Rheumatoid Arthritis: Geusens P

Geusens P. · Internal Medicine and Rheumatology, University Hospital, Maastricht, The Netherlands. · Minerva Med. · Pubmed #18431325 No free full text.

Abstract: Clinical features associated with osteoporotic fractures include increased morbidity (pain, physical impairment, decreased quality of life), increased risk for new fractures (even within short-term) and increased mortality. Readily recognizable clinical features that indicate a high risk for fracture include age, gender, low body weight, history of fracture, familial history of fracture, severe immobilization, smoking, rheumatoid arthritis, use of glucocorticoids and clinical risks for falls. In addition, many patients with fractures and osteoporosis have pre-existing contributors to secondary osteoporosis, many of which are correctable.

Keeling SO, Landewe R, van der Heijde D, Bathon J, Boers M, Garnero P, Geusens P, El-Gabalawy H, Inman RD, Kraus VB, Kvien TK, Mease PJ, Ostergaard M, Ritchlin C, Syversen SW, Maksymowych WP. · Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. · J Rheumatol. · Pubmed #17343310 No free full text.

Abstract: OBJECTIVE: A list of 14 criteria for guiding the validation of a soluble biomarker as reflecting structural damage endpoints in rheumatoid arthritis (RA) clinical trials was drafted by an international working group after a Delphi consensus exercise. C-reactive protein (CRP), a soluble biomarker extensively studied in RA, was then used to test these criteria. Our objectives were: (1) To assess the strength of evidence in support of CRP as a soluble biomarker reflecting structural damage in RA according to the draft validation criteria. (2) To assess the strength of recommendation for inclusion of individual criteria in the draft set. METHODS: A systematic literature review was conducted to elicit evidence in support of each specific criterion composing the 14-criteria draft set. A summary of the key literature findings per criterion was presented to both the working group and to participants in a special interest soluble biomarker group at OMERACT 8. Participants at OMERACT 8 were asked to rate the strength of evidence and the strength of the recommendation in support of each individual criterion on a 0-10 numerical rating scale. Working group members not present at OMERACT voted by a Web-based survey. RESULTS: Minimal data were extracted from the literature pertaining to those criteria listed under the category of truth. Ratings for strength of evidence were moderate to low (< 7) for CRP as a biomarker reflecting structural damage in RA; this was true for all criteria except those listed under the category of feasibility and 2 listed under the category of discrimination pertaining to assay reproducibility and evidence regarding sources of variability. Ratings for strength of recommendation for inclusion of each of the 14 criteria in the draft set were high (> 7) except for those criteria listed under the category of truth. CONCLUSION: The draft criteria serve as a useful template in the evaluation of the strength of evidence in support of a particular soluble biomarker as reflecting structural damage in RA.

Garnero P, Geusens P, Landewé R. · University Hospital Maastricht, Maastricht, The Netherlands. · Clin Exp Rheumatol. · Pubmed #14969051 No free full text.

Abstract: The progression of rheumatoid arthritis (RA), a disease characterized by synovitis, cartilage degradation and bone erosion, is highly variable from patient to patient. New specific biological markers reflecting quantitative and dynamic changes in joint tissue turnover have been recently developed and include assays for type II collagen synthesis and degradation and synovitis. Increasing evidence from prospective studies in early RA indicate that some of these markers may be useful to predict the progression and identify patients at risk for rapid joint damage, before any damage is detected by radiography. Although studies on their value in assessing the efficacy of treatments are still limited, preliminary data in early RA suggest that biological markers will play an important role in the development and the early monitoring of disease modifying antirheumatic drugs with respect to future radiographic progression.

VanderBorght A, Geusens P, Raus J, Stinissen P. · Biomedisch Onderzoeksinstituut DWI, Limburgs Universitair Centrum, Diepenbeek, Belgium. · Semin Arthritis Rheum. · Pubmed #11740797 No free full text.

Abstract: OBJECTIVES: To review the role of T lymphocytes in the pathogenesis of rheumatoid arthritis (RA) and discuss the relevance of the components of the trimolecular complex (synovial T cells, autoantigens, and antigen presenting cells) in the pathogenic autoimmune response in RA. METHODS: Currently available experimental data are combined into a hypothetical pathway that may explain some of the events in the RA process. The literature regarding the potential therapeutic strategies that interfere with specific components of the trimolecular complex and other mediators are discussed briefly. RESULTS: T cells are activated in the peripheral blood, cross the endothelial cell wall, and migrate into the joints. Once in the synovial joints, T cells are reactivated by cross-reactive antigens and clonally expand. Clonally expanded T cells accumulate in the diseased joint and secrete proinflammatory cytokines that attract and activate other cells, such as monocytes and macrophages. Treatment with anti-CD4 monoclonal antibodies or anticytokine agents that prevents antigen presentation and/or T-cell activation were effective in RA. Other therapies, such as T-cell vaccination and T-cell receptor peptide vaccination targeting autoreactive T cells, showed clinical improvement, suggesting a pathogenic role of these lymphocytes in disease progression. CONCLUSION: T cells appear to be actively involved in the pathogenesis of RA, but several parts of the pathway are hypothetical and further research is needed.

