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BackgroundTargeting MRI remission in rheumatoid arthritis (RA) patients in clinical remission may improve long term clinical, functional and MRI outcomes.ObjectivesTo investigate whether a 2-year treat-to-target (T2T) strategy, based on structured MRI assessments targeting absence of osteitis combined with clinical remission, compared with a conventional clinical T2T strategy targeting clinical remission only, improves disease activity, physical function and suppresses MRI-inflammation over 5 years in RA patients.MethodsThe IMAGINE-more trial was designed as an extension protocol to the 2-year IMAGINE-RA randomised controlled trial (RCT). IMAGINE-RA included 200 RA patients, in clinical remission (DAS28-CRPand no swollen joints), who received conventional synthetic disease-modifying antirheumatic drugs (csDMARD) and investigated whether an MRI T2T strategy targeting absence of osteitis in combination with clinical remission (DAS28-CRP≤3.2 and no swollen joints) could increase remission rates and prevent erosive progression compared with a conventional T2T strategy targeting clinical remission only. If target was not met, treatment was escalated according to a predefined treatment algorithm starting with increment in csDMARDs and then adding biologics. At the end of the study, participants were invited to participate in the IMAGINE-more follow-up study. Patients were managed in routine outpatient clinic and had three IMAGINE-more visits including clinical examination (year 3, 4 and 5) and contrast-enhanced MRI of the dominant wrist and 2nd-5th metacarpophalangeal joints (year 3 and 5). The primary clinical endpoint was the proportion of patients achieving DAS28-CRP remission (DAS28-CRPResultsFifty-nine patients in the MRI T2T arm and 72 patients in conventional T2T arm consented to participate. Of these, 47 patients (80%) in the MRI T2T group and 54 patients (75%) in the conventional T2T group reached the primary clinical endpoint (p=0.161) (Table 1 and Figure 1). No statistically significant differences between treatment strategies in key secondary outcomes were seen.Table 1.Primary and key secondary outcomes at 5 yearsMRI T2TConventional T2TDifference between groupsP valueN=59N=72Primary endpointDAS28-CRP remission (DAS28-CRP47 (80%)54 (75%)2.00 (0.76 to 5.28)0.161Key secondary endpointsDAS28-CRP1.79 (0.08)1.94 (0.08)-0.15 (-0.38 to 0.07)0.176Change from baseline in MRI osteitis (RAMRIS)-0.17 (0.58)0.18 (0.54)-0.35 (-1.96 to 1.25)0.663Change from baseline in HAQ-0.02 (0.03)0.05 (0.03)-0.07 (-0.15 to 0.01)0.080Group estimates are presented as No. (%) for dichotomous data and least squares means (SE) for continuous data. For the primary endpoint, adjusted odds ratio and 95%CI between groups were calculated from a logistic regression model including a fixed factor for treatment arm, and an adjustment for propensity score as a covariate. For endpoints with continuous data, least squares mean differences between groups were calculated based on repeated-measures mixed linear models adjusted for baseline values and propensity scores.ConclusionA 2-year MRI T2T strategy targeting absence of MRI osteitis combined with clinical remission as compared to a conventional clinical T2T strategy in RA patients had no effect on the long-term probability of achieving DAS28-CRP remission. These findnings do not support the use of an MRI-guided strategy for treating patients with RA.References[1]Møller-Bisgaard S et al: JAMA 2019, 321(5):461-472.Disclosure of InterestsSigne Møller-Bisgaard Grant/research support from: AbbVie, Kim Hørslev-Petersen: None declared, Daniel Glinatsi: None declared, Bo Ejbjerg: None declared, Merete L. Hetland: None declared, Jakob Møllenbach Møller: None declared, Robin Christensen: None declared, Sabrina Mai Nielsen: None declared, Mikael Boesen: None declared, Kristian Stengaard-Pedersen: None declared, Ole Madsen: None declared, Bente Jensen: None declared, Jan Alexander Villadsen: None declared, Ellen Margrethe Hauge: None declared, Oliver Hendricks: None declared, Hanne Merete Lindegaard: None declared, Niels Steen Krogh: None declared, Anne Grethe Jurik: None declared, Henrik Thomsen: None declared, Mikkel Østergaard Speakers bureau: Abbvie, BMS, Celgene, Eli-Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Orion, Pfizer, Roche and UCB, Consultant of: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi and UCB, Grant/research support from: Abbvie, Amgen, BMS, Merck, Celgene and Novartis.

