How Does Leflunomide Modulate the Immune Response in Rheumatoid Arthritis?

Leflunomide has recently been approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis. This approval was based on data from double-blind multicentre trials in the US (US 301; leflunomide versus methotrexate versus placebo) and multicentre European trials (leflunomide versus sulfasalazine versus placebo, and leflunomide versus methotrexate versus placebo). In these trials, leflunomide was superior to placebo and similar to methotrexate or sulfasalazine in efficacy and adverse effects. Both methotrexate and leflunomide retarded the rate of radiological progression, entitling them to qualify as disease-modifying agents (DMARDs). Leflunomide is an immunomodulatory drug that may exert its effects by inhibiting the mitochondrial enzyme dihydro-orotate dehydrogenase (DHO-DH), which plays a key role in the de novo synthesis of the pyrimidine ribonucleotide uridine monophosphate (rUMP). The inhibition of human DHO-DH by A77-1726, the active metabolite of leflunomide, occurs at concentrations (approximately 600 nmol/L) that are achieved during treatment of rheumatoid arthritis. We propose that leflunomide prevents the expansion of activated and autoimmune lymphocytes by interfering with cell cycle progression. This is mediated by inadequate production of rUMP and utilises mechanisms involving the sensor protein p53. The relative lack of toxicity of A77-1726 on nonlymphoid cells may be due to the ability of these cells to fulfil their ribonucleotide requirements by use of the salvage pyrimidine pathway, which makes them less dependent on de novo synthesis.     

Tumour Necrosis Factor-α Blockers in Rheumatoid Arthritis

Tumour necrosis factor (TNF)-α has been found to play a central role in the pathogenesis of rheumatoid arthritis, leading to development of novel drug therapies that neutralise the deleterious effects of this cytokine. This new concept of immunobiological treatment of rheumatoid arthritis has yielded successful results. Although the 2 currently available TNFα blockers, infliximab and etanercept, differ in structure, mechanism of action and pharmacokinetics, they have provided similar benefits both in clinical improvement and in slowing and even arresting the progression of radiographic damage. This therapeutic response seems to be unequalled by ‘conventional’ treatments in rheumatoid arthritis, and is incontestably a turning point in the therapeutic management of this disease.     

Circulating VEGF As a Biological Marker in Patients with Rheumatoid Arthritis? Preanalytical and Biological Variability in Healthy Persons and in Patients

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°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.     

LASSBio-596: a New Pre-clinical Candidate for Rheumatoid Arthritis?

Inflammation - Pain and inflammatory disorders are significant health problems because of prevalence and associated disabilities. In this context, LASSBio-596 is a hybrid compound able to modulate...     

Is there an Inflammation Role for MYD88 in Rheumatoid Arthritis?

Inflammation - Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease with strong genetic influence, especially upon immune response components. Several cytokines from the toll-like...     

Do Cognitive Processes Predict Mental Health in Individuals with Rheumatoid Arthritis?

The purpose of the present study was to assess the hypothesis that intellectual functioning affects the mental health of individuals with rheumatoid arthritis. Structural equation modeling techniques were used to assess the relative contributions of age, education, intellectual functioning, self-efficacy, and pain to mental health. It was hypothesized that individuals with rheumatoid arthritis who had higher intellectual functioning and higher self-efficacy would report better mental health than those with lower intellectual functioning and self-efficacy. One hundred twenty-one adults aged 34 to 84 with rheumatoid arthritis completed a battery of cognitive tasks, and multiple measures of self-efficacy, pain, and mental health, twice in 1 month. The data provided a good fit to the hypothesized model. Intellectual functioning was directly related to mental health and, also, indirectly related to mental health through self-efficacy and pain. Older individuals who performed poorly on cognitive tasks reported less self-efficacy, more pain, and poorer mental health than those individuals who performed well on cognitive tasks.     

Could Hormones Make a Difference in the Treatment of Juvenile Rheumatoid Arthritis?

Adrenal androgens dehydroepiandrosterone (DHEA; prasterone) and its sulphated form (DHEA-S) are among the most abundant hormonal steroids in men and nonpregnant women. Deficiencies of these adrenal androgens are associated with autoimmune disorders such as rheumatoid arthritis (RA). Recent studies from our laboratory have also identified low levels of adrenal androgens in the serum and synovial fluid of patients with juvenile rheumatoid arthritis (JRA). These findings support and complement those already published for RA and other autoimmune diseases. Because of the paucity of data on the hormonal status of patients with JRA, studies on the relationship between hypoandrogenicity and predisposition to develop JRA, and/or disease progression have not been conducted. In addition, despite the rapid expansion of research in the clinical use of these adrenal androgens in hyperlipidaemia, atherosclerosis, obesity, diabetes mellitus, insulin resistance and hypertension, their potential beneficial effects in JRA/RA have not been fully investigated. In fact, clinical trials of adrenal androgens in RA have only been conducted for the treatment of systemic lupus erythematosus. Further studies using prospective approaches are necessary to provide a unified consensus on the hormonal status of patients with JRA (as well as those with RA). This overview of our knowledge of the putative role(s) of hormones in arthritis will hopefully stimulate researchers in basic science and rheumatologists to synergistically collaborate in the effective translation of such knowledge to new clinical approaches.     