Bombardieri S, Ruiz AA, Fardellone P, Geusens P, McKenna F, Unnebrink K, Oezer U, Kary S, Kupper H, Burmester GR, Anonymous00347. · Department of Internal Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy. · Rheumatology (Oxford). · Pubmed #17504821 links to  free full text

Abstract: OBJECTIVE: To evaluate the effectiveness and safety of adalimumab in patients with rheumatoid arthritis (RA) who previously discontinued tumour necrosis factor (TNF) antagonists for any reason in clinical practice. METHODS: ReAct (Research in Active Rheumatoid Arthritis) was a large, open-label trial that enrolled adults with active RA who had previously been treated with traditional disease-modifying anti-rheumatic drugs or biological response modifiers. Patients self-administered adalimumab 40 mg subcutaneously every other week for 12 weeks and were allowed to enter an optional long-term extension phase. Measures of adalimumab effectiveness included American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria, Disease Activity Score 28 (DAS28) and the Health Assessment Questionnaire Disability Index (HAQ DI). RESULTS: Of 6610 patients, 899 had a history of etanercept and/or infliximab therapy; these patients experienced substantial clinical benefit from adalimumab treatment. At week 12, 60% of patients had an ACR20 and 33% had an ACR50 response; 76% had a moderate and 23% had a good EULAR response. In addition, 12% achieved a DAS28 < 2.6, indicating clinical remission, and 13% achieved a HAQ DI score <0.5. The allergic adverse event rate, regardless of relationship to adalimumab, was 6.5/100-patient-years (PYs) in previously TNF-antagonist-exposed patients and 4.3/100-PYs in TNF-antagonist-naive patients. A multiple regression analysis indicated no statistically significantly increased risk of serious infections in patients who received prior TNF antagonists compared with TNF-antagonist-naive patients. CONCLUSION: In typical clinical practice, adalimumab was effective and well-tolerated in patients with RA previously treated with etanercept and/or infliximab.

Geusens P, Alten R, Rovensky J, Sloan VS, Krammer G, Kralidis G, Richardson P. · Biomedisch Onderzoeksinstituut, Limburgs Universitair Centrum, Diepenbeek, Belgium. · Int J Clin Pract. · Pubmed #15605667 No free full text.

Abstract: A randomised, double-blind study was performed to assess the efficacy and tolerability of lumiracoxib in patients with rheumatoid arthritis (RA). Patients received lumiracoxib 200mg once daily (o.d.) (n= 280), lumiracoxib 400mg o.d. (n= 281), naproxen 500 mg twice daily (n= 279) or placebo (n= 284) for 26 weeks. The primary efficacy variable was response to treatment according to ACR20 criteria (adjusted for prohibited concomitant or excessive rescue medication use and discontinuations due to unsatisfactory therapeutic response) at week 13. Safety and tolerability was also assessed. Significantly more patients receiving lumiracoxib than placebo were responders according to ACR20 criteria at week 13 (41.1 and 42.7% for lumiracoxib 200 and 400 mg o.d., respectively; 32.4% for placebo; both p < 0.05). The proportion responding to naproxen (39.1%) was not significantly different from placebo. Prespecified gastrointestinal adverse events were more frequent with naproxen than with either lumiracoxib dose or placebo. Lumiracoxib is therefore an effective and well-tolerated therapy for RA.

Landewé R, Geusens P, Boers M, van der Heijde D, Lems W, te Koppele J, van der Linden S, Garnero P. · Department of Internal Medicine/Rheumatology, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands. · Arthritis Rheum. · Pubmed #15146408 links to  free full text

Abstract: OBJECTIVE: To investigate in a randomized clinical trial setting with an aggressive combination-therapy arm and a mild-monotherapy arm, whether therapy-induced changes in urinary C-terminal crosslinking telopeptide of type I collagen (CTX-I) and type II collagen (CTX-II) predict 5-year radiographic progression in patients with rheumatoid arthritis (RA). METHODS: Patients had participated in the COBRA (Combinatietherapie Bij Reumatoïde Artritis) trial comparing aggressive step-down combination therapy (the COBRA regimen, including temporary high-dose prednisolone, temporary low-dose methotrexate, and sulfasalazine [SSZ]) and mild monotherapy (SSZ). Urinary CTX-I and CTX-II levels were measured at baseline and 3, 6, 9, and 12 months after initiation of treatment. Radiographs were scored according to the modified Sharp/van der Heijde method (mean of 2 independent readers who were aware of the sequence). Individual long-term radiographic progression was estimated, using baseline radiographs and all radiographs obtained during the followup period, by simple linear regression analysis (curve fitting). RESULTS: Both COBRA therapy and SSZ monotherapy produced a significant decrease in urinary CTX-I and CTX-II levels at 3 months, and this decrease was amplified at 6 months. COBRA therapy suppressed CTX-II (change from baseline levels -36% and -43% at 3 and 6 months, respectively), but not CTX-I, significantly better than did SSZ (-17% and -21% at 3 and 6 months, respectively) at 3 and 6 months. The magnitude of the decrease in urinary CTX-II levels at 3 months significantly predicted long-term (5-year) radiographic progression (beta = 0.48 [95% confidence interval (95% CI) 0.13, 0.83]). This effect was independent of the change in disease activity and inflammation indices at 3 months. Patients whose CTX-II levels were normalized (<150 ng/mmoles of urinary creatinine) at 3 months had a significantly higher chance of radiographic stability (no progression over 5 years) than did patients whose CTX-II levels were increased both at baseline and at 3 months (odds ratio 4.5 [95% CI 1.5, 13]). CONCLUSION: The individual CTX-II response measured after 3 months of therapy in patients with active RA who had increased CTX-II levels at baseline independently predicts long-term radiographic progression. Urinary CTX-II levels may be used as early markers of treatment efficacy in patients with RA.

