Double blind placebo controlled trial of pulse treatment with methylprednisolone combined with disease modifying drugs in rheumatoid arthritis.

OBJECTIVE--To assess whether monthly treatment with intravenous methylprednisolone enhances or accelerates the effect of disease modifying drugs in patients with rheumatoid arthritis. DESIGN--A 12 month double blind, placebo controlled, multicentre trial in which patients with active rheumatoid arthritis were randomly allocated to receive pulses of either methylprednisolone or saline every four weeks for six months. At the start of the pulse treatment all patients were started on penicillamine or azathioprine. SETTING--Four rheumatology departments in Denmark. PATIENTS--97 Patients (71 women, 26 men) aged 23-84 (mean 60) who had active rheumatoid arthritis of at least four weeks'' duration despite treatment with non-steroidal anti-inflammatory drugs. MAIN OUTCOME MEASURES--Monthly clinical recording of morning stiffness, number of tender and swollen joints, blinded observers'' evaluation of therapeutic effect, and patients'' self assessed condition. Concomitant laboratory measurements of erythrocyte sedimentation rate and concentrations of C reactive protein and haemoglobin. Radiography to determine the number of erosions at the start of treatment and after 12 months. RESULTS--57 Patients completed the trial, taking the same disease modifying drug throughout. Evaluation four weeks after each pulse treatment and at 12 month follow up showed no significant differences between the methylprednisolone and placebo groups in any of the clinical or laboratory variables. Radiography showed the same degree of progression of erosions in both groups. Evaluation of the total data on 97 patients and on the 57 who completed the trial showed the same lack of significance between the treatment groups. CONCLUSIONS--Intravenous pulse treatment with steroids can be recommended only for rapid temporary relief of flares of disease in patients with rheumatoid arthritis. The response is short lived. Repeated pulses of methylprednisolone at four week intervals do not improve the results of treatment with drugs that induce remission such as penicillamine and azathioprine.     

Remission makes its way to rheumatology

Remission was a rare event, even in the most advanced rheumatology clinics, until recent times. However, in the early 1990s, it was chosen as the treatment goal and the primary outcome measure for the Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) trial, which can be considered the beginning of remission's way to rheumatology. In addition to remission in patients with rheumatoid arthritis, remission in patients with psoriatic arthritis is now being studied, although remission criteria for psoriatic arthritis have yet to be defined. Better treatment results with more active treatment strategies and availability of biologic agents motivate rheumatologists to monitor their patients as part of usual rheumatology care.     

Comparison between penicillamine and sulphasalazine in rheumatoid arthritis: Leeds-Birmingham trial.

Sulphasalazine was first formulated by Svartz in the early 1940s, specifically for use as a remission inducing drug in rheumatoid arthritis. After the publication of an unfavourable trial, however, the drug was restricted to patients with ulcerative colitis. In the late 1970s sulphasalazine was re-examined in rheumatoid arthritis and favourable results reported in "open" trials. A double blind controlled trial was therefore conducted comparing enteric coated sulphasalazine and D-penicillamine in patients with active rheumatoid arthritis. A total of 63 patients were recruited in two centres; 31 were treated with sulphasalazine and 32 received penicillamine. After 16 weeks'' treatment both drugs had produced significant improvements in clinical score, pain score measured on a visual analogue scale, grip strength, Ritchie articular index, erythrocyte sedimentation rate, and serum C reactive protein concentration. Nausea was the major side effect in the sulphasalazine treated group. No potentially dangerous effects of sulphasalazine were encountered in contrast with those seen in the penicillamine group. The results suggest that sulphasalazine is an effective and safe drug capable of producing remissions in active rheumatoid arthritis. They also lend confidence to the use of preliminary "open" trials as a means of screening for remission inducing drugs in rheumatoid arthritis.     

Are biologics more effective than classical disease-modifying antirheumatic drugs?

