarily imply that self-reactive T cells restricted to particular HLA alleles are eliciting the disease. In the present essay, we argue that HLA can be a major genetic factor in the development of autoimmune diseases without T cells being primarily involved in its initiation or perpetuation. There is now ample evidence that self-reactive, regulatory T cells can protect against pernicious autoimmunity. Hereafter, we propose that extended HLA haplotypes, such as DQ3-DR4, DQ3-DR9, DQ5-DR1 and DQ5-DR10 in the case of rheumatoid arthritis, predispose to impaired T-cell-mediated immune regulation. The haplotypes associated with impaired regulation are the combination of certain class II alleles and a yet unknown 'amplifier'. In this model, products of the HLA class II region are not involved in the presentation of particular organ-specific autoantigens. Therefore, HLA does not predispose to autoimmune disease per se, but rather fails to provide efficient protection.

Smolen JS, Breedveld FC, Burmester GR, Combe B, Emery P, Kalden JR, Klareskog L, Maini RN, Numo R, van De Putte LB, van Riel PL, Rodriguez-Valverde V. · University of Vienna, Berlin. · Ann Rheum Dis. · Pubmed #10873957 links to  free full text

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Breedveld FC. · Department of Rheumatology, Leiden University Medical Center, The Netherlands. · Baillieres Best Pract Res Clin Rheumatol. · Pubmed #10652649 No free full text.

Abstract: The active search for new treatment modalities of established rheumatoid arthritis have created a dynamic period for rheumatology. Both promising pharmaceutical products and targeted interventions with products of the biotechnology industry are being developed. Leflunomide and the selective blockade of the cytokine tumour necrosis factor (TNF) have recently been registered in several countries and others will follow. Like all new therapeutic strategies much remains to be learned about the optimal use of these therapies and their possible limitations. The success of these interventions have shown that a complex disease such as rheumatoid arthritis that is refractory to conventional treatment can be modulated by new therapeutic strategies. This experience has also resulted in further searches for new drugs that influence those pathogenetic pathways affected by the interventions found to be effective.

Breedveld FC. · Department of Rheumatology, Leiden University Medical Centre, The Netherlands. · Rheumatology (Oxford). · Pubmed #10646483 No free full text.

Abstract: Recently, anti-inflammatory cytokines and cytokine-blocking agents such as monoclonal antibodies, soluble receptors and receptor antagonists have been explored as therapeutic agents for patients with rheumatoid arthritis. The anti-inflammatory cytokines interleukin 10 (IL-10), which reverses the cartilage degradation induced by antigen-stimulated mononuclear cells, and IL-4, which reduces prostaglandin production by synoviocytes, are currently being tested for their clinical efficacy. Trials with the tumour necrosis factor alpha blocking agents infliximab (monoclonal antibody) and etanercept (the fusion protein of soluble tumour necrosis factor receptors linked to human immunoglobulin) have produced improvements in clinical and laboratory measures of inflammation with mild side-effects. Trials of IL-1 blockade with recombinant human IL-1 receptor antagonist produced significant improvement of clinical parameters with mild side-effects. Blockade of IL-6, the cytokine that induces biosynthesis of acute-phase proteins, has been attempted with i.v. injections of anti-IL-6 monoclonal antibodies with improvement in clinical variables as well as reduced acute-phase proteins.

Pincus T, Breedveld FC, Emery P. · Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-4500, USA. · Clin Exp Rheumatol. · Pubmed #10589350 No free full text.

This publication has no abstract.

Furst DE, Breedveld FC, Burmester GR, Crofford L, Emery P, Feldman M, Kalden JR, Kavanaugh A, Keystone E, Lipsky PE, Maini RN, Moreland L, Smolen JS, Van De Putte L, Vischer T, Weinblatt M, Weissman M. · No affiliation provided · Ann Rheum Dis. · Pubmed #10577989 links to  free full text

This publication has no abstract.

Aletaha D, Funovits J, Breedveld FC, Sharp J, Segurado O, Smolen JS. · Division of Rheumatology, Medical University of Vienna, Vienna, Austria. · Arthritis Rheum. · Pubmed #19404938 No free full text.