Garnero P, Landewé R, Boers M, Verhoeven A, Van Der Linden S, Christgau S, Van Der Heijde D, Boonen A, Geusens P. · INSERM Research Unit 403, and Synarc, Lyon, France. · Arthritis Rheum. · Pubmed #12428224 links to  free full text

Abstract: OBJECTIVE: The known risk factors for radiologic progression in rheumatoid arthritis (RA) are not optimally discriminative in patients with early disease who do not have evidence of radiologic damage. We sought to determine whether urinary C-terminal crosslinking telopeptide of type I (CTX-I) and type II (CTX-II) collagen (markers of bone and cartilage destruction, respectively) are associated with long-term radiologic progression in patients with early RA. METHODS: This was a prospective study of 110 patients with early RA who were participating in the COBRA (Combinatietherapie Bij Reumatoïde Artritis) clinical trial and followup study, a randomized controlled trial comparing the efficacy of oral pulse prednisolone, methotrexate, plus sulfasalazine with sulfasalazine alone. We investigated the relationship between baseline levels of urinary CTX-I and CTX-II and the mean annual progression of joint destruction over a median of 4 years, as measured by changes in the modified Sharp score (average of 2 independent readers). RESULTS: In multivariate logistic regression analysis, baseline urinary CTX-I and CTX-II levels in the highest tertile were the strongest predictors of radiologic progression (Sharp score increase >2 units/year; odds ratio 7.9 and 11.2, respectively), independently of treatment group, erythrocyte sedimentation rate (ESR), Disease Activity Score in 28 joints, rheumatoid factor (RF), and baseline joint damage (Sharp score). The likelihood ratios for a positive test were 3.8 and 8.0 for CTX-I and CTX-II, respectively, which compared favorably with the likelihood ratios for the ESR (3.0), baseline joint damage (1.6), and RF (1.8). When patients were grouped according to the presence (Sharp score >/=4, n = 49) and absence (Sharp score <4, n = 61) of joint damage at baseline, CTX-I and CTX-II levels were predictive only in those without baseline joint damage (odds ratio 14.9 and 25.7, respectively). CONCLUSION: High baseline levels of urinary CTX-I and CTX-II independently predict an increased risk of radiologic progression over 4 years in patients with early RA, especially those without radiologic joint damage. Urinary CTX-I and CTX-II may be useful for identifying individual RA patients at high risk of progression very early in the disease, before erosions can be detected radiographically. Such patients may be in special need of treatments that inhibit bone and cartilage degradation.

VanderBorght A, De Keyser F, Geusens P, De Backer M, Malaise M, Baeten D, Van den Bosch F, Veys EM, Raus J, Stinissen P. · Biomedisch Onderzoeksinstituut DWI, Limburgs Universitair Centrum, Diepenbeek, Belgium. · J Rheumatol. · Pubmed #11908552 No free full text.

Abstract: OBJECTIVE: To study T cell receptor (TCR) repertoire changes in synovial membrane over a 16 week period in patients with early rheumatoid arthritis (RA); and to study the influence of cyclosporin A (CSA) on TCR repertoire in a subgroup of these patients. METHODS: Synovial tissue biopsies and paired blood samples were obtained from 12 patients with early RA at 2 time points. Seven patients were treated with CSA (Neoral-Sandimmun, 3 mg/kg/day) and 5 patients with placebo for 16 weeks. TCR V gene repertoires were analyzed by semiquantitative PCR-ELISA. CDR3 spectratyping and sequence analysis was used to compare TCR clonotype distributions. RESULTS: TCR-specific mRNA was detected in all synovial tissue biopsies at the first sampling, but in only 8/12 biopsies 16 weeks later (4/7 CSA group, 4/5 placebo group). Overrepresented TCR BV genes were found in biopsies of 10/12 patients at the first time point, and in 7/12 patients after 16 weeks (3/7 CSA, 4/5 placebo). CDR3 sequence analysis revealed dynamic repertoire changes with only a few persisting clonotypes in the synovial tissue of placebo controls. Persisting T cell clonotypes were more frequently found in the synovial tissue of CSA treated patients compared to the placebo group. CONCLUSION: These data suggest a dynamic process of T cell recruitment in the joints of RA patients. This process, possibly due to activation and subsequent infiltration of new T cell clones, apparently is influenced by CSA treatment. Synovial tissue T cells were no longer detected after 16 weeks' CSA treatment in 3 patients. In the other CSA treated patients, new T cell clones infiltrated, while other clones were persistently represented in the joints. These data may have important consequences for the design of T cell targeted therapies for RA.

Verhoeven AC, Boers M, te Koppele JM, van der Laan WH, Markusse HM, Geusens P, van der Linden S. · Internal Medicine/Rheumatology Department, Maastricht University Hospital, Maastricht, The Netherlands. · Rheumatology (Oxford). · Pubmed #11709606 links to  free full text

Abstract: OBJECTIVES: Exploration of bone metabolism changes at different levels of disease activity, both with and without oral corticosteroid therapy, and prediction of changes in joint damage and bone density from the observed changes in markers of bone turnover. METHODS: Data analysis from a randomized clinical trial with 155 rheumatoid arthritis (RA) patients; median age 50 yr, early and active disease (diagnosis < 2 yr); one group treated with a combination of sulphasalazine (SSZ; 2000 mg/day), methotrexate (MTX; 7.5 mg/week) and prednisolone (initially 60 mg/day, tapered in six weekly steps to 7.5 mg/day), the other group with SSZ alone. Prednisolone and MTX were tapered and stopped after weeks 28 and 40, respectively, while SSZ was continued. Urine and serum samples were collected at baseline and weeks 16, 28, 40 and 56. Measurements of urinary pyridinoline (PYD) and deoxypyridinoline (DPD) and serum alkaline phosphatase (tAP) and osteocalcin (OC) were performed, as well as standard clinimetry and bone densitometry. RESULTS: Over time and in both treatment groups, bone formation and bone resorption markers showed a pattern similar to erythrocyte sedimentation rate (ESR): a significant decrease compared with baseline and a larger decrease with combined treatment at weeks 16 and 28. PYD excretion, tAP, OC, and joint damage scores were significantly lower in the combined treatment group. Changes in bone density (of spine and hips) did not significantly differ between treatment groups. Mainly cumulative ESR explained progression of joint damage. CONCLUSIONS: Prednisolone and disease-modifying anti-rheumatic drug therapy in patients with early and active RA are both independently associated with decreased levels of urinary excretion of bone collagen resorption markers PYD and DPD. Markers of bone formation and resorption closely followed changes in ESR in both treatment groups. Reduced bone resorption together with reduced bone formation-initially at a somewhat faster pace-resulted in less bone turnover and explain the observed (non-significant and partially reversible) extra bone loss in the lumbar spine associated with prednisolone (combined treatment).

