Rheumatoid Arthritis: Lottenburger T

Christensen AF, Lottenburger T, Lindegaard H, Christgau S, Hørslev-Petersen K, Junker P. · Departments of Rheumatology, Odense University Hospital, Odense and Institute of Clinical Research, University of Southern Denmark, Denmark. · Clin Exp Rheumatol. · Pubmed #19473573 No free full text.

Abstract: OBJECTIVES: To determine the N-terminal propeptide of collagen IIA (PIIANP) in early and established rheumatoid arthritis (RA) and to study the association with collagen II degradation assessed by its C-telopeptide (CTX-II), x-ray status and disease activity measures. METHODS: Two cohorts of RA patients were included: A) a one-year prospective cohort including 45 patients with early, untreated RA and B) a cross-sectional study comprising 50 RA patients with advanced disease. Blood donors and healthy volunteers served as controls. PIIANP in serum and urine CTX-II were measured by ELISA. RESULTS: PIIANP did not differ from control levels at any time in patients with early RA (p=0.16 and p=0.89), but at one-year follow-up, PIIANP was decreased compared with baseline (p=0.046). In patients with longstanding RA, PIIANP was lower than in controls (p=0.002) and RA patients with a 12-month disease (p=0.01). PIIANP was unrelated to joint counts and CRP in both cohorts, but baseline PIIANP was lower among x-ray progressors than in non-progressors (p=0.04). CTX-II was persistently increased in both cohorts (p<0.001 and p<0.001). CTX-II was positively associated with joint counts and CRP but not with x-ray progression (p=0.84). There was no correlation between PIIANP and CTX-II. CONCLUSION: Declining PIIANP with increasing RA duration and persistently increased CTX-II indicate that cartilage anabolic and degradative pathways are unbalanced from clinical RA onset. Furthermore, that collagen II depletion in RA is both mediated by anti-anabolic effects unassociated with synovitis (decreased PIIANP) and by excess collagen II degradation linked to synovitis (increased CTX-II).

Jacobsen S, Garred P, Madsen HO, Heegaard NH, Hetland ML, Stengaard-Pedersen K, Junker P, Lottenburger T, Ellingsen T, Smedegaard Andersen L, Hansen I, Skjødt H, Pedersen JK, Lauridsen UB, Svendsen AJ, Tarp U, Pødenphant J, Lindegaard H, Vestergaard A, Østergaard M, Hørslev-Petersen K. · Department of Rheumatology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. · J Rheumatol. · Pubmed #19273450 No free full text.

Abstract: OBJECTIVE: To study the association between polymorphisms in the mannose-binding lectin gene (MBL2) and disease activity, physical disability, and joint erosions in patients with newly diagnosed rheumatoid arthritis (RA). METHODS: Patients with early RA (n=158) not previously treated with disease modifying antirheumatic drugs, participating in a treatment trial (CIMESTRA study) were examined at inclusion for MBL2 pooled structural genotypes (O/O, A/O, A/A), regulatory MBL2 promoter polymorphism in position -221 (XX, XY, YY), anti-cyclic citrullinated peptide 2 antibodies (anti-CCP2), disease activity by Disease Activity Score-28 (DAS28 score), physical disability by Health Assessment Questionnaire (HAQ) score, and erosive changes in hands and feet (Sharp-van der Heijde score). RESULTS: Eight patients were homozygous MBL2 defective (O/O), 101 belonged to an intermediate group, and 49 were MBL2 high producers (YA/YA). Anti-CCP was present in 93 patients (59%). High scores of disease activity, C-reactive protein-based DAS28 (p=0.02), and physical disability by HAQ (p=0.01) were associated with high MBL2 expression genotypes in a gene-dose dependent way, but only in anti-CCP-positive patients. At this early stage of the disease there was no association with erosion score from radiographs. CONCLUSION: The results point to a synovitis-enhancing effect of MBL in anti-CCP-positive RA, whereas such an effect was not demonstrated for joint erosions.

