Rheumatoid Arthritis: van Schaardenburg D

Dijkmans BA, van Schaardenburg D, van der Horst-Bruinsma IE, Reesink HW, Vandenbroucke JP, Boers M. · VU Medisch Centrum, afd. Reumatologie, Postbus 7057, 1007 MB Amsterdam. · Ned Tijdschr Geneeskd. · Pubmed #15819133 No free full text.

Abstract: In some conditions e.g. osteoporosis, hypertension and hypercholesterolaemia, certain phenomena precede manifestation of the disease and preventive measures can be taken long before the disease presents itself. In the same way systemic lupus erythematosus (SLE) and rheumatoid arthritis can be explored. Recently, studies have been published on healthy blood donors, who later developed SLE or rheumatoid arthritis, and in whom specific autoantibodies could be demonstrated. In SLE the autoantibodies are not specific enough to develop preventive strategies, but in rheumatoid arthritis in particular there are specific antibodies against cyclic citrullinated peptides (anti-CCP-antibodies) which are very specific. A clinical trial has been initiated in which HLA-DR4-positive people with raised autoantibody concentrations are given 1-2 intramuscular injections of dexamethasone with the aim of halving the antibody concentration and in the long term lowering the incidence of rheumatoid arthritis.

Steultjens EM, Dekker J, Bouter LM, van Schaardenburg D, van Kuyk MA, van den Ende CH. · Nivel; Netherlands Institute for Health Services Research, P.O. Box 1568, Utrecht, Netherlands. · Cochrane Database Syst Rev. · Pubmed #14974005 No free full text.

Abstract: BACKGROUND: For persons with rheumatoid arthritis (RA) the physical, personal, familial, social and vocational consequences are extensive. Occupational therapy (OT), with the aim to facilitate task performance and to decrease the consequences of rheumatoid arthritis for daily life activities, is considered to be a cornerstone in the management of rheumatoid arthritis. Till now the efficacy of occupational therapy for patients with rheumatoid arthritis on functional performance and social participation has not been systematically reviewed. OBJECTIVES: To determine whether OT interventions (classified as comprehensive therapy, training of motor function, training of skills, instruction on joint protection and energy conservation, counseling, instruction about assistive devices and provision of splints) for rheumatoid arthritis patients improve outcome on functional ability, social participation and/or health related quality of life. SEARCH STRATEGY: Relevant full length articles were identified by electronic searches in Medline, Cinahl, Embase, Amed, Scisearch and the Cochrane Musculoskeletal group Specialised Register. The reference list of identified studies and reviews were examined for additional references. Date of last search: December 2002. SELECTION CRITERIA: Controlled (randomized and non-randomized) and other than controlled studies (OD) addressing OT for RA patients were eligible for inclusion. DATA COLLECTION AND ANALYSIS: The methodological quality of the included trials was independently assessed by two reviewers. Disagreements were resolved by discussion. A list proposed by Van Tulder et al. (Van Tulder 1997) was used to assess the methodological quality. For outcome measures, standardized mean differences were calculated. The results were analysed using a best evidence synthesis based on type of design, methodological quality and the significant findings of outcome and/or process measures. MAIN RESULTS: Thirty-eight out of 58 identified occupational therapy studies fulfilled all inclusion criteria. Six controlled studies had a high methodological quality. Given the methodological constraints of uncontrolled studies, nine of these studies were judged to be of sufficient methodological quality. The results of the best evidence synthesis shows that there is strong evidence for the efficacy of "instruction on joint protection" (an absolute benefit of 17.5 to 22.5, relative benefit of 100%) and that limited evidence exists for comprehensive occupational therapy in improving functional ability (an absolute benefit of 8.7, relative benefit of 20%). Indicative findings for evidence that "provision of splints" decreases pain are found (absolute benefit of 1.0, relative benefit of 19%). REVIEWER'S CONCLUSIONS: There is evidence that occupational therapy has a positive effect on functional ability in patients with rheumatoid arthritis.

Steultjens EM, Dekker J, Bouter LM, van Schaardenburg D, van Kuyk MA, van den Ende CH. · Netherlands Institute for Health Services Research, Utrecht, The Netherlands. · Arthritis Rheum. · Pubmed #12522844 links to  free full text

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van Schaardenburg D, Kaandorp C, Krijnen P. · Jan van Breemen Instituut, Centrum voor reumatologie en revalidatie, Dr. Jan van Breemenstraat 2, NL - 1056 AB, Amsterdam, The Netherlands. · Expert Opin Pharmacother. · Pubmed #11866678 No free full text.

Abstract: The outcome of bacterial arthritis is generally poor: the mortality is 10 - 15% and there is loss of joint function in 25 - 50% of the survivors. The incidence of bacterial arthritis is low: 2 - 6 cases per 100,000 people per year. Risk factors are age, joint disease (especially rheumatoid arthritis [RA]), diabetes mellitus and the presence of a prosthetic joint. The predominant situations that can lead to bacterial arthritis are skin infections of the feet and rarely invasive medical or dental procedures. Due to the severity of the disease, antibiotic prophylaxis of haematogenous bacterial arthritis in patients with prosthetic joints is advocated. However, due to the rarity of the disease it is unclear whether the advantages of prophylaxis outweigh the disadvantages of the large-scale use of antibiotics, such as side effects, costs and bacterial resistance. In a decision-analysis of a large group of patients with joint diseases, antibiotic treatment of skin infections appeared to be cost-effective in the prevention of haematogenous bacterial arthritis, mainly in high-risk patients. On the other hand, prophylaxis around medical or dental procedures was not cost-effective, except possibly in a small group of patients with increased risk.