Geusens P. · Department of Internal Medicine, Subdivision of Rheumatology, Maastricht University Medical Center, Maastricht, The Netherlands and Biomedical Research Institute, University Hasselt, Belgium. · Clin Interv Aging. · Pubmed #19554095 links to  free full text

Abstract: The pathway of the receptor activator of the nuclear factor kappaB ligand (RANKL), RANK and osteoprotegerin (OPG) plays a central role in coupling bone formation and resorption during normal bone turnover and in a wide spectrum of diseases characterized by disturbed bone remodeling, increased bone resorption and bone destruction (osteoporosis, Paget's disease of bone, rheumatoid arthritis [RA], metastatic bone disease). Clinical trials indicate that denosumab, a RANKL-specific recombinant humanized monoclonal antibody, is effective in suppressing bone resorption, resulting in increase in bone mineral density (BMD) in post-menopausal women with low BMD, and has the potential to prevent progression of erosions in RA and of skeletal-related events in metastatic bone disease. The effects on fracture reduction in postmenopausal osteoporosis are awaited from the recently finished FREEDOM study. In clinical trials with denosumab, overall adverse events were similar to placebo or comparators, indicating a favorable safety profile in these diseases, which until now have been available up to 4 years, but data on long-term safety will be needed.

Geens E, Geusens P, Vanhoof J, Berghs H, Praet J, Esselens G, Lens S, Dufour JP, Vandenberghe M, Van Mullem X, Westhovens R, Verschueren P. · Department of Rheumatology, University Hospitals Leuven, Leuven, Belgium. · Rheumatology (Oxford). · Pubmed #19254920 No free full text.

Abstract: OBJECTIVES: To assess discrepancies between perception of Belgian rheumatologists on eligibility of RA patients for anti-TNF treatment and Belgian reimbursement criteria and to compare Belgian with Dutch criteria and UK guidelines. METHODS: Consecutive MTX-experienced patients with active RA were recruited from 25 private and academic rheumatology practices. Discrepancies between eligibility for anti-TNF treatment according to the rheumatologist and fulfillment of Belgian reimbursement criteria [HAQ > or =25%, tender joint count (TJC) and swollen joint count (SJC) > or =8; > or =1 erosion; failure of > or =2 DMARDs including MTX; no tuberculosis] were recorded. Reasons for failing the Belgian criteria and results of applying Dutch reimbursement criteria and UK guidelines on the dataset were analysed. RESULTS: Of 492 patients, rheumatologists considered 135 (27.4%) as eligible, whereas Belgian criteria were fulfilled for only 34 (6.9%). Positive predictive value (PPV) of rheumatologists' perception on eligibility for fulfillment of Belgian criteria was 22.9%, whereas negative predictive value (NPV) was 99.1%. The 104 patients (21.1%) considered eligible despite criteria not being fulfilled had significantly greater TJCs, SJCs, disease activity score (DAS28) and Rheumatoid Arthritis Disease Activity Index scores than the 385 patients (78.2%) in the no-discrepancy group. Number of swollen joints, HAQ and erosions mainly accounted for discrepancies. Of 492 patients, 263 (53.4%) qualified for Dutch criteria and 41 (8.3%) for UK guidelines. PPV of Belgian rheumatologists' perception was 72.6% for fulfilling Dutch criteria (NPV 49.6%) and 23.4% for UK guidelines (NPV 96.7%). CONCLUSIONS: Rheumatologists consider more RA patients eligible for anti-TNF treatment than would be reimbursed according to Belgian criteria. Dutch guidelines, based on DAS28, match more closely eligibility according to Belgian rheumatologists.

Rahman MU, Strusberg I, Geusens P, Berman A, Yocum D, Baker D, Wagner C, Han J, Westhovens R. · Centocor Research and Development, Inc, Malvern, PA, USA. · Ann Rheum Dis. · Pubmed #17392352 No free full text.

Abstract: OBJECTIVE: To determine the efficacy, safety and pharmacokinetics of infliximab dose escalation in patients with rheumatoid arthritis (RA) who had an inadequate response to 3 mg/kg infliximab treatment or whose disease flared after initially responding. METHODS: Patients with active RA, despite receiving methotrexate, received infliximab 3 mg/kg at weeks 0, 2, 6 and 14 in one of the three arms of the START trial. Beginning at week 22, patients had their infliximab dose increased in a double-blind fashion in increments of 1.5 mg/kg if the total tender and swollen joint count did not improve by at least 20% from baseline (lack of response) or the improvement at week 22 or later worsened by 50% or more (criterion for flare). RESULTS: Of the 329 evaluable patients, 100 (30.4%) patients required dose escalation at or after week 22 because of flare or lack of response. The majority of patients (>80%) who received up to three dose escalations showed >/=20% improvement in the total tender and swollen joint count after their last dose escalation. Patients who required dose escalations generally had lower preinfusion serum infliximab concentrations than those who did not require them. The incidences of adverse events and serious adverse events for the patients who received dose escalation(s) were similar to those of patients who did not receive dose escalation. CONCLUSION: Fewer than one-third of patients required a dose escalation. The majority of patients showed improvement after receiving increased doses of infliximab, without an increased risk of adverse events.