Abstract: OBJECTIVE: Joint damage is related to disease activity in rheumatoid arthritis (RA), but the degree of its progression and the temporal associations between disease activity and joint damage are unclear. The aim of this study was to evaluate whether there is a latency in the effect of disease activity on radiographic progression in patients with RA. METHODS: Data were obtained from the PREMIER trial, a 2-year randomized, controlled clinical trial of adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in early RA. Radiographic progression of joint damage was calculated using the modified total Sharp score in a subset of patients whose disease was in remission (Simplified Disease Activity Index<or=3.3) in the second year of the trial. The progression of damage in the second year was compared between groups of patients whose disease was already in remission for an additional period of 3, 6, or 9 months during the first year. Analysis of variance was used to test for a linear trend. RESULTS: Among 794 patients with early RA, 119 (15%) achieved sustained remission during the second year, with no difference in radiographic progression across the 3 treatment groups. Radiographic progression in the second year was significantly different between patients with 3, 6, or 9 additional months of remission during year 1 (mean change in the modified Sharp score 1.19 in those with 3 additional months of remission versus 0.20 in those with 6 additional months of remission and -0.32 in those with 9 additional months of remission; P<0.05). The results were supported by similar findings in a series of sensitivity analyses. CONCLUSION: These data indicate that the level of disease activity as well as the duration of remission affect subsequent progression of radiographic damage in RA. This latency between disease activity and its effects on radiographic progression should be considered when evaluating radiographic outcomes in trials of RA.

van der Bijl AE, Breedveld FC, Antoni CE, Kalden JR, Kary S, Burmester GR, Beckmann C, Unnebrink K, Kupper H. · Department of Rheumatology, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands. · Clin Rheumatol. · Pubmed #18350329 links to  free full text

Abstract: This prospective open-label pilot study evaluated the effectiveness and safety of adalimumab and the relationship to antibodies against infliximab (IFX) in adult patients with active rheumatoid arthritis (RA) who had been treated previously with IFX and experienced treatment failure owing to lack or loss of response or intolerance. Patients self-administered adalimumab 40 mg subcutaneously every other week for 16 weeks, followed by maintenance therapy for up to Week 56. Measures of effectiveness included American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria, 28-joint Disease Activity Score, and the Health Assessment Questionnaire Disability Index. Serum IFX concentrations, human antichimeric antibody against IFX (HACA), adalimumab serum concentrations, antiadalimumab antibody, and safety also were assessed. Of the 41 enrolled patients, 37 completed 16 weeks and 30 completed 56 weeks of treatment. Patients experienced clinically meaningful improvements in all measures of RA activity, with greater response rates observed for patients who had experienced loss of initial response to or intolerance of IFX. At Week 16, 46% of patients achieved an ACR20 and 28% achieved an ACR50; 61% achieved an at least moderate and 17% achieved a good EULAR response. Clinical benefit was maintained through Week 56 in all effectiveness parameters. Baseline HACA status did not significantly impact effectiveness. No new safety signals were observed; neither former IFX intolerance status nor baseline HACA status had a clinically relevant impact on adverse event frequency or severity. Adalimumab was effective and well-tolerated in patients with RA who previously failed IFX therapy, irrespective of reason for discontinuation and of HACA status.

van der Bijl AE, Emmer BJ, Breedveld FC, Middelkoop HA, Jurgens CK, van Buchem MA, Huizinga TW, van der Grond J. · Departments of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Clin Exp Rheumatol. · Pubmed #17543158 No free full text.

Abstract: OBJECTIVE: Neurological symptoms have been reported in patients treated with anti-TNF-alpha. In a pilot study we evaluated the effect of anti-TNF-alpha on cerebral parenchyma using advanced Magnetic Resonance (MR) techniques. METHODS: Seven patients with a systemic inflammatory disease (5 rheumatoid arthritis, 2 psoriatic arthritis) had Magnetization Transfer Imaging, Diffusion Weighted Imaging (DWI) and Magnetic Resonance Spectroscopy (MRS) of the brain before and after administration of anti-TNF-alpha. Four patients were neuropsychologically evaluated. RESULTS: After treatment with TNF-alpha blocking agents the Magnetization Transfer Ratio histogram Peak-heights (MTR-Pht) of the white and gray matter decreased (p < 0.01 and p < 0.05 respectively). The Apparent Diffusion Coefficient for the white and gray matter and the metabolite ratios in the centrum semiovale did not significantly change after therapy. Neuropsychological assessment showed no difference before and after anti-TNF-alpha. CONCLUSION: The decrease of the MTR-Pht after anti-TNF-alpha therapy suggests loss of parenchyma integrity; however, these changes could not be attributed to inflammation or demyelination based on our complementary DWI and MRS data. The decrease of the MTR-Pht did not result in decreased cognitive function.