Kaandorp CJ, van Schaardenburg D, Krijnen P. · Jan van Breemen Instituut, Centrum voor Reumatologie en Revalidatie, Amsterdam. · Ned Tijdschr Geneeskd. · Pubmed #10526583 No free full text.

Abstract: The outcome of bacterial arthritis is generally poor: the mortality is 10-15% and there is loss of joint function in 25-50% of the survivors. Adverse prognostic factors are advanced age, a pre-existent joint disease and an infection of a prosthetic joint. The incidence of bacterial arthritis is low: 2-6 per 100,000 persons per year. Risk factors are advanced age, a joint disease--especially rheumatoid arthritis--diabetes mellitus and presence of a prosthetic joint. Situations that can lead to bacterial arthritis are mainly skin infections of the feet and only rarely invasive medical or dental procedures. Because of the severity of the disease, antibiotic prophylaxis of haematogenous bacterial arthritis in patients with prosthetic joints is advocated in guidelines. However, because of the rarity of the disease it is unclear whether the advantages of prophylaxis outweigh the disadvantages of the large-scale use of antibiotics, such as side effects, costs and increased resistance of bacteria. In a decision analysis of a large group of patients with joint diseases, antibiotic treatment of skin infections appeared to be (cost-)effective in the prevention of haematogenous bacterial arthritis, mainly in high-risk patients. On the other hand, prophylaxis around medical or dental procedures was not (cost-)effective, except possibly in a small group of patients with increased risk.

Giltay EJ, van Schaardenburg D, Gooren LJ, Dijkmans BA. · Institute of Endocrinology, Reproduction and Metabolism, Hospital Vrije Universiteit, Amsterdam, The Netherlands. · Ann N Y Acad Sci. · Pubmed #10415604 No free full text.

This publication has no abstract.

Vos K, Thurlings RM, Wijbrandts CA, van Schaardenburg D, Gerlag DM, Tak PP. · Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands. · Arthritis Rheum. · Pubmed #17328049 links to  free full text

Abstract: OBJECTIVE: To study the specific effects of rituximab treatment on the synovium in patients with rheumatoid arthritis (RA) early after initiation of treatment. METHODS: Seventeen RA patients underwent an arthroscopic synovial biopsy procedure directly before and 1 month after receiving 2 infusions of the chimeric anti-CD20 monoclonal antibody rituximab (1,000 mg on days 1 and 15; both without methylprednisolone premedication). Immunohistochemical analysis was performed to characterize the cell infiltrate. Stained tissue sections were analyzed by digital image analysis. Statistical analysis was performed using Wilcoxon's signed rank test. RESULTS: No significant change in the Disease Activity Score 28-joint assessment was found at 4 weeks after the first rituximab infusion. At 2 and 4 weeks after infusion, B cells in peripheral blood were almost completely depleted. Most B cells in the synovium were found in large lymphocyte aggregates. Interestingly, a significant reduction in B cell numbers at sites of inflammation was observed 4 weeks after treatment (median 26 cells/mm(2) [interquartile range 4-150] before treatment and 11 cells/mm(2) [interquartile range 0-29] after treatment; P < 0.02). B cells disappeared completely in 3 patients, whereas there was partial depletion in 11 patients. In the other 3 patients, no B cells were present in biopsy tissues obtained either pretreatment or posttreatment. No reductions in other synovial cell populations were observed at 4 weeks. CONCLUSION: Rituximab treatment leads to a rapid and significant decrease in synovial B cell numbers, but not in all patients. Whether the variable tissue response is related to the clinical response over time remains to be clarified.

Munneke M, de Jong Z, Zwinderman AH, Ronday HK, van Schaardenburg D, Dijkmans BA, Kroon HM, Vliet Vlieland TP, Hazes JM. · Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #15934121 links to  free full text

Abstract: OBJECTIVE: To investigate whether a high-intensity exercise program accelerates the rate of radiologic damage of the large joints in predefined subgroups of patients with rheumatoid arthritis. METHODS: The data of 277 participants in a 2-year randomized controlled trial, comparing the effects of high-intensity exercises with usual care, were used. Linear regression analysis was used to test which predefined variables at baseline (age, disease duration, disease activity, physical capacity, functional ability, joint damage) modified the effect of high-intensity exercise on the progression of radiologic damage of the large joints over 24 months. RESULTS: Baseline radiologic joint damage was the only variable associated with the effect of high-intensity exercise on joint damage progression in large joints. In a subgroup of 218 patients with no or little joint damage (defined as Larsen score < or = 5; 80% of our study population) the proportions of patients with an increase in joint damage were similar for the exercise and usual-care group (35% versus 36%, risk ratio [RR] 1.0 [0.7-1.4]; P = not significant), whereas, in a subgroup of 59 patients who already had extensive damage of large joints (defined as Larsen score >5) the proportion was significantly higher in the exercise group (85% versus 48%, RR 1.8 [1.2-2.6]; P < 0.05). CONCLUSION: High-intensity weight-bearing exercises appear to accelerate joint damage progression in patients with preexisting extensive damage. Patients with extensive large joint damage should, therefore, be advised to refrain from activities excessively loading the damaged joints.