Maksymowych WP, Landewe R, Boers M, Garnero P, Geusens P, El-Gabalawy H, Heinegard D, Kraus VB, Krause V, Lohmander S, Matyas J, Saxne T, van der Heijde D. · Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. · J Rheumatol. · Pubmed #17343311 No free full text.

Abstract: OBJECTIVE: Recent work has shown that several soluble biomarkers, detectable in peripheral blood, synovial fluid, and/or urine, reflect remodeling of joint tissues and may therefore constitute outcome measures that reflect joint damage. Consequently, it is now desirable to begin the process of developing criteria for validation of a soluble biomarker as an outcome measure reflecting structural damage progression in trials of disease-modifying therapies for rheumatoid arthritis (RA) and spondyloarthritis (SpA). Our objective was to develop validation criteria for a soluble biomarker to be regarded as a valid biomarker reflecting radiological endpoints in RA and SpA clinical trials. METHODS: A special interest group was established comprising investigators with expertise in soluble biomarker assay development as well as in outcomes research. This project was initiated by means of a Delphi consensus exercise. A list of draft criteria was first generated following a review of a US National Institutes of Health (NIH) 2000 white paper (available at: http://www.niams.nih.gov/ne/oi/ oabiomarwhipap.htm) that focused on biomarkers in OA, and these were organized under subject headings relevant to the OMERACT filter: truth, discrimination, and feasibility. Additional criteria were solicited from the working group. This was followed by 3 rounds of voting. RESULTS: A list of 31 criteria was generated prior to voting. The first 2 rounds of voting resulted in cumulative agreement that 19 criteria be retained and 4 discarded, while discrepancies were recorded for 8 criteria. In the third round of voting, cumulative agreement was achieved to retain 5 of the 8 discrepant criteria, so that the final list included 24 criteria. CONCLUSION: A draft set of criteria for validation of a soluble biomarker to be regarded as reflecting radiological damage endpoints in clinical trials has been proposed on the basis of consensus.

Thewissen M, Somers V, Venken K, Linsen L, van Paassen P, Geusens P, Damoiseaux J, Stinissen P. · Hasselt University, Biomedical Research Institute and Transnationale Universiteit Limburg, School of Life Sciences, Agoralaan, Diepenbeek, Belgium, and Department of Clinical and Experimental Immunology, University Hospital Maastricht, The Netherlands. · Clin Immunol. · Pubmed #17317320 No free full text.

Abstract: The objective of this study was to evaluate the degree of immunosenescence in patients with autoimmune disease. T cell receptor excision circles (TREC) and the percentage of CD4+CD28null T cells were studied as markers of immunosenescence in 175 patients with chronic autoimmune arthritis, other connective tissue autoimmune diseases, multiple sclerosis and 60 healthy controls. In both the rheumatoid arthritis (RA) and multiple sclerosis patient group, TREC numbers were age-inappropriately declined which points to an accelerated thymic output. Furthermore, enhanced percentages of CD4+CD28null T cells could be detected in a significant proportion of patients included in this study. These immunosenescent phenomena seemed to be present already early in the disease process. High percentages of CD4+CD28null T cells were associated with the presence of RA linked HLA DR4 alleles and with plasma reactivity to cytomegalovirus. Further analysis of CD4+CD28null T cells provided indications for a restricted T cell receptor (TCR) BV gene expression and cytoplasmic stores of various cytotoxic molecules. This study indicates that the immune system of patients with autoimmune diseases shows signs of an accelerated aging. Both genetic factors, such as HLA DR4, and environmental factors, like CMV infection, might speed up this immunosenescence and contribute in this way to disease pathogenesis.

van Staa TP, Geusens P, Bijlsma JW, Leufkens HG, Cooper C. · MRC Epidemiology Resource Centre, University of Southampton, Southampton, UK. · Arthritis Rheum. · Pubmed #17009229 links to  free full text

Abstract: OBJECTIVE: To determine whether patients with rheumatoid arthritis (RA) have an increased risk of fracture, and to estimate their long-term absolute fracture risk. METHODS: We studied patients with RA ages >or=40 years in the British General Practice Research Database, each matched by age, sex, calendar time, and practice to 3 control patients. Incident fractures, as recorded in the computerized medical records, were ascertained over a median followup of 7.6 years. The fracture rate in RA patients compared with controls was adjusted for smoking, body mass index (BMI), and several clinical risk factors, and Cox proportional hazards models were used to calculate the relative risk (RR) of fracture in RA. A risk score was then developed to provide an estimate of the 5- and 10-year fracture risk among RA patients. RESULTS: There were 30,262 patients with RA, of whom 2,460 experienced a fracture during followup. Compared with controls, patients with RA had an increased risk of fracture, which was most marked at the hip (RR 2.0, 95% confidence interval [95% CI] 1.8-2.3) and spine (RR 2.4, 95% CI 2.0-2.8). Indicators of a substantially elevated risk of fracture (at the hip) included >10 years' duration of RA (RR 3.4, 95% CI 3.0-3.9), low BMI (RR 3.9, 95% CI 3.1-4.9), and use of oral glucocorticoids (RR 3.4, 95% CI 3.0-4.0). Modeling of the long-term risk profiles revealed that, for example, in a woman age 65 years with longstanding RA whose risk factors also included low BMI, a history of fracture, and frequent use of oral glucocorticoids, the 5-year risk of hip fracture was 5.7% (95% CI 5.3-6.1%). CONCLUSION: Patients with RA are at increased risk of osteoporotic fractures. This increased risk is attributable to a combination of disease activity and use of oral glucocorticoids.