Smolen JS, Han C, Bala M, Maini RN, Kalden JR, van der Heijde D, Breedveld FC, Furst DE, Lipsky PE, Anonymous00345. · Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna and Lainz Hospital, Vienna, Austria. · Arthritis Rheum. · Pubmed #15818697 links to  free full text

Abstract: OBJECTIVE: To assess the relationship between inflammation and joint destruction in rheumatoid arthritis (RA) patients who have not responded clinically to treatment. METHODS: Changes from baseline to week 54 in clinical variables and measures of radiographic progression were compared between patients who received infliximab (3 mg/kg or 10 mg/kg every 4 or 8 weeks) plus methotrexate (MTX) and those who received MTX plus placebo in the Anti-Tumor Necrosis Factor Trial in RA with Concomitant Therapy trial. RESULTS: At week 54, patients who did not show 20% improvement by American College of Rheumatology criteria (ACR20 nonresponders) while receiving infliximab plus MTX exhibited mild but statistically significant improvement in clinical variables, including the 28-joint Disease Activity Score (DAS28) (P < 0.001), tender joint count (P = 0.014), swollen joint count (P < 0.001), and C-reactive protein (CRP) level (P < 0.001). Whereas the clinical and CRP changes among ACR20 nonresponders to infliximab plus MTX were small and much lower than among ACR20 responders to this treatment, radiographic progression among ACR20 nonresponders to infliximab plus MTX was significantly inhibited (P < 0.001) compared with ACR20 nonresponders to MTX plus placebo. Radiographic progression was much greater in patients receiving MTX plus placebo than in patients receiving infliximab plus MTX, irrespective of ACR response status (mean change in modified Sharp/van der Heijde score 6.0 in ACR20 responders and 7.2 in ACR20 nonresponders in the MTX plus placebo-treated group, versus 0.1 in ACR20 responders and 1.2 in ACR20 nonresponders in the infliximab plus MTX-treated group). Furthermore, among patients who were ACR20 nonresponders through week 54, patients who were DAS nonresponders at weeks 30 and 54, and patients without any improvement in individual clinical variables, those receiving infliximab plus MTX still demonstrated inhibition of structural damage that was statistically significant compared with inhibition in patients who received MTX plus placebo (P < 0.05 to P < 0.001). CONCLUSION: Even in patients without clinical improvement, treatment with infliximab plus MTX provided significant benefit with regard to the destructive process, suggesting that in such patients these 2 measures of disease are dissociated.

van den Hout WB, de Jong Z, Munneke M, Hazes JM, Breedveld FC, Vliet Vlieland TP. · Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #15696568 links to  free full text

Abstract: OBJECTIVE: To estimate the cost utility and cost effectiveness of long-term, high-intensity exercise classes compared with usual care in rheumatoid arthritis (RA) patients. METHODS: RA patients (n = 300) were randomly assigned to either exercise classes or UC; followup lasted for 2 years. Outcome measures were quality-adjusted life years (QALYs) according to the EuroQol (EQ-5D), Short Form 6D (SF-6D), and a transformed visual analog scale (VAS) rating personal health; functional ability according to the Health Assessment Questionnaire (HAQ) and McMaster Toronto Arthritis Patient Preference Interview (MACTAR); and societal costs. RESULTS: QALYs in both randomization groups were similar according to the EQ-5D and SF-6D, but were in favor of usual care according to the VAS (annual difference 0.037 QALY; 95% confidence interval [95% CI] 0.002, 0.069). Functional ability was similar according to the HAQ, but in favor of the exercise classes according to the MACTAR (annual difference 2.9 QALY; 95% CI 0.9, 4.9). Annual medical costs of the exercise program were estimated at 780 per participating patient (1 approximately $1.05). The increase per patient in total medical costs of physical therapy was estimated at 430 (95% CI 318, 577), and the increase in total societal costs at 602 (95% CI -490, 1,664). For societal willingness-to-pay equal to 50,000 per QALY, usual care had better cost utility than exercise classes, and significantly so according to the VAS. CONCLUSION: From a societal perspective and without taking possible preventive health effects into account, long-term, high-intensity exercise classes provide insufficient improvement in the valuation of health to justify the additional costs.