de Jong Z, Munneke M, Zwinderman AH, Kroon HM, Jansen A, Ronday KH, van Schaardenburg D, Dijkmans BA, Van den Ende CH, Breedveld FC, Vliet Vlieland TP, Hazes JM. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #13130460 links to  free full text

Abstract: OBJECTIVE: There are insufficient data on the effects of long-term intensive exercise in patients with rheumatoid arthritis (RA). We undertook this randomized, controlled, multicenter trial to compare the effectiveness and safety of a 2-year intensive exercise program (Rheumatoid Arthritis Patients In Training [RAPIT]) with those of physical therapy (termed usual care [UC]). METHODS: Three hundred nine RA patients were assigned to either the RAPIT program or UC. The primary end points were functional ability (assessed by the McMaster Toronto Arthritis [MACTAR] Patient Preference Disability Questionnaire and the Health Assessment Questionnaire [HAQ]) and the effects on radiographic progression in large joints. Secondary end points concerned emotional status and disease activity. RESULTS: After 2 years, participants in the RAPIT program showed greater improvement in functional ability than participants in UC. The mean difference in change of the MACTAR Questionnaire score was 2.6 (95% confidence interval [95% CI] 0.1, 5.2) over the first year and 3.1 (95% CI 0.7, 5.5) over the second year. After 2 years, the mean difference in change of the HAQ score was -0.09 (95% CI -0.18, -0.01). The median radiographic damage of the large joints did not increase in either group. In both groups, participants with considerable baseline damage showed slightly more progression in damage, and this was more obvious in the RAPIT group. The RAPIT program proved to be effective in improving emotional status. No detrimental effects on disease activity were found. CONCLUSION: A long-term high-intensity exercise program is more effective than UC in improving functional ability of RA patients. Intensive exercise does not increase radiographic damage of the large joints, except possibly in patients with considerable baseline damage of the large joints.

Ursum J, Bos WH, van de Stadt RJ, Dijkmans BA, van Schaardenburg D. · Jan van Breemen Institute, 1056 AB Amsterdam, The Netherlands. · Arthritis Res Ther. · Pubmed #19460147 links to  free full text

Abstract: INTRODUCTION: The aim of this study was to examine seroconversion and the relationship with age and inflammation of autoantibodies in a large group of patients attending an outpatient rheumatology clinic. METHODS: Levels of antibodies to citrullinated proteins/peptides (ACPAs) and IgM rheumatoid factor (IgM-RF) were determined in 22,427 samples collected from 18,658 patients. The diagnosis was derived from a diagnosis registration system. The degree of seroconversion in repeated samples and the correlation of levels with age and inflammatory markers were determined for ACPA and IgM-RF in rheumatoid arthritis (RA) and non-RA patients. RESULTS: Seventy-one percent of RA patients (n = 1,524) were ACPA-positive and 53% were IgM-RF-positive; in non-RA patients (n = 2,245), the corresponding values were 2% and 4%, respectively. In patients with at least two samples (n = 3,769), ACPA status was more stable than IgM-RF status in RA patients. ACPA- or IgM-RF-negative non-RA patients seldom became positive. ACPA positivity was unrelated to age in both RA and non-RA patients. IgM-RF positivity was unrelated to age in RA patients; however, it increased with age in non-RA patients. The correlation between autoantibody levels and inflammatory markers was low in general and was somewhat higher for IgM-RF than for ACPA. CONCLUSIONS: ACPA status is more stable in time and with increasing age than IgM-RF status, further establishing its role as a disease-specific marker. ACPA and IgM-RF levels are only moderately correlated with markers of inflammation.

de Jong Z, Munneke M, Kroon HM, van Schaardenburg D, Dijkmans BA, Hazes JM, Vliet Vlieland TP. · Department of Rheumatology, C1-R, Leiden University Medical Center, Post-box 9600, 2300 RC, Leiden, The Netherlands. · Clin Rheumatol. · Pubmed #19247575 No free full text.

Abstract: The aims of this study were to describe rheumatoid arthritis patients' compliance with continued exercise after participation in a 2-year supervised high-intensity exercise program and to investigate if the initially achieved effectiveness and safety were sustained. Data were gathered by follow-up of the participants who completed the 2-year high-intensity intervention in a randomized controlled trial (Rheumatoid Arthritis Patient In Training study). Eighteen months thereafter, measurements of compliance, aerobic capacity, muscle strength, functional ability, disease activity, and radiological damage of the large joints were performed. Seventy-one patients were available for follow-up at 18 months, of whom 60 (84%) were still exercising (exercise group: EG), with average similar intensity but at a lower frequency as the initial intervention. Eleven patients (16%) reported low intensity or no exercises (no-exercise group: no-EG). Patients in the EG had better aerobic fitness and functional ability, lower disease activity, and higher attendance rate after the initial 2-year intervention. At follow-up, both groups showed a deterioration of aerobic fitness and only patients in the EG were able to behold their muscle strength gains. Functional ability, gained during the previous participation in high-intensity exercises, remained stable in both groups. Importantly, no detrimental effects on disease activity or radiological damage of the large joints were found in either group. In conclusion, the majority of the patients who participated in the 24-month high-intensity exercise program continued exercising in the ensuing 18 months. In contrast to those who did not continue exercising, they were able to preserve their gains in muscle strength without increased disease activity or progression of radiological damage.