van Staa TP, Geusens P, Zhang B, Leufkens HG, Boonen A, Cooper C. · Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. · Rheumatology (Oxford). · Pubmed #16899499 links to  free full text

Abstract: OBJECTIVES: There are few data on the cost-effectiveness of bisphosphonates with oral glucocorticoids (GCs). An individual patient-based pharmaco-economic model was developed. METHODS: Data were obtained from a cohort of oral GC users aged 40+ (n = 190 000) in the UK General Practice Research Database. Individualized fracture and mortality risks were calculated specific for age, sex, daily and cumulative GC dose, indication and other clinical risk factors. UK costs of medication and direct costs of fracture were obtained from National Institute for Clinical Excellence and used to estimate costs per quality-adjusted life-year (QALY) gained and fracture prevented for bisphosphonates in patients treated for 5 yrs with GCs. RESULTS: With the use of 5 mg GCs daily, the cost per one QALY gained with bisphosphonates was 41k UK pounds (95% confidence intervals 22-72k) in women aged <60 [men 40k pounds (29-54k)], 17k pounds (13-24k) in women aged 60-79 [men 43k pounds (31-60k)], 5k pounds(3-6k) in women aged 80+ [men 35k pounds (25-46k)]. With 15 mg GC, these figures were 17k pounds (14-21k), 13k pounds (10-16k) and 15k pounds (9-26k) in women and 22k pounds (17-26k), 34 pounds (23-53k) and 33k pounds (27-42k) in men, respectively. When stratifying by overall fracture risk and life expectancy at the start of GC therapy, cost per QALY increased with decreasing life expectancy. Patients with rheumatoid arthritis had comparatively better cost-effectiveness, given higher fracture risk and better life expectancy. CONCLUSIONS: The cost-effectiveness of bisphosphonates varied substantially. Bisphosphonates can be considered cost-effective in patients with higher fracture risks, such as elderly patients (with a life expectancy over 5 yrs), and younger patients with a fracture history, low body mass index, rheumatoid arthritis or using high GC doses.

Lems WF, Lodder MC, Lips P, Bijlsma JW, Geusens P, Schrameijer N, van de Ven CM, Dijkmans BA. · VU University Medical Centre, Department of Rheumatology, 4A 42, P.O. Box 7057, 1007 MB, and Slotervaart Hospital, Department of Rheumatology, Amsterdam, The Netherlands. · Osteoporos Int. · Pubmed #16463007 No free full text.

Abstract: INTRODUCTION: Alendronate has been described to have a bone-sparing effect in patients treated with moderate and high dosages of prednisone for heterogeneous diseases, however no data are available on groups of patients with the same underlying diseases who receive chronic low-dose prednisone treatment. The objective of the investigation reported here was, therefore, to study the effect of alendronate on bone mineral density (BMD) of the lumbar spine and hips in patients with rheumatoid arthritis (RA) who are on chronic low-dose prednisone treatment. METHODS: A total of 163 patients with RA, according to the ACR-criteria, were enrolled in a double-blind, placebo-controlled trial. The patients were treated with low-dose prednisone (<or=10 mg/day) for at least 3 months. The patients were randomized to receive daily doses of alendronate or placebo: men and premenopausal women received 5 mg alendronate (or placebo) daily; postmenopausal women received 10 mg alendronate (or placebo) daily. All patients received daily calcium (500 mg, or 1000 mg, depending on baseline dietary calcium intake) and vitamin D3 (400 IU) supplementation. BMD of the lumbar spine (L1-L4) and the (total) hip was measured at baseline and after 6 and 12 months. The primary endpoint was change in BMD of the lumbar spine after 12 months (ITT). At baseline and after 3 and 12 months, serum bone-specific alkaline phosphatase (BAP) and urinary excretion of N-telopeptide (NTX) were measured. Radiographs of the thoracic and lumbar spine were made at baseline and after 12 months and subsequently scored for vertebral deformities. RESULTS: The groups were comparable at baseline in age, gender, daily dosage of prednisone, BMD at the spine and the hip and markers of bone turnover, while the number of patients with prevalent vertebral deformities was slightly higher in the alendronate-treated patients (54% versus 39%, not significant). After 12 months, BMD at the lumbar spine had increased by 3.7% in the alendronate-treated patients and decreased by -1.0% in the placebo-treated patients (p<0.0001); at the hip, the changes were +1.0% and -0.1%, respectively (not significant). After 3 months, serum BAP had decreased by 16.9% in the alendronate group versus 3.3% in the placebo group (p=0.0005), while urinary NTX had decreased by 46.4% in the alendronate group versus 12.1% in the placebo group (p<0.0001). After 12 months, no statistically significant difference was found between the groups with respect to number of patients with incident vertebral or non-vertebral fractures. Adverse effects were relatively common in these patients with severe RA: adverse effects were observed in 68% of the alendronate-treated patients and in 73% of the placebo patients (not significant), while serious adverse events were observed in 13% and 17%, respectively (not significant). CONCLUSION: We observed a favourable effect of alendronate on the BMD of the lumbar spine and on the markers of bone turnover in patients with RA treated with low-dose prednisone. These data support the conclusion that the prescribing of alendronate is not only beneficial in patients treated with high-dose prednisone but also in RA patients chronically treated with low-dose prednisone.

Thewissen M, Linsen L, Geusens P, Raus J, Stinissen P. · Biomedisch Onderzoeksinstituut, Limburgs Universitair Centrum and School of Life Sciences, Transnationale Universiteit Limburg, Universitaire Campus, B-3590 Diepenbeek, Belgium. · Immunol Lett. · Pubmed #16154497 No free full text.