Major achievements have been reached in the treatment of rheumatoid arthritis during past decades due to the recognition of methotrexate as an anchor drug for treatment of rheumatoid arthritis, due to the notion of a treatment window of opportunity in patients with recent-onset rheumatoid arthritis necessitating early aggressive therapy, due to the development of biologics and due to remission as a treatment target. Most biologics have a much faster onset of action than synthetic disease-modifying anti-rheumatic drugs, but presently there is no convincing evidence that biologic drugs have a superior clinical efficacy in comparison with the synthetic drugs. Biologics are, however, accompanied by less radiological deterioration.     

Time to achieve remission determines time to be in remission

Introduction  

Though remission is currently a treatment goal in patients with rheumatoid arthritis (RA), the number of patients who achieve and sustain remission in daily practice is still small. It is suggested that early remission will be associated with sustainability of remission. The aim was to study the association between time-to-remission and sustainability of remission in a cohort of early RA patients treated according to daily practice.     

T淋巴细胞亚群、血红蛋白及血小板在类风湿关节炎患者中的表达及临床意义分析

摘要 目的：探讨T淋巴细胞亚群、血红蛋白及血小板在类风湿关节炎患者中的表达及临床意义。方法：选取我院2020年1月到2023年1月收治的100例类风湿关节炎患者作为研究对象,依照患者病情活动性进行分组,将活动期类风湿关节炎的35例患者分为活动期组,将65例缓解期类风湿关节炎患者分为缓解期组,另选取同期体检的50名健康志愿者作为对照组,对比三组患者CD3⁺、CD4⁺、CD8⁺以及CD4⁺/CD8⁺比值,并对比三组受检者血红蛋白及血小板表达水平。应用Spearman相关分析分析T淋巴细胞亚群、血红蛋白及血小板与类风湿关节炎活动程度的相关性,并应用logistic回归分析分析T淋巴细胞亚群、血红蛋白及血小板对类风湿关节炎活动期的独立预测价值。结果：三组受检者T淋巴细胞亚群表达水平对比有差异,且活动期组CD3⁺、CD4⁺、CD4⁺/CD8⁺水平较缓解期组和对照组低,CD8⁺水平较高（P＜0.05）;三组受检者血红蛋白及血小板表达水平对比差异显著,且活动期组血红蛋白水平较缓解期组和对照组低,血小板水平较高（P＜0.05）;Spearman相关分析结果显示：CD3⁺、CD4⁺、CD4⁺/CD8⁺、血红蛋白与类风湿关节炎病情活动程度呈负相关,CD8⁺、血小板与类风湿关节炎病情活动程度呈正相关（P＜0.05）;logistic回归分析结果表明：CD4⁺/CD8⁺升高、血红蛋白升高及血小板降低为类风湿关节炎活动期的独立影响因素（P＜0.05）。结论：类风湿关节炎患者在疾病活动期T淋巴细胞亚群相关细胞比例、血红蛋白及血小板表达水平会出现明显变化,且与其活动程度具有明显相关性。以CD4⁺/CD8⁺升高、血红蛋白升高及血小板降低情况可独立判定类风湿关节炎活动期,因此临床上对于上述指标升高的类风湿关节炎患者需及时改善治疗措施,改善患者预后水平。     