Protein catabolism in chronic uremia: is it due to malnutrition?

The high prevalence of anthropometric measurements and laboratory values that are similar to those in patients with protein-energy malnutrition has lead to the classification of a large number of dialysis patients as being malnourished. However, malnutrition in the strict sense implies that abnormalities will be reversed if more food is eaten. There is virtually no evidence, however, that simply providing more nutrients in the diet of dialysis patients will reverse the abnormalities attributed to malnutrition. This suggests that the diagnosis of malnutrition is a misdiagnosis. In this review, we discuss mechanisms that will cause the loss of protein stores, including albumin, other plasma proteins, and muscle mass in dialysis patients. We will also review the shortcomings of techniques that are used to measure the nutritional status of these patients.     

Two-partner secretion: as simple as it sounds?

The two-partner secretion (TPS) pathway is a branch of type V secretion. TPS systems are dedicated to the secretion across the outer membrane of long proteins that form extended β-helices. They are composed of a ‘TpsA’ cargo protein and a ‘TpsB’ transporter, which belongs to the Omp85 superfamily. This basic design can be supplemented by additional components in some TPS systems. X-ray structures are available for the conserved TPS domain of several TpsA proteins and for one TpsB transporter. However, the molecular mechanisms of two-partner secretion remain to be deciphered, and in particular, the specific role(s) of the TPS domain and the conformational dynamics of the TpsB transporter. Deciphering the TPS pathway may reveal functional features of other transporters of the Omp85 superfamily.     

Changes in Proliferation Kinetics of T Cells: A New Predictive Cellular Biomarkers for Early Rheumatoid Arthritis?

Objective

It has been demonstrated that early treatment of rheumatoid arthritis (RA) patients prevents further joint damage and disability, but biomarkers enabling early RA to be distinguished within the undifferentiated arthritis (UA) cohort are still being sought.

Purpose

The aim of the research was to study the pathomechanism of initiation and progression of UA→RA and to find such new predictive biomarkers on the basis of functional studies of the immune system.

Methods

55 patients with UA were enrolled into the study and followed up for 2?years. The dynamic parameters of proliferation of the peripheral blood CD4+ T cells were recorded at the UA stage. During the follow-up study, standard diagnostic procedures were performed to make the final diagnosis. Comparison of the CD4+ T cell proliferation parameters in the UA-RA and UA-non-RA patients was conducted after the final diagnosis was established.

Results

Our studies showed that the G0-G1 transition time, the cell cycle duration, the number of cell divisions per dividing CD4+ cells and the percentage of dividing CD4+ T cells differed significantly between UA-RA and UA-non-RA patients. Moreover, these proliferation parameters achieved higher specificity and sensitivity in the detection of early RA within UA patients compared to the routine serological tests available.

Conclusion

The proliferation parameters of CD4+ T cells reflect central pathophysiological changes in RA and can be used as new biomarkers for early RA diagnosis, which would enable the international rheumatology recommendation to be achieved concerning the early diagnosis and treatment of RA patients.     

Are There Differences in Methotrexate Kinetics Between Responding and Nonresponding Patients with Rheumatoid Arthritis?

Objective and Study Design

The purpose of this study was to investigate the presence of a correlation between methotrexate pharmacokinetics and clinical efficacy in patients with rheumatoid arthritis.

Patients and Methods

The study was carried out in 29 patients with rheumatoid arthritis. The patients received intramuscular methotrexate (MTX) 7.5mg once a week for 8 weeks. Before and 0.5, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the first administration, MTX serum concentrations were measured and pharmacokinetic investigations were carried out. The clinical status of the disease was evaluated before and after 8 weeks of therapy. In addition, before and after 2 and 8 weeks of treatment, the patients were monitored for a complete biochemical profile. After 8 weeks of treatment, on the basis of improvement in clinical parameters, the patients were designated responders or nonresponders.

Results

A clinical response was obtained in 62% of patients (18 patients responded and 11 did not) and was associated with a low incidence of adverse effects. There were no differences in the pharmacokinetic parameters of MTX between the 2 groups of patients (responders vs nonresponders), except that t_max was significantly higher in nonresponders than in responders (p < 0.05).

Conclusions

These data confirm the efficacy and tolerability of low dose MTX in patients with rheumatoid arthritis in the short term, but appear to exclude a relationship between MTX kinetics and clinical response.     

Does Hemopoietic Stem Cell Transplantation Have a Role in Treatment of Severe Rheumatoid Arthritis?