van der Kooij SM, le Cessie S, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, van Zeben D, Kerstens PJ, Hazes JM, van Schaardenburg D, Breedveld FC, Dijkmans BA, Allaart CF. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #18930988 No free full text.

Abstract: OBJECTIVES: To compare the clinical and radiological efficacy of initial vs delayed treatment with methotrexate (MTX) and infliximab (IFX) in patients with recent onset rheumatoid arthritis (RA). METHODS: In a post hoc analysis of the BeSt study (for Behandel Stratagieen, Dutch for treatment strategies), 117 patients who started initial MTX+IFX were compared with 67 patients who started MTX+IFX treatment after failing (disease activity score (DAS)>2.4; median delay to IFX: 13 months) on > or =3 traditional DMARDs. If the DAS remained >2.4, the protocol dictated IFX dose increases to 6, 7.5 and 10 mg/kg. In case of a DAS < or =2.4 for > or =6 months, IFX was tapered and finally stopped. We aimed to correct for allocation bias using propensity scores. Functional ability was measured by the Health Assessment Questionnaire (HAQ), radiological progression by Sharp/van der Heijde scoring (SHS). RESULTS: Baseline differences between the initial and delayed groups were no longer significant after propensity score adjustment. At 3 years after baseline, patients treated with initial MTX+IFX experienced more improvement in HAQ over time and were less likely to have SHS progression than patients treated with delayed MTX+IFX (p = 0.034). At 2 years after IFX initiation, more patients in the initial group compared with the delayed group could discontinue IFX after a good response (56% vs 29%, p = 0.008). CONCLUSIONS: The results of this post hoc analysis suggest that using MTX+IFX as initial treatment for patients with recent onset RA is more effective than reserving MTX+IFX for patients who failed on traditional DMARDs, with more HAQ improvement over time, more IFX discontinuation and less progression of joint damage.

Bos WH, Bartelds GM, Wolbink GJ, de Koning MH, van de Stadt RJ, van Schaardenburg D, Dijkmans BA, Nurmohamed MT. · Jan van Breemen Instituut, Sanquin Research, and VU University Medical Center, Department of Rheumatology, Amsterdam, The Netherlands. · J Rheumatol. · Pubmed #18785316 No free full text.

Abstract: OBJECTIVE: To investigate the effect of anti-tumor necrosis factor (TNF) treatment on rheumatoid factor (IgM-RF) and anticitrullinated protein antibodies (ACPA) and its association with treatment response and acute-phase reactants. METHODS: In a cohort of 188 consecutive patients with rheumatoid arthritis (RA) treated with adalimumab, baseline IgM-RF and ACPA were determined by ELISA, and compared to levels after 28 weeks of treatment. ACPA were measured as antibodies to cyclic citrullinated peptide (anti-CCP). The relative change of antibody levels was correlated to the European League Against Rheumatism response criteria and to the change in acute-phase reactants [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)]. RESULTS: The median decline in IgM-RF levels was greater than the decline in ACPA levels (31% vs 8%; p<0.001). The decrease in antibody levels was greater in the group of good responders than in the group of nonresponders [43% vs 7% for IgM-RF (p<0.0001) and 16 vs -4% for ACPA (p=0.03)]. Seventeen percent of IgM-RF-positive patients at baseline turned negative at 28 weeks; this qualitative effect was not observed for ACPA. Further, the decline in IgM-RF, but not ACPA, was associated with a decrease in CRP and ESR (p=0.004 and p=0.006, respectively). CONCLUSION: TNF treatment directly influences IgM-RF and ACPA levels, but in those responding to treatment only. The effect on IgM-RF levels and positivity status is greater than on ACPA levels and is associated with the decline in markers of inflammation. These results further emphasize the differential role these autoantibodies may play in RA; IgM-RF as marker of inflammatory activity, and ACPA as qualitatively stable hallmark of RA.

Bos WH, Bartelds GM, Vis M, van der Horst AR, Wolbink GJ, van de Stadt RJ, van Schaardenburg D, Dijkmans BA, Lems WF, Nurmohamed MT, Aarden L, Hamann D. · Sanquin Research, Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #18445623 No free full text.