High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism

Recent data suggest that IL-15 plays an important role in the pathogenesis of rheumatoid arthritis. In the present study, we hypothesized that elevated in the joints of rheumatoid arthritis, but not osteoarthritis, patients, IL-15 may exert its proinflammatory properties via the induction of IL-17, a cytokine known to stimulate synoviocytes to release several mediators of inflammation including IL-6, IL-8, GM-CSF and PGE2. To test this hypothesis, we first measured the levels of IL-17 and IL-15 using specific ELISA and found that synovial fluids of patients with rheumatoid arthritis, but not with osteoarthritis, contain high levels of these cytokines. A strong correlation between IL-15 and IL-17 levels in synovial fluids was observed. Among tested factors, LPS and TNF-alpha failed, IL-15 and IL-2 were equipotent, and PMA + ionomycin was far more efficient in the induction of IL-17 secretion by PBMCs isolated from healthy blood donors. Interestingly, synovial fluid cells, in contrast to PBMCs isolated from patients with rheumatoid arthritis, but not osteoarthritis, respond to PMA + ionomycin with much lower, comparable to IL-15-triggered IL-17 secretion. Moreover, PMA + ionomycin-triggered IL-17 secretion is completely or partially blocked in the presence of low doses of cyclosporin A or high doses of methylprednisolone, respectively. IL-15-triggered IL-17 secretion by PBMCs was completely inhibited by these drugs. Thus, our results suggest for the first time that IL-15 may represent a physiological trigger that via cyclosporin A and steroid sensitive pathways leads to the overproduction of IL-17 in the joints of rheumatoid arthritis patients.     

Red cell ferritin content: a re-evaluation of indices for iron deficiency in the anaemia of rheumatoid arthritis.

In iron deficiency anaemia basic red cell content of ferritin is appreciably reduced. This variable was determined in 62 patients with rheumatoid arthritis to evaluate conventional laboratory indices for iron deficiency in the anaemia of rheumatoid arthritis. For 23 patients with rheumatoid arthritis and normocytic anaemia irrespective of plasma ferritin concentration, red cell ferritin content did not differ significantly from that for non-anaemic patients with rheumatoid arthritis. For 27 patients with rheumatoid arthritis and microcytic anaemia, the mean red cell ferritin content for patients with a plasma ferritin concentration in the 13-110 micrograms/l range was appreciably reduced. It was indistinguishable from that for patients with rheumatoid arthritis and classical iron deficiency anaemia, indicated by plasma ferritin concentrations of less than 12 micrograms/l. In contrast, the mean red cell ferritin content for patients with rheumatoid arthritis, microcytic anaemia, and plasma ferritin concentrations above 110 micrograms/l did not differ from that for patients with rheumatoid arthritis and normocytic anaemia. Oral treatment with iron in patients with rheumatoid arthritis, microcytic anaemia, and appreciably reduced red cell ferritin concentrations was accompanied by significant increases in haemoglobin concentration (p less than 0.01), mean corpuscular volume (p less than 0.01), and red cell ferritin contents (p less than 0.05). This treatment, however, did not produce any appreciable change in haemoglobin concentration in patients with rheumatoid arthritis, normocytic anaemia, and normal red cell ferritin contents. These findings suggest that the indices for iron deficiency in patients with rheumatoid arthritis and anaemia should include peripheral blood microcytosis together with a plasma ferritin concentration of less than 110 micrograms/l.     

PEDF 在类风湿关节炎滑膜组织中的表达及临床意义

目的:研究类风湿关节炎患者滑膜组织中色素上皮衍生因子(Piment epithelial-derived factor,PEDF)的表达情况。方法:采用免疫组化法,检测30例类风湿关节炎活动期膝关节滑膜组织中PEDF蛋白表达,以16例退行性关节炎患者、16例正常人及该30例患者治疗后(稳定期)关节滑膜组织中PEDF蛋白作对照,进行对比分析。结果:PEDF在类风湿关节炎患者明显低于正常人、退行性关节炎患者滑膜组织中的表达,在活动期滑膜组织中的表达明显低于稳定期,组间比较,差异均有统计学意义(P均<0.05)。结论:PEDF与类风湿关节炎的疾病过程密切相关,针对色素上皮衍生因子的靶点治疗有望成为类风湿关节炎治疗的新的方向及策略。     

Myasthenia gravis associated with penicillamine treatment for rheumatoid arthritis.

Four patients with rheumatoid arthritis (R.A.) developed myasthenia gravis after taking penicillamine. In one patient withdrawal of the drug was followed by spontaneous remission of the myasthenia, and in two the dose of anticholinesterase was subsequently reduced. In the fourth patient continuing penicillamine treatment was associated with increasingly severe myasthenic features, but on withdrawal of the drug these resolved. As myasthenia gravis rarely complicates R.A. its onset in these patients shortly after the start of penicillamine treatment suggested that penicillamine may have precipitated this condition.     