Abstract: Although telomerase activity is important in normal immune function, it is unclear whether telomerase or telomerase (dys)regulation plays a role in the pathogenic immune response in autoimmune diseases like rheumatoid arthritis (RA). In this study, we evaluated the dynamics of the activation-induced human telomerase reverse transcriptase (hTERT) response in RA patients and non-RA controls. The expression of the catalytic subunit of telomerase, hTERT, was measured in peripheral blood mononuclear cells (PBMC) of RA patients and controls after in vitro stimulation with anti-CD3 monoclonal antibody (mAb) using real-time PCR. Anti-CD3 mAb stimulation induced activation and proliferation of the T cells in all populations studied. In early RA patients with a disease duration of less than 1 year, the activation-induced hTERT mRNA levels were found to be reduced as compared to healthy controls (HC). Chronic RA patients, with a disease duration of more than 1 year, did not show these impaired hTERT mRNA levels after stimulation with anti-CD3 mAb. Decreased hTERT mRNA levels were also found in multiple sclerosis patients and patients suffering from flu-like symptoms, indicating that these deviations are not disease-specific. The impaired activation-induced hTERT response in PBMC may be a general response of the immune cells in cases of acute or chronic immune activation, presumably to control unwanted clonal expansions and to maintain the diversity of the TCR repertoire. Our results also indicate that clonal T cell expansions, described in RA, are probably not mediated by an elevated potency to express hTERT.

Thewissen M, Linsen L, Somers V, Geusens P, Raus J, Stinissen P. · Biomedisch Onderzoeksinstituut, Limburgs Universitair Centrum, Universitary Campus, B-3590 Diepenbeek, Belgium. · Ann N Y Acad Sci. · Pubmed #16126966 No free full text.

Abstract: Patients with T-cell-mediated autoimmune diseases show immune system abnormalities that resemble the typical characteristics of autoimmune dysfunction described in the elderly. In addition, the incidence of autoimmune disease increases with advancing age. To evaluate whether patients with rheumatoid arthritis (RA) and multiple sclerosis (MS) have premature immuno-senescence, we measured two indicators of aging: the number of T-cell-receptor excision circles (TRECs) and the percentage of CD4+CD28(null) T cells. We studied them in the peripheral blood mononuclear cells (PBMCs) of 60 RA patients, 32 MS patients, and 40 healthy controls (HCs). We found that TREC numbers were lower in RA and MS patients than in age-matched HCs, indicating premature thymic involution. Moreover, a subset of these patients contained age-inappropriate high frequencies of CD4+CD28(null) T cells. This study provides evidence of premature immune system senescence in both RA and MS patients. Premature aging could be a risk factor for developing autoimmune disorders in genetically predisposed individuals in a susceptible environment.

Landewé RB, Geusens P, van der Heijde DM, Boers M, van der Linden SJ, Garnero P. · Department of Internal Medicine/Rheumatology, University Hospital Maastricht, Netherlands. · Ann Rheum Dis. · Pubmed #16126801 links to  free full text

Abstract: BACKGROUND: Markers of collagen type I (CTX-1) and type II (CTX-II) degradation, reflecting bone and cartilage breakdown, appear to predict long term radiographic progression in chronic persistent arthritis. OBJECTIVE: To analyse longitudinally whether changes in arthritis severity are linked to immediate changes in the level of CTX-I and CTX-II degradation. METHODS: CTX-I and CTX-II were measured in urine samples from 105 patients with early rheumatoid arthritis who had participated in the COBRA trial at baseline and at 3, 6, 9, and 12 months after the start of treatment. The course of the biomarkers over time was compared with the course of ESR, swollen and tender joint counts, and 28 joint disease activity score (DAS28), measured at the same time points, with adjustment for rheumatoid factor, treatment, and baseline radiographic damage, by generalised estimating equations (GEE) with first order autoregression. RESULTS: GEE showed that CTX-I was longitudinally associated with DAS28, but not with ESR, swollen joint count, or tender joint count. CTX-II, however, was longitudinally associated with ESR, swollen joint count and DAS28, but not with tender joint count. The longitudinal association implies that an increase in the extent of arthritis is immediately followed by an increase in collagen type II degradation, and to a lesser extent collagen type I degradation. CONCLUSIONS: Cartilage degradation as measured by CTX-II and to a lesser extent bone degradation as measured by CTX-I closely follows indices of arthritis. Clinically perceptible arthritis is responsible for immediate damage, which will become visible on plain x rays only much later.

Linsen L, Thewissen M, Baeten K, Somers V, Geusens P, Raus J, Stinissen P. · Biomedisch Onderzoeksinstituut, Limburgs Universitair Centrum and School of Life Sciences, Transnationale Universiteit Limburg, Universitaire Campus, Diepenbeek, Belgium. · Arthritis Res Ther. · Pubmed #15899036 links to  free full text

Abstract: Natural killer T (NKT) cells have been implicated in the regulatory immune mechanisms that control autoimmunity. However, their precise role in the pathogenesis of rheumatoid arthritis (RA) remains unclear. The frequency, cytokine profile and heterogeneity of NKT cells were studied in peripheral blood mononuclear cells (PBMCs) from 23 RA patients and 22 healthy control individuals, including paired PBMC-synovial fluid samples from seven and paired PBMC-synovial tissue samples from four RA patients. Flow cytometry revealed a decreased frequency of NKT cells in PBMCs from RA patients. NKT cells were present in paired synovial fluid and synovial tissue samples. Based on the reactivity of PBMC-derived NKT cells toward alpha-galactosylceramide, RA patients could be divided into responders (53.8%) and nonresponders (46.2%). However, NKT cells isolated from synovial fluid from both responders and nonresponders expanded upon stimulation with alpha-galactosylceramide. Analysis of the cytokine profile of CD4+ and CD4- PBMC derived NKT cell lines from RA patients revealed a significantly reduced number of IL-4 producing cells. In contrast, synovial fluid derived NKT cell lines exhibited a Th0-like phenotype, which was comparable to that in healthy control individuals. This suggests that synovial fluid NKT cells are functional, even in patients with nonresponding NKT cells in their blood. We conclude that, because the number of Valpha24+Vbeta11+CD3+ NKT cells is decreased and the cytokine profile of blood-derived NKT cells is biased toward a Th1-like phenotype in RA patients, NKT cells might be functionally related to resistance or progression of RA. Providing a local boost to the regulatory potential of NKT cells might represent a useful candidate therapy for RA.