Abstract: OBJECTIVE: To investigate the dynamics of IgG1 and IgG4 anti-citrullinated protein antibody (ACPA) subclasses during anti-tumour necrosis factor (TNF) treatment in patients with rheumatoid arthritis (RA). METHODS: IgG, IgG1 and IgG4 ACPA levels were determined by ELISA on anti-citrullinated fibrinogen (ACF) and IgG1 : IgG4 ACPA ratios were calculated. A pilot study was performed in 28 ACF-positive patients treated with infliximab for one year. Confirmation of the results was obtained using a cohort of 180 consecutive patients treated with adalimumab for 28 weeks. RESULTS: The median reduction in ACF levels was 31% for total IgG, 29% for IgG1, 40% for IgG4 and 22% for the IgG4 : IgG1 ACF ratio in the infliximab cohort. In adalimumab-treated patients, ACF levels declined 14% for total IgG and IgG1, and 36% for IgG4 ACF; the IgG4 : IgG1 ratio was reduced by 24% (all percentage values p<0.05). The decrease in antibody levels was correlated with the clinical response; European League Against Rheumatism good responders had the greatest decline in antibody levels and this effect was most pronounced for IgG4 (48% reduction). The IgG4 : IgG1 ACF ratio preferentially decreased in patients with adequate therapeutic adalimumab levels. CONCLUSION: ACPA subclass distribution is modulated by effective anti-inflammatory treatment. The preferential decline of IgG4 ACPA, reflected by the decreased IgG4 : IgG1 ratio, suggests a beneficial effect of anti-TNF treatment on chronic antigenic stimulation by citrullinated proteins. This effect may be directly anti-TNF mediated or the result of effective dampening of the inflammation in the rheumatoid joint.

Bos WH, Ursum J, de Vries N, Bartelds GM, Wolbink GJ, Nurmohamed MT, van der Horst-Bruinsma IE, van de Stadt RJ, Crusius JB, Tak PP, Dijkmans BA, van Schaardenburg D. · Jan van Breemen Institute, Department of Rheumatology, Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #18388157 No free full text.

Abstract: OBJECTIVES: Patients presenting with both arthralgia and antibodies to cyclic citrullinated peptide (anti-CCP) have an increased risk of developing rheumatoid arthritis (RA). To further characterise this patient group and shed more light on its relationship with clinically manifest early arthritis and established RA, an immunogenetic and serological analysis was performed. METHODS: In a group of 111 patients with anti-CCP-positive arthralgia, anti-CCP levels and shared epitope (SE) status were determined. Data were compared with 125 and 128 patients with anti-CCP-positive early arthritis and established RA respectively. RESULTS: In patients with anti-CCP-positive arthralgia, the frequency of SE allele positivity is significantly lower when compared with anti-CCP-positive early arthritis and established RA (58% vs 80%, and 58% vs 92%, respectively, both p<0.001). Median anti-CCP levels were higher in the group of patients with SE-positive arthralgia compared with the group of patients with SE-negative arthralgia (p = 0.02). Median anti-CCP levels were similar in the groups of patients with SE-positive arthralgia and arthritis. CONCLUSIONS: The lower frequency of SE positivity in patients with arthralgia compared with patients with RA indicates that, compared with patients who were SE positive, patients who were SE negative as a group go through a longer arthralgia phase, or alternatively have a lower risk for transition from anti-CCP positive arthralgia to RA. Furthermore, the present results suggest that in this early stage the effect of the SE on disease risk may be mediated through higher anti-CCP levels.

Ursum J, Nielen MM, van Schaardenburg D, van der Horst AR, van de Stadt RJ, Dijkmans BA, Hamann D. · Jan van Breemen Institute, Dr Jan van Breemenstraat, 1056 AB Amsterdam, The Netherlands. · Arthritis Res Ther. · Pubmed #18226202 links to  free full text

Abstract: INTRODUCTION: The aim of our study was to investigate the association between arthritic disease activity and antibodies to mutated citrullinated vimentin (anti-MCV), because such a relation has been suggested. METHODS: Anti-MCV levels were measured in 162 patients with early arthritis (123 with rheumatoid arthritis and 39 with undifferentiated arthritis) at baseline and at 1 and 2 years of follow up. Disease activity was measured using the disease activity score (Disease Activity Score based on 28 joints [DAS28]) and serum C-reactive protein. General estimation equation analysis was used to assess the relation between anti-MCV levels and DAS28 over time. RESULTS: Both, anti-MCV levels and DAS28 exhibited a significant decrease during the first and second year. However, the association between anti-MCV levels and DAS28, adjusted for dependency on sequential measurements within one individual, was very low (beta = 0.00075). In a population of patients with rheumatoid arthritis or undifferentiated arthritis, anti-MCV had a specificity of 92.3% and a sensitivity of 59.3% when using the recommended cut-off of 20 U/ml. Specificity and sensitivity of antibodies against second-generation cyclic citrullinated peptide, using the recommended cut-off value of 25 U/ml, were 92.1% and 55.3%, respectively. Anti-MCV-positive early arthritis patients had significantly higher Sharp-van der Heijde score, erythrocyte sedimentation rate and C-reactive protein levels than did anti-MCV-negative patients at all time points (P < 0.005), but DAS28 was higher in anti-MCV-positive patients at 2 years of follow up only (P < 0.05). CONCLUSION: Because the correlation between anti-MCV levels and parameters of disease activity was very low, we conclude that it is not useful to monitor disease activity with anti-MCV levels.