Baseline Serum Osteopontin Levels Predict the Clinical Effectiveness of Tocilizumab but Not Infliximab in Biologic-Na?ve Patients with Rheumatoid Arthritis: A Single-Center Prospective Study at 1 Year (the Keio First-Bio Cohort Study)

ObjectiveTo explore the baseline predictors of clinical effectiveness after tocilizumab or infliximab treatment in biologic-naïve rheumatoid arthritis patients.MethodsConsecutive biologic-naïve patients with rheumatoid arthritis initiating infliximab (n = 57) or tocilizumab (n = 70) treatment were included in our prospective cohort study. Our cohort started in February 2010, and the patients observed for at least 1 year as of April 2013 were analysed. We assessed baseline variables including patients'' characteristics (age, sex, disease duration, prednisolone dose, methotrexate dose, other disease-modifying antirheumatic drug use, Clinical Disease Activity Index [CDAI]) and serum biomarker levels (C-reactive protein, immunoglobulin M-rheumatoid factor, anti-cyclic citrullinated protein/peptide antibodies, interferon-γ, interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, IL-17, tumor necrosis factor-α, soluble intercellular adhesion molecule-1, bone alkaline phosphatase, osteonectin, osteopontin) to extract factors associated with clinical remission (CDAI≤2.8) at 1 year using univariate analyses, and the extracted factors were entered into a multivariate logistic regression model. Similar analyses were also performed for Simplified Disease Activity Index (SDAI) remission (≤3.3) and Disease Activity Score with 28 joint counts, erythrocyte sedimentation rate (DAS28-ESR) remission (<2.6).ResultsThere were no significant differences in the baseline characteristics except for methotrexate use between the groups. In the multivariate analyses, the low baseline osteopontin levels (OR 0.9145, 95% CI 0.8399–0.9857) were identified as predictors of CDAI remission in the tocilizumab group, whereas no predictors of CDAI remission were found in the infliximab group. Similar results were obtained when using SDAI and DAS28-ESR remission criteria.ConclusionBaseline low serum osteopontin levels predict clinical remission 1 year after tocilizumab treatment and not infliximab treatment in biologic-naïve patients with rheumatoid arthritis. Our prediction model provided insights into how to optimize the choice of biologics and warrants external validation in other cohorts.     

Risk factors for bone loss in patients with rheumatoid arthritis treated with biologic disease-modifying anti-rheumatic drugs

Objective

Osteoporosis is a complication of rheumatoid arthritis. We examined the risk factors for bone loss in rheumatoid arthritis patients receiving biological disease-modifying anti-rheumatic drugs. Lumbar spine and femoral neck bone mineral density was measured at two time points in 153 patients with rheumatoid arthritis managed with biological disease-modifying anti-rheumatic drugs. We examined patients’ variables to identify risk factors for least significant reduction of bone mineral density.

Results

Least significant reduction of lumbar spine bone mineral density (≤ ? 2.4%) was seen in 13.1% of patients. Least significant reduction of femoral neck bone mineral density (≤ ? 1.9%) was seen in 34.0% of patients. Multiple logistic regression analysis showed that a risk factor for least significant reduction of the lumbar spine was high-dose methylprednisolone use. Multiple regression analysis showed that a risk factor for least significant reduction of the femoral neck was short disease duration. Our findings showed that a risk factor for femoral neck bone mineral density reduction was a short disease duration. These findings suggest that rheumatoid arthritis patients receiving treatment with biological disease-modifying anti-rheumatic drugs may benefit from earlier osteoporosis treatments to prevent femoral neck bone loss.