de Jong Z, Munneke M, Zwinderman AH, Kroon HM, Ronday KH, Lems WF, Dijkmans BA, Breedveld FC, Vliet Vlieland TP, Hazes JM, Huizinga TW. · Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #15479889 links to  free full text

Abstract: OBJECTIVE: To investigate the effect of long term high intensity weightbearing exercises on radiological damage of the joints of the hands and feet in patients with rheumatoid arthritis (RA). METHODS: Data of the 281 completers of a 2 year randomised controlled trial comparing the effects of usual care physical therapy (UC) with high intensity weightbearing exercises were analysed for the rate of radiological joint damage (Larsen score) of the hands and feet. Potential determinants of outcome were defined: disease activity, use of drugs, change in physical capacity and in bone mineral density, and attendance rate at exercise sessions. RESULTS: After 2 years, the 136 participants in high intensity weightbearing exercises developed significantly less radiological damage than the 145 participants in UC. The mean (SD) increase in damage was 3.5 (7.9) in the exercise group and 5.7 (10.2) in the UC group, p = 0.045. Separate analysis of the damage to the hands and feet suggests that this difference in rate of increase of damage is more pronounced in the joints of the feet than in the hands. The rate of damage was independently associated with less disease activity, less frequent use of glucocorticoids, and with an improvement in aerobic fitness. CONCLUSION: The progression of radiological joint damage of the hands and feet in patients with RA is not increased by long term high intensity weightbearing exercises. These exercises may have a protective effect on the joints of the feet.

Breedveld FC, Han C, Bala M, van der Heijde D, Baker D, Kavanaugh AF, Maini RN, Lipsky PE. · Department of Rheumatology, Leiden University Medical Centre, Leiden, Netherlands. · Ann Rheum Dis. · Pubmed #15286005 links to  free full text

Abstract: OBJECTIVES: To identify factors associated with poor physical function in rheumatoid arthritis and to assess whether baseline joint damage has an impact on improvement in physical function during infliximab treatment. METHODS: 428 patients with active rheumatoid arthritis despite methotrexate treatment received methotrexate alone or with infliximab (3 mg/kg or 10 mg/kg every four or eight weeks) for 54 weeks (the ATTRACT trial). Data on clinical outcomes and physical function (assessed by the health assessment questionnaire (HAQ)) were collected. Structural damage was assessed using the van der Heijde modification of the Sharp score. Odds ratios (OR) for factors associated with severe functional disability (HAQ > or =2.0) at baseline were estimated using multiple logistic regression analyses, and baseline factors related to the change in physical function after treatment at week 54 were determined. RESULTS: Baseline radiographic scores were correlated with baseline HAQ scores. After adjustment for demographic characteristics in the logistic regression model, baseline disease activity scores, radiological joint damage, fatigue, and morning stiffness were found to be associated with severe functional disability (HAQ >2.0), with OR values of 2.00 (1.53 to 2.63), 1.82 (1.15 to 2.87), 1.19 (1.05 to 1.34), and 1.07 (1.01 to 1.13), respectively. In multiple linear regression analysis, physical disability, joint damage, and fatigue at baseline were correlated with less improvement in physical function after treatment. Infliximab treatment was associated with greater improvement in physical function. CONCLUSIONS: Greater joint damage at baseline was associated with poorer physical function at baseline and less improvement in physical function after treatment, underlining the importance of early intervention to slow the progression of joint destruction.

Rau R, Simianer S, van Riel PL, van de Putte LB, Krüger K, Schattenkirchner M, Allaart CF, Breedveld FC, Kempeni J, Beck K, Kupper H. · Rheumaklinik, Ratingen, Germany. · Scand J Rheumatol. · Pubmed #15228184 No free full text.