Feitsma AL, Worthington J, van der Helm-van Mil AH, Plant D, Thomson W, Ursum J, van Schaardenburg D, van der Horst-Bruinsma IE, van Rood JJ, Huizinga TW, Toes RE, de Vries RR. · Departments of Immunohematology and Blood Transfusion and Rheumatology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands. · Proc Natl Acad Sci U S A. · Pubmed #18077428 links to  free full text

Abstract: Rheumatoid arthritis (RA) is a complex genetic disorder in which the HLA-region contributes most to the genetic risk. HLA-DRB1-molecules containing the amino acid sequence DERAA (i.e., HLA-DRB1*0103, *0402, *1102, *1103, *1301, *1302, and *1304) are associated with protection from RA. It has been proposed that not only inherited but also noninherited HLA-antigens from the mother (NIMA) can influence RA-susceptibility. Up to now, no protective NIMAs were described. Here, we studied whether DERAA-containing HLA-DRB1-alleles as NIMA are associated with a protective effect. One hundred seventy-nine families were studied, 88 from the Netherlands and 91 from the United Kingdom. The frequency of DERAA-containing HLA-DRB1-alleles of the Dutch mothers (16.1%), but not of the fathers (26.2%), was lower compared with the general Dutch population (29.3%; P = 0.02). This was replicated in the English set of patients and controls (P = 0.01). Further, of all families, 45 contained at least one DERAA-negative child with RA and at least one DERAA-positive parent. The odds for the DERAA-negative RA patients of having a DERAA-positive mother was significantly lower compared with having a DERAA-positive father (OR 0.25; P = 0.003). These data show a protective NIMA-effect in a human autoimmune disease and indicate that a DERAA-positive mother can transfer protection against RA to her DERAA-negative child.

van Schaardenburg D, Wolbink G, Nurmohamed MT, Dijkmans BA. · Department of Rheumatology, Jan van Breemen Institute, VU University Medical Center, Amsterdam, The Netherlands. · Nat Clin Pract Rheumatol. · Pubmed #17437031 No free full text.

This publication has no abstract.

van Halm VP, Nielen MM, Nurmohamed MT, van Schaardenburg D, Reesink HW, Voskuyl AE, Twisk JW, van de Stadt RJ, de Koning MH, Habibuw MR, van der Horst-Bruinsma IE, Dijkmans BA. · Departments of Internal Medicine and Rheumatology, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #16760255 No free full text.

Abstract: BACKGROUND: Rheumatoid arthritis is characterised by inflammation and an increased cardiovascular risk. It was recently shown that active early rheumatoid arthritis is associated with dyslipidaemia, which may partially explain the enhanced cardiovascular risk. However, it is unknown when this dyslipidaemia starts. OBJECTIVE: To investigate the progression of the lipid profile over time and the influence of inflammatory parameters on this lipid profile, in people who later developed rheumatoid arthritis. METHODS: Levels of total cholesterol, high-density lipoprotein cholesterol (HDLc), triglycerides, apolipoprotein AI (apo AI), apolipoprotein B (apo B) and lipoprotein(a) (Lp(a)) were determined in 1078 stored, deep-frozen, serial blood bank samples, collected between 1984 and 1999, of 79 blood donors who later developed rheumatoid arthritis. These samples were compared with 1071 control samples of unselected blood donors, matched for age, sex and storage time. RESULTS: Samples of patients who later developed rheumatoid arthritis showed, on average, 4% higher total cholesterol, 9% lower HDLc, 17% higher triglyceride and 6% higher apo B levels than matched controls (p< or =0.05). The magnitude of the differences in lipid levels between groups, explained by C reactive protein (CRP), was limited. For example, only 3.6% of the difference in HDLc levels between the groups was explained by the CRP concentrations. CONCLUSION: Patients who later develop rheumatoid arthritis have a considerably more atherogenic lipid profile than matched blood donors at least 10 years before onset of symptoms. As inflammation only marginally explains the differences between the two groups, a modulating effect of lipids on inflammatory processes is hypothesised.

Nielen MM, van Schaardenburg D, Reesink HW, Twisk JW, van de Stadt RJ, van der Horst-Bruinsma IE, de Koning MH, Habibuw MR, Dijkmans BA. · Jan van Breemen Institute, Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #16079166 links to  free full text

Abstract: OBJECTIVE: To investigate the temporal relationship between onset of inflammation (as measured by secretory phospholipase A2 (sPLA2) and C reactive protein (CRP)) and the presence of autoantibodies (IgM rheumatoid factor (IgM RF) and antibodies against citrullinated peptides (anti-CCP)) in the preclinical phase of rheumatoid arthritis (RA). METHODS: For 79 patients with RA who had been blood donors before the onset of disease, a median of 13 serum samples per patient was available. sPLA2 was measured in patient and matched control samples and related to previous CRP, IgM RF, and anti-CCP measurements. The temporal relationship between the increased markers of inflammation and autoantibodies was analysed with time lag analysis. RESULTS: IgM RF and anti-CCP concentrations were significantly associated (p<0.001) with concentrations of sPLA2, CRP, and the combination of sPLA2 and CRP at the same time point. However, we found no stronger association between the two autoantibody tests and the three inflammation measures 1, 2, and 3 years before or after a time point than for measurements at the same time, in the whole group or in subgroups of IgM RF and anti-CCP positive patients. CONCLUSION: Both the acute phase response and autoantibody formation often develop years before the first symptoms of RA occur, and these phenomena are probably closely connected in time.