     

5-Methylcytosine content of DNA in blood, synovial mononuclear cells and synovial tissue from patients affected by autoimmune rheumatic diseases

The percentage of 5-methylcytosine (m⁵Cyt) has been determined in peripheral blood, synovial mononuclear cells and synovial tissue from patients affected by various rheumatic autoimmune diseases. The determination was performed by reversed-phase high-performance liquid chromatography. Fifteen controls were compared to twenty-one patients affected by rheumatoid arthritis and to nine patients affected by systemic lupus erythematosus. The mean percentage of m⁵Cyt in normal individuals was significantly higher than in the rheumatoid arthritis and systemic lupus erythematosus patients. In addition, patients with active disease showed lower values than patients in remission. This finding is in agreement with the hypothesis that DNA hypomethylation may play a role in the pathogenesis of the autoimmune diseases, resulting in altered oncogen expression. Therapy with cyclosporin A led to a decrease in the percentage of m⁵Cyt in three rheumatoid arthritis patients, but a rebound was observed when the cyclosporin A was suspended. The percentage of m⁵Cyt in the DNA of synovial tissue from four rheumatoid arthritis patients and five patients with osteoarthritis was similar; this observation confirms that, in addition to disease-specific and disease activity-specific variations, the percentage of m⁵Cyt may also show tissue-specific variations.     

Aspects of early arthritis. Definition of disease states in early arthritis: remission versus minimal disease activity

With regard to rheumatoid arthritis, remission as currently used in the literature can have two meanings: either a state with persistent absence of clinical and radiological signs of disease activity without being treated for a specific time period, or it may point to a disease state with minimal disease activity during antirheumatic treatment. A risk factor for the first is absence of autoantibodies, with the anti-CCP-antibodies as best predictors, whereas risk factors for achieving a drug-induced state of minimal disease activity are not well defined. These definitions of remission refer to different disease states; therefore, we propose that the term remission is reserved for patients that are not treated with antirheumatic drugs.     

The LE cell: crime scene or crime stopper?

Remission is key to prevent progression of rheumatoid arthritis, but it is still rarely seen in clinical practice, not to speak of sustained remission, which is the best possible disease outcome of rheumatoid arthritis. New strategies and recommendations focus on achievement of remission, but it is unclear how long remission can actually be maintained in clinical practice. A study by Prince and colleagues gives insights into this question, and raises some other questions for the future.     

Changes in Soluble CD18 in Murine Autoimmune Arthritis and Rheumatoid Arthritis Reflect Disease Establishment and Treatment Response

Introduction

In rheumatoid arthritis (RA) immune activation and presence of autoantibodies may precede clinical onset of disease, and joint destruction can progress despite remission. However, the underlying temporal changes of such immune system abnormalities in the inflammatory response during treat-to-target strategies remain poorly understood. We have previously reported low levels of the soluble form of CD18 (sCD18) in plasma from patients with chronic RA and spondyloarthritis. Here, we study the changes of sCD18 before and during treatment of early RA and following arthritis induction in murine models of rheumatoid arthritis.

Methods

The level of sCD18 was analyzed with a time-resolved immunoflourometric assay in 1) plasma from early treatment naïve RA patients during a treat-to-target strategy (the OPERA cohort), 2) plasma from chronic RA patients, 3) serum from SKG and CIA mice following arthritis induction, and 4) supernatants from synovial fluid mononuclear cells (SFMCs) and peripheral blood mononuclear cells (PBMCs) from 6 RA patients cultured with TNFα or adalimumab.

Results

Plasma levels of sCD18 were decreased in chronic RA patients compared with early RA patients and in early RA patients compared with healthy controls. After 12 months of treatment the levels in early RA patients were similar to healthy controls. This normalization of plasma sCD18 levels was more pronounced in patients with very early disease who achieved an early ACR response. Plasma sCD18 levels were associated with radiographic progression. Correspondingly, the serum level of sCD18 was decreased in SKG mice 6 weeks after arthritis induction compared with healthy littermates. The sCD18 levels in both SKG and CIA mice exhibited a biphasic course after arthritis induction with an initial increase above baseline followed by a decline. Shedding of CD18 from RA SFMC and RA PBMC cultures was increased by TNFα and decreased by adalimumab.

