Cytokines in the pathogenesis of rheumatoid arthritis

Cytokines regulate a broad range of inflammatory processes that are implicated in the pathogenesis of rheumatoid arthritis. In rheumatoid joints, it is well known that an imbalance between pro- and anti-inflammatory cytokine activities favours the induction of autoimmunity, chronic inflammation and thereby joint damage. However, it remains less clear how cytokines are organized within a hierarchical regulatory network, and therefore which cytokines may be the best targets for clinical intervention a priori. Here, we discuss the crucial effector function of cytokines in the immunological processes that are central to the pathogenesis of rheumatoid arthritis.     

Gene therapy: trials and tribulations

The art and science of gene therapy has received much attention of late. The tragic death of 18-year-old Jesse Gelsinger, a volunteer in a Phase I clinical trial, has overshadowed the successful treatment of three children suffering from a rare but fatal immunological disease. In the light of the success and tragedy, it is timely to consider the challenges faced by gene therapy--a novel form of molecular medicine that may be poised to have an important impact on human health in the new millennium.     

Mammalian embryo co-culture: trials and tribulations of a misunderstood method

Embryo-somatic cell co-culture was devised over 40 years ago in an attempt to improve the development and viability of mammalian preimplantation embryos generated and cultured in vitro. While initial endeavours were successful in this respect, other studies soon highlighted a number of significant long-term detrimental impacts of this approach. Surprisingly little is known about the mechanisms underlying the beneficial effects of co-culture, although the production of embryotrophic compounds, modulation of nutrient profile, protection against culture-induced stress and/or toxin clearance are all contenders. The extent to which the inadvertent exposure of embryos to serum accounts for many of these effects remains open to question. Although the popularity of somatic cell co-culture has recently declined in favour of the use of sequential media due to concerns associated with its risk of disease transmission and long-term sequelae, we argue that complete dismissal of this technique is ill advised, given that our limited understanding of basic somatic cell interactions has prevented us from fully exploiting its potential. In this respect, there is some merit in focussing future research strategies based on reconstructed maternal tract tissue. Although the use of co-culture in clinical practice is unacceptable and its implementation in domestic species for commercial purposes should be viewed with diffidence, this technique can still provide a wealth of information on the development of novel, more physiological embryo in vitro culture systems. The proviso for acquiring such information is to gain a fuller understanding of the culture requirements/biochemistry of somatic cells and their interaction with the early conceptus.     

The trials and tribulations of membrane protein folding in vitro

Membrane proteins are hard to handle and consequently the purification of functional protein in milligram quantities is a major problem. One reason for this is that once integral membrane proteins are outside their native membrane, they are prone to aggregation, are unstable and are frequently only partially functional. Knowledge of membrane protein folding mechanisms in vitro can help to understand the causes of these problems and work toward strategies to disaggregate and fold proteins correctly. Kinetic and stability studies are emerging on membrane protein folding, mainly on bacterial proteins. Mutagenesis methods have also been used to probe specific structural features or bonds in proteins. In addition, manipulation of lipid properties can be used to improve the efficiency of folding as well as the stability and function of the protein.     

The trials and tribulations of membrane protein folding in vitro

Membrane proteins are hard to handle and consequently the purification of functional protein in milligram quantities is a major problem. One reason for this is that once integral membrane proteins are outside their native membrane, they are prone to aggregation, are unstable and are frequently only partially functional. Knowledge of membrane protein folding mechanisms in vitro can help to understand the causes of these problems and work toward strategies to disaggregate and fold proteins correctly. Kinetic and stability studies are emerging on membrane protein folding, mainly on bacterial proteins. Mutagenesis methods have also been used to probe specific structural features or bonds in proteins. In addition, manipulation of lipid properties can be used to improve the efficiency of folding as well as the stability and function of the protein.     

The road to regenerative liver therapies: The triumphs,trials and tribulations

The liver is one of the few organs that possess a high capacity to regenerate after liver failure or liver damage. The parenchymal cells of the liver, hepatocytes, contribute to the majority of the regeneration process. Thus, hepatocyte transplantation presents an alternative method to treating liver damage. However, shortage of hepatocytes and difficulties in maintaining primary hepatocytes still remain key obstacles that researchers must overcome before hepatocyte transplantation can be used in clinical practice. The unique properties of pluripotent stem cells (PSCs) and induced pluripotent stem cells (iPSCs) have provided an alternative approach to generating enough functional hepatocytes for cellular therapy. In this review, we will present a brief overview on the current state of hepatocyte differentiation from PSCs and iPSCs. Studies of liver regenerative processes using different cell sources (adult liver stem cells, hepatoblasts, hepatic progenitor cells, etc.) will be described in detail as well as how this knowledge can be applied towards optimizing culture conditions for the maintenance and differentiation of these cells towards hepatocytes. As the outlook of stem cell-derived therapy begins to look more plausible, researchers will need to address the challenges we must overcome in order to translate stem cell research to clinical applications.     