To investigate the quantitative arthritic and bone erosive changes, including the number of osteoclasts and osteoclast precursors in the new SKG-model of inflammatory polyarthritis using three-dimensional (3D) stereological methods.Arthritis was induced in female SKG-mice with Zymosan A. Quantitative histology was made in four control mice and four mice with arthritis euthanised after 6 and 12 weeks. The right hind paw was embedded undecalcified in methylmethacrylate and cut exhaustively generating vertical uniform random sections. A computer controlled microscope and stereological software was used for histological quantification. Total volumes were estimated according to the Cavalieri principle, total surfaces were estimated using the vertical sections design, and the number of osteoclasts was counted in a physical fractionator.The arthritis score increased during the 12-week period and was paralleled by an increase in the volume of inflammatory tissue (r=0.96, p0.001). The number of osteoclasts on bone (r=0.77, p0.05) and osteoclast-covered bone surface (r=0.62, p0.05) increased resulting in a decrease in the volume of bone (r=-0.65, p0.05). However, the number of osteoclast precursors declined between week 6 and 12 (p0.05). Furthermore, the total cartilage surface (r=-0.74, p0.05) and cartilage volume (r=-0.74, p0.05) decreased during the 12 weeks of arthritis.In this study we demonstrated changes in 3D stereological parameters of inflammatory tissue, bone erosion, osteoclasts, and cartilage in mouse paws during the course of arthritis in the SKG mouse. This is the first time 3D quantitative histology has been applied in a mouse model of rheumatoid arthritis.

Monocyte chemoattractant protein 1 (MCP-1) level in plasma is described as a marker for joint inflammation in rheumatoid arthritis (RA).MCP-1 in plasma and synovial fluid (SF) was quantified by ELISA in 36 RA patients with synovitis of the knee at Day 1 and 30. Disease activity was assessed by the swollen joint count, Ritchie Articular Index (RAI), global assessment, pain on visual analog scale, Health Assessment Questionnaire, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP).By linear regression analysis plasma MCP-1 levels correlated significantly with the swollen joint count (Day 1: R = 0.47, p = 0.005; Day 30: R = 0.53, p0.001) and the RAI (Day 1: R = 0.37, p = 0.03; Day 30: R = 0.41, p = 0.01). The correlations of swollen joint count and RAI with ESR and CRP were significant only on Day 30 for the ESR (R = 0.40, p = 0.02). No association was found between plasma MCP-1 levels and the ESR/CRP levels. MCP-1 levels in plasma in RA patients were elevated compared to controls (p0.001) and MCP-I levels in SF were higher than in plasma (p0.001). No correlation was found between SF MCP-1 levels and in vitro migration of mononuclear cells towards SF. MCP-1 appears to participate in the disease process in RA, and plasma MCP-1 may be useful in monitoring joint inflammation.

OBJECTIVE: To evaluate the effect of methotrexate (MTX) and other disease-modifying anti-rheumatic drugs (DMARDs) alone or in combination with non-steroidal anti-inflammatory drugs (NSAIDs) on the urinary excretion of alpha-glutathione S-transferase (alpha-GST) and albumin in rheumatoid arthritis (RA) patients.METHODS: Nineteen RA patients starting treatment with MTX were followed for 1 year with measurements of urinary alpha-GST, urinary albumin, and urinary and plasma creatinine at the start of treatment, and after 16, 28, and 52 weeks. A larger group of RA patients (n = 72) undergoing long-term treatment with different DMARDs was compared with 79 healthy controls regarding urinary alpha-GST and albumin. alpha-GST was quantified by an enzyme immunoassay. Urine albumin was measured turbidimetrically.RESULTS: The urine-alpha-GST/urine-creatinine ratio and the urine-albumin/urine-creatinine ratio did not change during 52 weeks of treatment with MTX. The long-term DMARD-treated RA patients and the healthy controls were comparable with regard to the urine-alpha-GST/urine-creatinine ratio and the urine-albumin/urine-creatinine ratio. All patients had preserved renal function as assessed by plasma creatinine, and none had proteinuria using urine dipstick methods.CONCLUSION: DMARD-treated RA patients with normal serum creatinine had no detectable renal injuries assessed by the urinary excretions of alpha-GST and albumin.