Conclusions

The plasma sCD18 levels were altered in patients with RA, in mice with autoimmune arthritis and in cell cultures treated with TNFα and adalimumab. Decreased levels of plasma sCD18 could reflect autoimmunity in transition from early to chronic disease and normalization in response to treatment could reflect autoimmunity in remission.     

Health-related quality of life and functional ability in patients with early arthritis during remission steered treatment: results of the IMPROVED study

Introduction

The aim of this study was to investigate patient reported outcomes (PROs) of functional ability and health related quality of life (HRQoL) in patients with early (rheumatoid) arthritis during one year of remission steered treatment.

Methods

In this study, 610 patients with early rheumatoid arthritis (RA) or undifferentiated arthritis (UA) were treated with methotrexate (MTX) and tapered high dose of prednisone. Patients in early remission (Disease Activity Score (DAS) <1.6 after 4 months) tapered prednisone to zero and when in persistent remission, also tapered MTX. Patients not in early remission were randomized to either MTX + hydroxychloroquine + sulphasalazine + prednisone (arm 1) or to MTX + adalimumab (arm 2). Every 4 months, patients filled out the Health Assessment Questionnaire (HAQ) and the McMaster Toronto Arthritis Patient Preference Questionnaire (MACTAR), the Short Form 36 (SF-36) and visual analogue scales (VAS). Change scores were compared between treatment groups. The association with achieving remission was analyzed using linear mixed models.

Results

During year 1, patients who achieved early remission had the most improvement in PROs with scores comparable to the general population. Patients in the randomization arms showed less improvement. Scores were comparable between the arms. There was a significant association between achieving remission and scores of HAQ, MACTAR and physical HRQoL.

Conclusions

In early arthritis, PROs of functional ability and HRQoL after one year of remission steered treatment reach normal values in patients who achieved early remission. In patients not in early remission, who were randomized to two strategy arms, PROs improved less, with similar scores in both treatment arms.

Trial registrations

ISRCTN11916566 and EudraCT2006-006186-16     

Forefoot disease activity in rheumatoid arthritis patients in remission: results of a cohort study

Introduction  

The aim of our study was to investigate the presence of disease activity in the metatarsophalangeal (MTP) joints of the forefoot in rheumatoid arthritis (RA) patients in remission according to the Disease Activity Score based on 28 joints (DAS28) remission criterion.     

Expression of TNFα membrane-bound receptors in the peripheral blood mononuclear cells (PMBC) in rheumatoid arthritis patients

ObjectiveTo investigate the expression of TNFα membrane-bound receptors: the percentage of cells expressing these receptors and the number of molecules expressed on different immune cell subsets, and to evaluate serum concentrations of soluble TNFα and its receptors (sTNFRI and sTNFRII) in patients with rheumatoid arthritis in acute stage and after response to treatment compared to healthy donors.MethodsThe objects of the study are peripheral blood mononuclear cells (PBMC) of healthy donors (n = 150) and RA patients (n = 40) subjected to hospital treatment with either biological agents (Rituximab) or glucocorticosteroids (methylprednisolone). To determine PBMC phenotype antibodies anti-hCD3-APC, anti-hCD19 PECy7, anti-hCD14 FITC (eBioscience), as well as anti-hTNFRI-PE and anti-hTNFRII-PE (R&D Systems) were used. To determine receptor number on the cells Quantibrite PE Beads (BD) were used.ResultsCells obtained from patients who responded to therapy and achieved disease remission exhibited either an increase in the percentage of TNFRI+ cells or elevated expression density of this receptor type.ConclusionSubsets of immunocompetent cells from RA patients show variation in the percentage of membrane-bound receptor positive cells and receptor expression density, which influences the development and progression of the pathological processes in RA. Response to therapy and achievement of disease remission are associated with an increase of TNFRI expression.