Hetland ML, Ejbjerg B, Hørslev-Petersen K, Jacobsen S, Vestergaard A, Jurik AG, Stengaard-Pedersen K, Junker P, Lottenburger T, Hansen I, Andersen LS, Tarp U, Skjødt H, Pedersen JK, Majgaard O, Svendsen AJ, Ellingsen T, Lindegaard H, Christensen AF, Vallø J, Torfing T, Narvestad E, Thomsen HS, Ostergaard M, Anonymous00063. · Department of Rheumatology, Copenhagen University Hospital, Hvidovre, Denmark. · Ann Rheum Dis. · Pubmed #18388160 No free full text.

Abstract: OBJECTIVE: To identify predictors of radiographic progression in a 2-year randomised, double-blind, clinical study (CIMESTRA) of patients with early rheumatoid arthritis (RA). METHODS: Patients with early RA (n = 130) were treated with methotrexate, intra-articular betamethasone and ciclosporin/placebo-ciclosporin. Baseline magnetic resonance imaging (MRI) of the wrist (wrist-only group, n = 130) or MRI of wrist and metacarpophalangeal (MCP) joints (wrist+MCP group, n = 89) (OMERACT RAMRIS), x-ray examination of hands, wrists and forefeet (Sharp/van der Heijde Score (TSS)), Disease Activity Score (DAS28), anti-cyclic citrullinated peptide antibodies (anti-CCP), HLA-DRB1-shared epitope (SE) and smoking status were assessed. Multiple regression analysis was performed with delta-TSS (0-2 years) as dependent variable and baseline DAS28, TSS, MRI bone oedema score, MRI synovitis score, MRI erosion score, anti-CCP, smoking, SE, age and gender as explanatory variables. RESULTS: Baseline values: median DAS28 5.6 (range 2.4-8.0); anti-CCP positive 61%; radiographic erosions 56%. At 2 years: DAS28 2.0 (0.5-5.7), in DAS remission: 56%, radiographic progression 26% (wrist+MCP group, similar for wrist-only group). MRI bone oedema score was the only independent predictor of delta-TSS (wrist+MCP group: coefficient = 0.75 (95% CI 0.55 to 0.94), p<0.001; wrist-only group: coefficient = 0.59 (95% CI 0.40 to 0.77), p<0.001). Bone oedema score explained 41% of the variation in the progression of TSS (wrist+MCP group), 25% in wrist-only group (Pearson's r = 0.64 and r = 0.50, respectively). Results were confirmed by sensitivity analyses. CONCLUSION: In a randomised controlled trial aiming at remission in patients with early RA, baseline RAMRIS MRI bone oedema score of MCP and wrist joints (and of wrist only) was the strongest independent predictor of radiographic progression in hands, wrists and forefeet after 2 years. MRI synovitis score, MRI erosion score, DAS28, anti-CCP, SE, smoking, age and gender were not independent risk factors. TRIAL REGISTRATION NUMBER: NCT00209859.

Hetland ML, Christensen IJ, Lottenburger T, Johansen JS, Svendsen MN, Hørslev-Petersen K, Nielsen L, Nielsen HJ. · Department of Rheumatology, Copenhagen University Hospital, Hvidovre, Denmark. · Dis Markers. · Pubmed #18057530 No free full text.

Abstract: BACKGROUND: Soluble vascular endothelial growth factor (VEGF) is a promising biomarker in monitoring rheumatoid arthritis (RA), but studies of pre-analytical and biologic variability are few. METHODS: VEGF was measured by ELISA methods in serum and plasma from healthy persons and RA patients. Pre-analytical factors were investigated. A reference interval for VEGF was established in serum and plasma from 306 healthy persons. Diurnal, day-to-day, week-to-week, long-term variability, and impact of exercise were evaluated. RESULTS: Delayed processing time, room temperature, low centrifugal force and contamination of plasma with cellular elements lead to significant increases in VEGF levels, whereas storage for up to 2 years at -80 degrees C or up to 10 freeze/thaw cycles did not affect VEGF levels. Serum VEGF levels were 7-10 fold higher than plasma VEGF levels. Reference intervals for VEGF (plasma: 45 pg/ml (range: non-detectable to 352); serum: 328 pg/ml (53-1791)) were independent of gender and age. Short- and long-term biologic variability included diurnal variation (sampling should take place after 7 AM) and impact of exercise (increased VEGF immediately after bicycling normalised within 1 hour). CONCLUSIONS: Pre-analytical factors and biologic variability including diurnal variation and impact of exercise should be accounted for in future studies that include circulating VEGF as a biological marker.