Abstract: OBJECTIVE: This randomized, placebo-controlled, double-blind, Phase 1 study assessed the magnitude, onset, and duration of response with intravenous (i.v.) and subcutaneous (s.c.) adalimumab (Humira, Abbott Laboratories) combined with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) despite previous MTX therapy. METHODS: Fifty-four patients were randomized to two injections of i.v. or s.c. adalimumab (1 mg/kg) or placebo while continuing on MTX (mean dose, 15.7 mg/week). Dosing intervals were determined by the European League Against Rheumatism (EULAR) response criteria, and were allowed to range from 1 to 3 months. Efficacy was mainly assessed using the EULAR response criteria and the American College of Rheumatology (ACR) response criteria. RESULTS: Moderate EULAR response was achieved at least once within 29 days after the first injection in 83% and 61% of patients receiving i.v. and s.c. adalimumab respectively, compared with 44% for placebo [probability (p) < or = 0.05 for i.v. adalimumab versus placebo]. A 20% improvement in disease activity according to the ACR criteria (ACR20 response) was achieved by 72% and 67% of patients receiving i.v. and s.c. adalimumab respectively, compared with 28% for placebo (p < or = 0.01 and p < or = 0.05, respectively, versus placebo). By Day 15 after the first and second injections, statistically significant moderate EULAR and ACR20 response rates were achieved with either i.v. or s.c. adalimumab compared with placebo (p < or = 0.05). The mean times to second injection for i.v. adalimumab, s.c. adalimumab, and placebo were 42.2 days (range: 27-84 days), 38.3 days (range: 26-85 days), and 28.4 days (range: 26-32 days), respectively (minimum time allowed by the protocol between the first and second injections was 4 weeks). Adalimumab in combination with MTX was well tolerated, with no patients being withdrawn because of adverse events. CONCLUSION: Either i.v. or s.c. adalimumab added to MTX significantly improved the signs and symptoms of RA compared with MTX alone. Subcutaneously administered adalimumab appeared to provide a response that was as great, as rapid, and as enduring as that with i.v. adalimumab.

Hall SK, Perregaux DG, Gabel CA, Woodworth T, Durham LK, Huizinga TW, Breedveld FC, Seymour AB. · Pfizer Global Research and Development, Groton, Connecticut 06340, USA. · Arthritis Rheum. · Pubmed #15188375 links to  free full text

Abstract: OBJECTIVE: Significant variation in interleukin-1 beta (IL-1 beta) protein secretion between subjects has been observed when using a lipopolysaccharide (LPS)/ATP-mediated ex vivo blood stimulation assay. To explore the potential relationships between genetic polymorphisms in the IL1B cytokine gene and cellular responses to inflammatory stimuli such as LPS, we investigated the hypothesis that polymorphisms within the promoter and exon 5 of the IL1B gene contribute to the observed differences in IL-1 beta protein secretion. METHODS: The IL1B gene polymorphisms C-511T, T-31C, and C3954T were tested for association with LPS-induced secretion of IL-1 beta protein as measured by an ex vivo blood stimulation assay. Samples from 2 independent study populations (n = 31 and n = 25) were available for use in the ex vivo assay after consent was obtained to analyze the DNA. RESULTS: A specific haplotype, composed of the T allele at -511 and the C allele at -31, was significantly associated with a 2-3-fold increase in LPS-induced IL-1 beta protein secretion. This association was observed in both of the independent study populations (P = 0.0084 and P = 0.0017). CONCLUSION: These data suggest that polymorphisms within the promoter region of the IL1B gene contribute to observed differences in LPS-induced IL-1 beta protein secretion.

Remans PH, Sont JK, Wagenaar LW, Wouters-Wesseling W, Zuijderduin WM, Jongma A, Breedveld FC, Van Laar JM. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Eur J Clin Nutr. · Pubmed #15164103 No free full text.

Abstract: OBJECTIVE: To investigate in a double-blind placebo-controlled, parallel group study, the effects of a nutrient supplement, containing, among other ingredients, the omega-3 fatty acids eicosapentaenoic acid (1.4 g EPA), docosahexaenoic acid (0.211 g DHA), omega-6 fatty acid gamma-linolenic acid (0.5 g GLA) and micronutrients in patients with active rheumatoid arthritis (RA). DESIGN, SUBJECTS AND INTERVENTION: RA patients were randomized to receive either daily liquid nutrient supplementation or placebo for 4 months. The primary end point was the change in tender joint count at 2 and 4 months. Other clinical variables included swollen joint count, visual analogue scales for pain and disease activity, grip strength, functionality score and morning stiffness. Biochemical parameters included plasma concentrations of PUFA and vitamins C and E. SETTING: Outpatient university clinic. RESULTS: In all, 66 patients enrolled, 55 completed the study. No significant change from baseline in tender joint count or any of the other clinical parameters was detected in either group. Patients receiving nutrient supplementation, but not those receiving placebo, had significant increases in plasma concentrations of vitamin E (P=0.015), and EPA, DHA and docosapentaenoic acid concomitant with decreases of arachidonic acid (P=0.01). Intergroup differences for PUFA and vitamin E were significantly different (P=0.01 and 0.03, respectively). CONCLUSIONS: This double-blind, placebo-controlled study in RA patients did not show superior clinical benefit of daily nutrient supplementation with EPA, GLA and micronutrients at the doses tested as compared to placebo. The study adds information regarding doses of omega-3 fatty acids, below which anti-inflammatory effects in RA are not seen.