Nielen MM, van der Horst AR, van Schaardenburg D, van der Horst-Bruinsma IE, van de Stadt RJ, Aarden L, Dijkmans BA, Hamann D. · Jan van Breemen Institute, Amsterdam, Netherlands. · Ann Rheum Dis. · Pubmed #15640269 links to  free full text

Abstract: BACKGROUND: The anti-cyclic citrullinated peptide (CCP) test has a high sensitivity and specificity for rheumatoid arthritis, although CCP is not the physiological target of the autoantibodies. Citrullinated fibrin is abundant in inflamed synovium OBJECTIVE: To assess the diagnostic and prognostic value of antibodies against citrullinated fibrinogen (ACF), a soluble precursor of fibrin, in comparison with IgM-rheumatoid factor (IgM-RF) and the second generation anti-CCP test. METHODS: In 379 patients with early arthritis (258 rheumatoid and 121 undifferentiated), the sensitivity, specificity, and positive predictive value of ACF, anti-CCP, and IgM-RF for diagnosing rheumatoid arthritis were calculated. Multivariate logistic regression analysis was used to assess the diagnostic and prognostic value (radiographic progression after two years) of the tests. RESULTS: The sensitivities of the ACF, anti-CCP, and IgM-RF tests were 55.8%, 57.8%, and 44.6%, with specificities of 92.6%, 94.2%, and 96.7%, respectively. Approximately 30% of the IgM-RF negative patients were positive for ACF or anti-CCP or both. The ACF and anti-CCP test had a high agreement in early arthritis (kappa = 0.84). Of all baseline characteristics, the ACF test and the anti-CCP test were the best predictors for diagnosing rheumatoid arthritis at one year (odds ratio (OR) = 10.3 and 10.6, respectively) and for radiographic progression after two years (OR = 12.1 and 14.8). CONCLUSIONS: ACF is as sensitive as anti-CCP and more sensitive than IgM-RF in diagnosing rheumatoid arthritis in early arthritis. The ACF test is also a good predictor of radiographic progression, with a performance similar to the anti-CCP test. The ACF test and the anti-CCP test are especially valuable in IgM-RF negative arthritis.

Nielen MM, van Schaardenburg D, Reesink HW, Twisk JW, van de Stadt RJ, van der Horst-Bruinsma IE, de Gast T, Habibuw MR, Vandenbroucke JP, Dijkmans BA. · Jan van Breemen Institute, Amsterdam, The Netherlands. · Arthritis Rheum. · Pubmed #15334453 links to  free full text

Abstract: OBJECTIVE: We previously reported that approximately half of the patients with rheumatoid arthritis (RA) have specific serologic abnormalities (elevated serum concentrations of IgM rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies) starting several years before the onset of symptoms. In this study, the presence of serologic signs of inflammation in patients with preclinical RA was investigated with serial measurements of C-reactive protein (CRP). METHODS: Seventy-nine patients (61% female; mean age at onset of symptoms 51 years) who had been blood donors before the onset of RA were identified. Frozen serum samples from each donor were retrieved, together with 1 sample from a control donor matched for age, sex, and date of donation. CRP was measured using a highly sensitive latex-enhanced assay. The dates of donation were categorized into 15 1-year periods preceding the onset of RA symptoms. For each period, the median CRP levels in the patient and control groups were compared using the Mann-Whitney U test. The course of CRP concentrations over time in the patient group was estimated with random coefficient analysis. RESULTS: A median of 13 samples (range 1-51) per patient were available; the earliest donation was made a median of 7.5 years (range 0.4-14.5 years) before the onset of symptoms. A total of 1,078 patient samples and 1,071 control samples were tested. For all 1-year periods, the median CRP concentration was increased in the patient group compared with the control group, but this difference was statistically significant only for the periods 0-1 year, 1-2 years, and 4-5 years before the onset of symptoms. The CRP concentration increased significantly over time in patients with preclinical RA; levels were slightly higher in the group of patients who had serologic abnormalities before the onset of symptoms than in those without such serologic abnormalities. CONCLUSION: After observing specific serologic abnormalities 5 years before the onset of RA symptoms, we now report increased levels of CRP in blood donors in whom RA later developed; these increases were most common within the 2 years before the onset of symptoms. The preclinical increase in CRP levels was observed both in donors with and in those without serologic abnormalities.

Jansen LM, van der Horst-Bruinsma IE, van Schaardenburg D, Lard LR, Hazes JM, Huizinga TW, Dijkmans BA. · Jan van Breemen Instituut, Amsterdam, The Netherlands. · Clin Exp Rheumatol. · Pubmed #15301242 No free full text.