Udgivelsesdato: 2008-Sep OBJECTIVE: To investigate the accumulation of methotrexate (MTX) in circulating erythrocytes and the association with pharmacokinetic variables, weekly dose, and clinical efficacy in 2 cohorts of patients with chronic active rheumatoid arthritis (RA) undergoing MTX monotherapy. METHODS: Seventy-six patients with RA were included in this open prospective study: 40 were included before initiation of MTX therapy. Laboratory analyses, intracellular MTX concentrations in erythrocytes (Ery-MTX), and clinical examinations including toxicity data were performed prospectively for 52 weeks. Plasma concentrations of MTX were measured and area under the plasma concentration versus time curve (AUC) was estimated along with other pharmacokinetic variables in a population based software model.RESULTS: Ery-MTX rose after initiation of therapy and reached a steady state after 6-8 weeks. The correlation between steady-state Ery-MTX and dose was poor (r(2) = 0.16), whereas steady-state Ery-MTX levels correlated strongly with the estimated AUC (r(2) = 0.51, log-transformed variables). Both steady-state Ery-MTX levels and estimated AUC were significantly higher in patients responding to MTX therapy than in patients classified as nonresponders according to American College of Rheumatology core criteria and were similar to patients on longterm MTX therapy. CONCLUSION: Our results indicate that clinical efficacy and Ery-MTX may have a causal relation and that measurement of Ery-MTX or estimation of AUC in a software model provides useful guidelines to the clinician when starting MTX therapy in patients with RA. The latter can be performed immediately after initiation of therapy.

Methotrexate (MTX) in low doses is widely used in the treatment of rheumatoid arthritis (RA) and it is not known whether its effects are due to immunosuppressive and/or anti-inflammatory actions. High concentrations of MTX inhibit the activity of thymidylate synthetase (TS) and dihydrofolate reductase essential for DNA synthesis. This study investigated the effects of low-dose MTX on TS activity and proliferation in human peripheral blood mononuclear cells (PBMC).The MTX concentrations in our experiments were chosen according to the plasma concentrations measured in 8 RA patients treated with MTX. The effect of MTX on TS activity and DNA synthesis were measured in stimulated normal PBMC and in PBMC obtained from 6 RA patients treated with oral MTX before and 2 hours after intake of their weekly MTX dose. The effect of MTX on the TS mRNA concentration was also investigated in order to elucidate its effect on TS production.Low-dose MTX significantly inhibited TS activity and the proliferation of stimulated PBMC independent of the mode of activation. Interestingly, the concentration of TS mRNA in normal PBMC was upregulated by the presence of MTX. Finally, there was no difference between TS activity measured before and after MTX intake in 6 RA patients on long-term MTX treatment.We show that low concentrations of MTX inhibit TS activity in vitro. An in vivo effect cannot, however, be proven given our study design. The role of these in vitro findings is discussed, particularly in relation to the in vivo effects of MTX.

To investigate the expression of the soluble form of the resident macrophage marker CD163 (sCD163) and its association with core parameters for disease activity, including radiographic progression in early rheumatoid arthritis (RA).In a longitudinal sample set from early RA patients (n=34) we measured plasma levels of sCD163 at initiation of treatment and after 9 months of treatment and correlated levels with disease activity in 28 joints (DAS28), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and total Sharp score (TSS). We also measured plasma levels of sCD163 in 55 healthy volunteers (HV) and in a transverse sample set of chronic (8 years of disease) RA patients (n=24) and OA patients (n=24) with paired plasma and joint fluid.Early RA patients had significantly higher plasma levels of sCD163 (1.69mg/l (1.42-2.10)) (median (IQR)) at baseline than after 9 months of treatment (1.28mg/l (0.963-1.66), p=0.001), but not significantly changed compared with HV (1.66mg/l (1.22-2.02)). In early RA patients, baseline levels of sCD163, correlated with DAS28, CRP and ESR. Interestingly, sCD163 at 9 months was associated with radiographic progression (TSS) between year 0 and 5 (r=0.468, p=0.02). Levels of sCD163 were higher in RA patients, than in OA patients and higher in SF than in plasma.Plasma levels of macrophage derived sCD163 are associated with disease activity and predict radiographic progression in early RA patients, supporting that sCD163 may have a role as a biomarker of disease activity and that resident macrophages are important for joint destruction.

Nine normotensive healthy females received timolol 5 mg daily for a 4-day period and subsequently 20 mg daily for another 4-day period. None of the two dosages of timolol caused significant changes in serum uric acid or 24-h urinary fractional excretion of uric acid. Thus the increments of serum uric acid previously found in hypertensive patients is not likely to be caused by beta-adrenoceptor blockade per se.