Association of MHC and rheumatoid arthritis: HLA polymorphisms in phenotypic variants of rheumatoid arthritis

Genes in the human leukocyte antigen (HLA) region remain the most powerful disease risk genes in rheumatoid arthritis (RA). Several allelic variants of HLA-DRB1 genes have been associated with RA, supporting a role for T-cell receptor-HLA-antigen interactions in the pathologic process. Disease-associated HLA-DRB1 alleles are similar but not identical and certain allelic variants are preferentially enriched in patient populations with defined clinical characteristics. Also, a gene dosing effect of HLA-DRB1 alleles has been suggested by the accumulation of patients with two RA-associated alleles, especially in patient subsets with a severe disease course. Therefore, polymorphisms in HLA genes are being explored as tools to dissect the clinical heterogeneity of the rheumatoid syndrome. Besides HLA polymorphisms, other risk genes will be helpful in defining genotypic profiles correlating with disease phenotypes. One such phenotype is the type of synovial lesion generated by the patient. HLA genes in conjunction with other genetic determinants may predispose patients to a certain pathway of synovial inflammation. Also, patients may or may not develop extraarticular manifestations, which are critical in determining morbidity and mortality. HLA genes, complemented by other RA risk genes, are likely involved in shaping the T-cell repertoire, including the emergence of an unusual T-cell population characterized by the potential of vascular injury, such as seen in extraarticular RA.     

Association of MHC and rheumatoid arthritis: HLA-DR4 and rheumatoid arthritis - studies in mice and men

Inherited susceptibility to rheumatoid arthritis (RA) is associated with the DRB1 genes encoding the human leukocyte antigen (HLA)-DR4 and HLA-DR1 molecules. Transgenic mice expressing these major histocompatibility complex (MHC) class II molecules have been developed to generate humanized models for RA. The relevance of these models for understanding RA will be discussed.     

Association of MHC and rheumatoid arthritis. HLA-DR4 and rheumatoid arthritis: studies in mice and men

Inherited susceptibility to rheumatoid arthritis (RA) is associated with the DRB1 genes encoding the human leukocyte antigen (HLA)-DR4 and HLA-DR1 molecules. Transgenic mice expressing these major histocompatibility complex (MHC) class II molecules have been developed to generate humanized models for RA. The relevance of these models for understanding RA will be discussed.     

A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview

Background

We sought to compare the benefits and safety of 6 biologics (abatacept, adalimumab, anakinra, etanercept, infliximab and rituximab) in patients with rheumatoid arthritis.

Methods

In this network meta-analysis, we included all completed and updated Cochrane reviews on biologics for rheumatoid arthritis. We included data from all placebo-controlled trials that used standard dosing regimens. The major outcomes were benefit (defined as a 50% improvement in patient- and physician-reported criteria of the American College of Rheumatology [ACR50]) and safety (determined by the number of withdrawals related to adverse events). We used mixed-effects logistic regression to carry out an indirect comparison of the treatment effects between biologics.

Results

Compared with placebo, biologics were associated with a clinically important higher ACR50 rate (odds ratio [OR] 3.35, 95% confidence interval [CI] 2.62–4.29) and a number needed to treat for benefit of 4 (95% CI 4–6). However, biologics were associated with more withdrawals related to adverse events (OR 1.39, 95% CI 1.13–1.71), with a number needed to treat for harm of 52 (95% CI 29–152). Anakinra was less effective than all of the other biologics, although this difference was statistically significant only for the comparison with adalimumab (OR 0.45, 95% CI 0.21–0.99) and etanercept (OR 0.34, 95% CI 0.14–0.81). Adalimumab, anakinra and infliximab were more likely than etanercept to lead to withdrawals related to adverse events (adalimumab OR 1.89, 95% CI 1.18–3.04; anakinra OR 2.05, 95% CI 1.27–3.29; and infliximab OR 2.70, 95% CI 1.43–5.26).

Interpretation

Given the limitations of indirect comparisons, anakinra was less effective than adalimumab and etanercept, and etanercept was safer than adalimumab, anakinra and infliximab. This summary of the evidence will help physicians and patients to make evidence-based choices about biologics for the treatment of rheumatoid arthritis.Rheumatoid arthritis is one of the most common types of inflammatory arthritis, affecting 0.5%–1.0% of adults in Western countries.¹ Rheumatoid arthritis is associated with joint inflammation and destruction, which leads to major decrements in health-related quality of life,² functional limitations and work disability.^3,4In the last decade, several biologics have been approved, and their use has revolutionized the treatment of rheumatoid arthritis. These biologics are targeted therapies that dramatically inhibit the progression of joint damage in rheumatoid arthritis. These include inhibitors of tumour necrosis factor⁵ (infliximab, etanercept, adalimumab, certolizumab and golimumab), anti-interleukin 1 therapy (anakinra), anti-CD28 therapy (abatacept) and anti–B-cell therapy (rituximab). Biologics are recommended for use in patients with rheumatoid arthritis who have a suboptimal response or intolerance to traditional disease-modifying antirheumatic drugs, such as methotrexate. Although biologics have typically been compared with placebo, with both groups taking the same dose of methotrexate concomitantly, there have been no large randomized controlled trials comparing the biologics to one another. One randomized controlled trial included 2 biologics but compared both only to placebo and not to each other.⁶ Because of the high cost of biologics, different routes and administration schedules and different adverse event profiles, general practitioners and rheumatologists need to know their relative benefits and safety when deciding on treatment.One previous systematic review compared the benefits and safety of biologics using data from randomized and nonrandomized controlled trials. This review combined both recommended and nonrecommended doses;⁷ it found only one difference: infliximab was superior to anakinra in achieving a 20% improvement in the American College of Rheumatology response criteria for rheumatoid arthritis (ACR20). Overviews of systematic reviews for comparing and combining different systematic reviews assessing single agents have only recently been adopted by Cochrane.⁸ In the absence of direct head-to-head comparisons, we performed an overview of the sys tematic reviews of biologics for rheumatoid arthritis using network meta-analyses of updated Cochrane systematic reviews. We sought to provide estimates of the benefits and safety of biologics to assist patients and clinicians decide between biologics in clinical practice.