Abstract: OBJECTIVE: Many early arthritis clinics (EACs) have been started in the last decade in order to detect and treat rheumatoid arthritis early. The present study evaluates whether the disease activity at admission of patients with early oligo- and polyarthritis changed during the period 1993--1998 in two EACs in the Netherlands. METHODS: Patients were selected who were diagnosed after one year as having rheumatoid arthritis (RA) or oligo- or polyarthritis (UPA), had a symptom duration of less than 2 years, and were referred from two Dutch EACs between 1993 and 1998. The data from the two clinics were combined and stratified by referral year. Differences in baseline disease characteristics as well as changes in radiological and functional scores after two years of follow-up between referral years were analysed by ANOVA using Bonferroni corrected p levels. RESULTS: A total of 405 patients (66% females; median age 57 yrs (18-93): 80% diagnosed as RA, the remainder as UPA) were included in the study. The year-groups did not differ significantly in demographic characteristics or in the duration of complaints (median 6 months). The number of patients with a diagnosis of RA declined over the years, as did the mean baseline erythrocyte sedimentation rate (ESR), in RA and UPA patients. The functional status (Health Assessment Questionnaire: HAQ) was enhanced in 1998 compared with the previous years (p < 0.001). Radiographic progression (Sharp/van der Heijde score) after the 2-year follow-up decreased (p < 0.001) in the later referral years compared to the referral group of 1994. Disease modifying anti-rheumnatic drugs (DMARDs) were started in an earlier stage and the prescription rate of sulfasalazine and methotrexate increased over the years, whereas the number of patients not treated with DMARDs declined. CONCLUSION: The pattern of patient referral changed over 6 years towards fewer patients who fulfilled the RA diagnosis and a lower ESR (among UPA as well as RA patients), whereas the number of swollen joints and the duration of complaints remained the same. The radiological progression declined over time, probably due to less inflammation at the first visit and the increased use of DMARDs.

Jansen LM, van der Horst-Bruinsma I, Lems WF, van Schaardenburg D, van de Stadt R, de Koning M, Dijkmans BA. · Jan van Breemen Instituut and the Department of Rheumatology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands. · J Rheumatol. · Pubmed #15290726 No free full text.

Abstract: OBJECTIVE: To investigate the relationship between osteocalcin (OC), a marker of bone formation, and the recently developed serum marker of bone resorption, beta-C-telopeptide (beta-CTx), and radiographic damage in patients with early oligo- and polyarthritis. METHODS: Patients with peripheral arthritis of > or = 2 joints and < 2 years of symptom duration were studied. The OC and beta-CTx concentrations at baseline were correlated with disease activity and radiographic damage at baseline, and with radiographic progressive disease after 2 years (delta Sharp/van der Heijde score > or = 5). The additional value of serum bone metabolism markers to predict radiographic progressive disease was compared to that of established prognostic factors by multivariate logistic regression analysis. RESULTS: Two hundred seventy-nine patients (67% female; median age 56 yrs, range 18-83) were included in the study, of whom 73% were diagnosed with rheumatoid arthritis (RA). Baseline levels of beta-CTx (p < 0.05) were significantly correlated with baseline radiographic damage whereas OC was not. beta-CTx was also significantly (p < 0.001) related to measures of disease activity like erythrocyte sedimentation rate, C-reactive protein, and the disease activity score DAS28. Radiographic progressive disease after 2 years corresponded univariately with increased levels of beta-CTx (p < 0.001), but not with OC. In multivariate analysis, beta-CTx was not superior to other measures of radiographic progressive disease such as autoantibodies and disease activity. CONCLUSION: Increased serum levels of the bone turnover marker beta-CTx are associated with radiographic damage at baseline and radiographic progression after 2 years. However, beta-CTX is less predictive than markers already in use.

Nielen MM, van Schaardenburg D, Reesink HW, van de Stadt RJ, van der Horst-Bruinsma IE, de Koning MH, Habibuw MR, Vandenbroucke JP, Dijkmans BA. · Jan van Breemen Institute, Amsterdam, The Netherlands. · Arthritis Rheum. · Pubmed #14872479 links to  free full text

Abstract: OBJECTIVE: Autoantibodies have been demonstrated in single serum samples from healthy subjects up to 10 years before they developed rheumatoid arthritis (RA). However, the time course for the development of antibodies before onset of clinical RA is unknown, nor is it known which antibody, or combinations of antibodies, might be most sensitive or specific for predicting future development of the disease. The present study was undertaken to investigate this. METHODS: Patients with RA who had been blood donors before the onset of disease symptoms were enrolled. Frozen serum samples from each donor were retrieved, together with 2 serum samples from controls matched for age, sex, and date of donation. All samples were tested for IgM rheumatoid factor (IgM-RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies. RESULTS: Seventy-nine patients with RA (62% female; mean age at onset of symptoms 51 years) were included. A median of 13 samples (range 1-51) per patient were available; the earliest samples had been collected a median of 7.5 years (range 0.1-14.5) before the onset of symptoms. Thirty-nine patients (49%) were positive for IgM-RF and/or anti-CCP on at least one occasion before the development of RA symptoms, a median of 4.5 years (range 0.1-13.8) before symptom onset. Of the 2,138 control samples, 1.1% were positive for IgM-RF, and 0.6% were positive for anti-CCP. CONCLUSION: Approximately half of patients with RA have specific serologic abnormalities several years before the onset of symptoms. A finding of an elevated serum level of IgM-RF or anti-CCP in a healthy individual implies a high risk for the development of RA. We conclude that IgM-RF and anti-CCP testing with appropriately high specificity may assist in the early detection of RA in high-risk populations.