Hetland ML, Stengaard-Pedersen K, Junker P, Lottenburger T, Hansen I, Andersen LS, Tarp U, Svendsen A, Pedersen JK, Skjødt H, Lauridsen UB, Ellingsen T, Hansen GV, Lindegaard H, Vestergaard A, Jurik AG, Østergaard M, Hørslev-Petersen K, Anonymous00425. · Department of Rheumatology, Copenhagen University Hospital, Hvidovre, Denmark. · Ann Rheum Dis. · Pubmed #17878209 No free full text.

Abstract: OBJECTIVE: To investigate whether clinical and radiographic disease control can be achieved and maintained in patients with early, active rheumatoid arthritis (RA) during the second year of aggressive treatment with conventional disease-modifying antirheumatic drugs (DMARDs) and intra-articular corticosteroid. This paper presents the results of the second year of the randomised, controlled double-blind CIMESTRA (Ciclosporine, Methotrexate, Steroid in RA) study. METHODS: 160 patients with early RA (duration <6 months) were randomised to receive intra-articular betamethasone in any swollen joint in combination with step-up treatment with either methotrexate and placebo-ciclosporine (monotherapy) or methotrexate plus ciclosporine (combination therapy) during the first 76 weeks. At week 68 hydroxychlorochine 200 mg daily was added. From week 76-104 ciclosporine/placebo-ciclosporine was tapered to zero. RESULTS: American College of Rheumatology 20% improvement (ACR20), ACR50 and ACR70 levels were achieved in 88%, 79% and 59% of patients in the combination vs 72%, 62% and 54% in the monotherapy group (p = 0.03, 0.02 and 0.6 between groups). The patients globally declined from 50 to 12 vs 52 to 9, with 51% and 50% in Disease Activity Score (DAS) remission, respectively. Mean (SD) progressions in total Sharp-van der Heijde scores were 1.42 (3.52) and 2.03 (5.86) in combination and monotherapy groups, respectively (not significant). Serum creatinine levels increased by 7% in the combination group (4% in monotherapy), but hypertension was not more prevalent. CONCLUSION: Continuous methotrexate and intra-articular corticosteroid treatment resulted in excellent clinical response and disease control at 2 years, and the radiographic erosive progression was minimal. Addition of ciclosporine during the first 76 weeks resulted in significantly better ACR20 and ACR50 responses, but did not have any additional effect on remission rate and radiographic outcome.

Knudsen LS, Christensen IJ, Lottenburger T, Svendsen MN, Nielsen HJ, Nielsen L, Hørslev-Petersen K, Jensen JE, Kollerup G, Johansen JS. · Department of Rheumatology Q 107, Herlev Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark. · Biomarkers. · Pubmed #17852075 No free full text.

Abstract: Interleukin (IL)-6, a key player in the inflammatory response, may be a useful biomarker in rheumatoid arthritis (RA). The aim was to determine analytical variability, a reference interval in healthy subjects, and long- and short-term variation in serum and plasma IL-6 in healthy subjects and RA patients. An enzyme-linked immunosorbent assay from R&D was used for determination of serum and plasma IL-6. The IL-6 concentration did not depend on the type of anticoagulant used or the 3-h time delay between sampling and processing or repeated freeze-thaw cycles. The median plasma and serum IL-6 in 318 healthy subjects were 1.3 pg ml(-1) (range 0.33-26) and 1.4 pg ml(-1) (range 0.25-23), respectively. The median coefficient of variation in plasma IL-6 in 27 healthy subjects during 1 month, and repeated after 6 and 12 months were 27%, 31% and 26%, respectively. No significant long-term changes were observed in serum IL-6 over a 3-year period (14%, p = 0.33). Exercise (cycling) increased serum IL-6 in healthy subjects but not in RA patients. In conclusion, circulating IL-6 is stable regarding sample handling and shows little variation over time. Changes in IL-6 concentrations > 60% (2 times the biological variation) are likely to reflect changes in disease activity and not only pre-analytical or normal biological variability.