Based on animal models and limited clinical experience, there is considerable interest in use of high-dose immunosuppression followed by hemopoietic stem cell transplantation as treatment for severe rheumatoid arthritis. Because of its relatively low treatment-related mortality and morbidity, autologous transplantation is a more attractive option than allogeneic transplantation for initial clinical trials, even though anecdotal reports suggest that allogeneic transplantation has a greater likelihood of bringing about long-term disease control. The approach remains experimental with many unanswered questions such as the value and safety of high-dose therapy without transplantation, the need for T cell purging, the possible deleterious effects of post-transplant hemopoietic growth factors and the potential of mini allogeneic transplantation (a process whereby intense immunosuppression is combined with less intense myelosuppression). To achieve quick progress it is essential that clinical trials be carefully designed with all cases being reported to the Autoimmune Disease Stem Cell Project Database.     

Effects of α-Glucosylhesperidin,a Bioactive Food Material,on Collagen-Induced Arthritis in Mice and Rheumatoid Arthritis in Humans

Hesperidin (Hsp) is an abundant flavonoid in citrus fruits, and the oral administration of Hsp has been recently reported to suppress collagen-induced arthritis in mice. Therefore, we sought to determine whether α-glucosylhesperidin (Hsp-G), which is an Hsp derivative with enhanced water-solubility, is effective on treating arthritis in both mice and humans. Hsp-G was orally administered to mice with collagen-induced arthritis, and its effects were evaluated clinically and histologically. Oral administration of Hsp-G improved collagen-induced arthritis when administered before the onset of arthritis as well as when administered after its onset. A decrease in tumor necrosis factor-α production was found to cause this improvement. In the human study, 19 patients with rheumatoid arthritis (RA) were enrolled in a 12-week double-blind, placebo-controlled trial. Patients were administered beverages containing 3 g Hsp-G (n?=?9) or placebo (n?=?10) every morning for the duration of the 3-month trial. Additionally, patients received standard therapy from a physician every 4 weeks. As a result, 3 of 9 patients in the Hsp-G group improved, while only 1 of 10 patients in the placebo group improved; this was in accordance with the American College of Rheumatology criteria. The present study revealed that the food material Hsp-G was effective when administered with standard anti-rheumatoid therapy in ameliorating RA in mice and humans without any adverse effects and may improve the quality of life for patients with RA as a complementary/alternative medicine.     

Does cyclosporine act in vivo as it does in vitro?

Cyclosporine aborts the activation of lymphocytes in vitro before DNA synthesis begins, yet there is also compelling evidence that lymphocytes can become primed, i.e. presumably proliferate in vivo, under the cover of immunosuppressive levels of the drug. Here, Gerry Klaus and Patricia Chisholm discuss the possibility that cyclosporine has a different mode of action in vivo and in vitro.     

Serum Uric Acid as a Diagnostic Biomarker for Rheumatoid Arthritis–Associated Interstitial Lung Disease

Inflammation - Previous studies have suggested a correlation between uric acid (UA) and lung lesion in some diseases. However, it remains unknown whether UA contributes to the lung injury in...     

Rheumatoid arthritis: what is refractory disease and how to manage it?

Despite the enthusiastic progresses in the field of rheumatoid arthritis pharmacotherapy the presence of prognostic factors associated with an unfavorable outcome and the inappropriate and/or delayed initiation of DMARDs can diminish the likelihood of achieving remission and increase the probability of refractoriness to treatment. During the last decade we have experience exciting developments regarding the approval of new treatment options but few patients are reaching sustained remission and refractory patients continue to be a problem. Thus, it is critical to understand how clinicians can decrease the risk of refractoriness by close monitoring disease activity, using well defined and accepted composite measures, and by early and optimized use of DMARDs, including biologics. The goal of this review paper is to offer an evidence based roadmap to prevent and to deal with refractory RA.     

Understanding the Regulatory Roles of Natural Killer T Cells in Rheumatoid Arthritis: T Helper Cell Differentiation Dependent or Independent?

Rheumatoid arthritis (RA) is the most common chronic systemic autoimmune disease. This disease is thought to be caused by pathogenic T cells. Th1, Th2, Th17 and Treg cells have been implicated in the pathogenesis of RA. These Th cells differentiate from CD4+ T cells primarily due to the effects of cytokines. Natural killer T (NKT) cells are a distinct subset of lymphocytes that can rapidly secrete massive amount of cytokines, including IL‐2, IL‐4, IL‐12 and IFN‐γ. Numerous studies showed that NKT cells can influence the differentiation of CD4+ T cells via cytokines in vitro. These findings suggest that NKT cells play an important role in RA by polarizing Th1, Th2, Th17 and Treg cells. In view of the complexity of RA, we discussed whether NKT cells really influence the development of RA through regulating the differentiation of Th cells.