Vanderborght A, Linsen L, Thewissen M, Geusens P, Raus J, Stinissen P. · Limburgs Universitair Centrum, Biomedisch Onderzoeksinstituut, Diepenbeek, Belgium. · J Rheumatol. · Pubmed #15290725 No free full text.

Abstract: OBJECTIVE: To further understand the role of osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANK-L) in rheumatoid arthritis (RA), we studied the levels of RANK-L and OPG mRNA in peripheral blood mononuclear cells (PBMC) and synovial tissue of patients with RA and controls. METHODS: RANK-L and OPG mRNA levels were measured in PBMC and CD4+/CD8+ T cell subsets of patients with chronic RA, osteoarthritis (OA), and healthy controls, using quantitative real-time polymerase chain reaction. OPG and RANK-L mRNA levels were measured in paired blood and synovial tissue samples of patients with early, untreated RA at 2 timepoints with an interval of 16 weeks. RESULTS: RANK-L mRNA levels were significantly higher in PBMC of patients with early and chronic RA compared to healthy controls. Contrary to healthy controls, RANK-L mRNA levels in patients with chronic RA were mainly of CD4+ T cell origin. OPG mRNA was observed in the blood of all (17/17) early RA patients, but could not be detected in chronic RA patients (0/14) or in patients with OA (0/8). Three out of 17 healthy controls showed measurable levels of OPG mRNA. The OPG/RANK-L ratio tended to be higher in the synovium than in the PBMC of early RA patients. RANK-L mRNA in synovial tissue was mainly of non-T cell origin. CONCLUSION: Since RANK-L and OPG mRNA levels are elevated in PBMC of RA patients, and CD4+ T cells are the major contributors to RANK-L mRNA expression, mononuclear cells in patients with RA may be involved in the pathways that regulate bone metabolism.

Vanhoof J, Declerck K, Geusens P. · Clinical Research Centre for Bone and Joint Diseases, Biomedical Research Institute, Limburg University Centre, Diepenbeek, Belgium. · Ann Rheum Dis. · Pubmed #11959771 links to  free full text

Abstract: OBJECTIVE: To assess the prevalence and distribution of rheumatic diseases in a community based rheumatological outpatient practice. METHODS: Rheumatological diagnoses of 3751 consecutive new and returning patients were recorded using a standard diagnosis form. RESULTS: 6264 rheumatological diagnoses were made in 3751 patients, of whom 1097 were newly referred; 69% of all patients were female. Inflammatory joint and spine diseases were diagnosed in 42% of all patients (including 5% with connective tissue diseases), soft tissue rheumatism in 37%, degenerative joint and spine diseases in 36%, and metabolic bone diseases in 17% of all patients. In new patients soft tissue rheumatism was most prevalent (51%), 45% had osteoarthritis, 24% had inflammatory joint and spine disease (including 2% with connective tissue disease), and 13% had metabolic bone disease. One of 10 new patients was diagnosed with definite rheumatoid arthritis. In returning patients the prevalence of inflammatory rheumatic diseases was higher (49%, including 6% with connective tissue diseases). 28% of the returning patients had rheumatoid arthritis. Osteoarthritis was present in 33% and metabolic bone disease in 19% of the returning patients. CONCLUSIONS: Soft tissue rheumatism and degenerative joint and spine diseases are the most common rheumatological diagnoses in newly referred patients visiting a community based rheumatological outpatient practice. Inflammatory rheumatic diseases were most prevalent in returning patients.

Buntinx M, Ameloot M, Steels P, Janssen P, Medaer R, Geusens P, Raus J, Stinissen P. · Biomedisch Onderzoeksinstituut, Limburgs Universitair Centrum and School of Life Sciences, Transnational University Limburg, Universitaire Campus gebouw A, B-3590 Diepenbeek, Belgium. · J Neuroimmunol. · Pubmed #11958824 No free full text.

Abstract: Autoreactive T lymphocytes are considered to play a crucial role in orchestrating a chronic inflammation in the central nervous system (CNS) of multiple sclerosis (MS) patients and in the joints of rheumatoid arthritis (RA) patients. However, it has been suggested that the majority of T cells in the immune infiltrate are nonspecifically recruited into the CNS and into the inflamed joint. In addition, several lines of evidence suggest an important role for interferon-gamma (IFN-gamma) in the pathogenesis of MS and RA. We have studied whether peripheral blood T cells from patients with autoimmune diseases are more susceptible to activation in the presence of IFN-gamma. The results indicate that IFN-gamma mediates a sustained elevated [Ca(2+)](i) in T cells of (active) MS and RA patients as compared to healthy controls and patients with common viral infections. No [Ca(2+)](i) increase was observed in Ca(2+)-free medium, excluding an effect of IFN-gamma on Ca(2+)-release from intracellular stores. Although the IFN-gamma-activated Ca(2+)-influx is insufficient to induce T cell proliferation in vitro, our data indicate a significantly augmented proliferation in response to suboptimal doses of PHA in the presence of IFN-gamma. This study suggests that the IFN-gamma-induced Ca(2+)-influx can act as a complementary mechanism in the activation of blood T lymphocytes from MS and RA patients.