Hansen IB, Ellingsen T, Hornung N, Poulsen JH, Lottenburger T, Stengaard-Pedersen K. · Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark. · J Rheumatol. · Pubmed #16960937 No free full text.

Abstract: OBJECTIVE: Several actions of the chemokine CXCL12 have potential relevance for rheumatoid arthritis (RA). Interaction with CXCR4, the unique receptor for CXCL12, stimulates angiogenesis, mononuclear cell trafficking into the joints, lymphoid-tissue-like rearrangement of T cells within the synovium, and chondrocyte release of cartilage-degrading metalloproteinases. We investigated the level of CXCL12 in plasma (p-CXCL12) as a marker of RA diagnosis, RA disease activity, and response to methotrexate (MTX) treatment. METHODS: A prospective study including 36 patients with RA (ACR criteria) of at least 6 months' duration, and 50 sex and age matched healthy controls. ELISA for CXCL12 was performed on plasma prior to and after 16 and 28 weeks of MTX treatment in the patients with RA and once in controls. RESULTS: The p-CXCL12 was 1855 +/- 145 pg/ml in RA patients and 1273 +/- 79 pg/ml in controls (p < 0.001). During the 28 weeks of MTX treatment, the ACR disease activity variables decreased, whereas the p-CXCL12 level remained constant and increased. P-CXCL12 was not correlated to any ACR disease activity variable at any time (p > 0.05). CONCLUSION: Patients with RA had a significantly and constantly increased p-CXCL12 level compared to controls. The p-CXCL12 level was independent of any ACR disease activity variables, as well as response to MTX treatment.

Hetland ML, Stengaard-Pedersen K, Junker P, Lottenburger T, Ellingsen T, Andersen LS, Hansen I, Skjødt H, Pedersen JK, Lauridsen UB, Svendsen A, Tarp U, Pødenphant J, Hansen G, Lindegaard H, de Carvalho A, Østergaard M, Hørslev-Petersen K, Anonymous00339. · Copenhagen University Hospital, Hvidovre, Denmark. · Arthritis Rheum. · Pubmed #16645967 links to  free full text

Abstract: OBJECTIVE: To investigate whether disease control can be achieved in early active rheumatoid arthritis (RA) by treatment with methotrexate and intraarticular betamethasone, and whether the addition of cyclosporine to the regimen has any additional effect. METHODS: Patients (n = 160) were randomized to receive methotrexate 7.5 mg/week plus cyclosporine 2.5 mg/kg of body weight/day (combination therapy) or methotrexate plus placebo-cyclosporine (monotherapy). At weeks 0, 2, 4, 6, and 8 and every 4 weeks thereafter, betamethasone was injected into swollen joints (maximum 4 joints or 4 ml per visit). Beginning at week 8, if synovitis was present, the methotrexate dosage was increased stepwise up to 20 mg/week, with a subsequent stepwise increase in the cyclosporine or placebo-cyclosporine dosage up to 4 mg/kg. RESULTS: At 52 weeks, 20% improvement according to the American College of Rheumatology criteria (ACR20) was achieved in 85% of the combination therapy group versus 68% of the monotherapy group (P = 0.02). The median individual overall ACR response (ACR-N) in the 2 groups was 80.0% (interquartile range 40.1-91.8%) and 54.5% (interquartile range 2.4-87.8%), respectively (P = 0.025). At 48 and 52 weeks, ACR remission criteria were met in 35% of the combination therapy group and 28% of the monotherapy group. Progression in the Larsen score at 52 weeks was -0.2 +/- 6.5 and 0.4 +/- 6.9 (mean +/- SD) in the combination therapy and monotherapy groups, respectively. Serum creatinine levels increased by 7%, and hypertrichosis was more prevalent, in the combination therapy group. CONCLUSION: Combined treatment with methotrexate and intraarticular glucocorticoid showed excellent disease control and stopped the progression of erosions in patients with early active RA, who had a poor prognosis. Addition of cyclosporine improved the ACR20 and ACR-N responses, whereas the ACR50 and ACR70 responses, remission rates, and radiographic changes did not differ between the 2 study groups.