Kraan MC, Smeets TJ, van Loon MJ, Breedveld FC, Dijkmans BA, Tak PP. · Division of Clinical Immunology and Rheumatology, Department of Internal Medicine, University of Amsterdam/Academic Medical Centre, Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #15115713 links to  free full text

Abstract: BACKGROUND: T cells have a pivotal role in RA. Leflunomide inhibits pyrimidine biosynthesis, to which T cells are especially susceptible, and therefore may have a different cytokine profile than methotrexate. MATERIALS AND METHODS: Serum samples of 100 patients with RA, treated with leflunomide (n = 50) or methotrexate (n = 50), were collected at baseline, after 16 weeks and after 1 year's treatment. Serum levels of interleukin 6 (IL6), and interferon (IFN) gamma were determined by ELISA. Additionally, peripheral blood mononuclear cells (PBMC) of five healthy volunteers and three patients with RA were isolated and the effects of the active metabolite of leflunomide (A77-1726, 0-200 mmol/l) on cell proliferation and on IL6 and IFNgamma production were determined by ELISA. In peripheral blood lymphocytes (PBL) and monocytes (PBM) from two healthy volunteers the effects of A77-1726 on IL6 production were measured by ELISA and PCR. RESULTS: Mean (SEM) serum levels of IFNgamma were significantly reduced after leflunomide treatment (baseline 43 (10) pg/ml; 1 year 29 (7) (p = 0.015), but there was no change in IL6 levels (baseline 158 (41), 1 year 151 (48)). Both IFNgamma and IL6 levels were significantly reduced after methotrexate treatment. This observation was supported by in vitro experiments. The production of IFNgamma by PBL was inhibited by A77-1726, but IL6 production by PBM was not inhibited. CONCLUSION: The differential effect on IFNgamma and IL6 production supports the hypothesis that activated T cells are preferentially inhibited by leflunomide. An explanation may be either inhibition of uridine synthesis or effects on signal transduction pathways.

de Jong Z, Munneke M, Lems WF, Zwinderman AH, Kroon HM, Pauwels EK, Jansen A, Ronday KH, Dijkmans BA, Breedveld FC, Vliet Vlieland TP, Hazes JM. · Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #15077288 links to  free full text

Abstract: OBJECTIVE: Patients with rheumatoid arthritis (RA) are more at risk for the development of osteoporosis and osteoporotic fractures than are their healthy peers. In this randomized, controlled, multicenter trial, the effectiveness of a 2-year high-intensity weight-bearing exercise program (the Rheumatoid-Arthritis-Patients-In-Training [RAPIT] program) on bone mineral density (BMD) was compared with usual care physical therapy, and the exercise modalities associated with changes in BMD were determined. METHODS: Three hundred nine patients with RA were assigned to an intervention group, either the RAPIT program or usual care physical therapy. The primary end points were BMD of the hip and spine. The exercise modalities examined were aerobic fitness, muscle strength, and, as a surrogate for those effects not directly measured by the RAPIT program, attendance rate. RESULTS: The data on the 136 RAPIT participants and 145 usual care participants who completed the study were analyzed. The mean rate of decrease in hip BMD, but not in lumbar spine BMD, was smaller in patients participating in the RAPIT program when compared with that in the usual care group, with a mean decrease of 1.6% (95% confidence interval [95% CI] 0.8-2.5) over the first year and 0.5% (95% CI 1.1-2.0) over the second year. The change in hip BMD was significantly and independently associated with changes in both muscle strength (multivariate odds ratio [OR] 1.75, 95% CI 1.07-2.86) and aerobic fitness (OR 1.79, 95% CI 1.10-2.90), but not with the attendance rate (OR 1.00, 95% CI 0.99-1.00). CONCLUSION: A long-term high-intensity weight-bearing exercise program for RA patients is effective in slowing down the loss of BMD at the hip. The exercise modalities associated with this effect are muscle strength and aerobic fitness.