The effect of motor control exercise versus placebo in patients with chronic low back pain

Background: While one in ten Australians suffer from chronic low back pain this condition remains extremely difficult to treat. Many contemporary treatments are of unknown value. One potentially useful therapy is the use of motor control exercise. This therapy has a biologically plausible effect, is readily available in primary care and it is of modest cost. However, to date, the efficacy of motor control exercise has not been established. Methods: This paper describes the protocol for a clinical trial comparing the effects of motor control exercise versus placebo in the treatment of chronic non-specific low back pain. One hundred and fifty-four participants will be randomly allocated to receive an 8-week program of motor control exercise or placebo (detuned short wave and detuned ultrasound). Measures of outcomes will be obtained at follow-up appointments at 2, 6 and 12 months after randomisation. The primary outcomes are: pain, global perceived effect and patient-generated measure of disability at 2 months and recurrence at 12 months. Discussion: This trial will be the first placebo-controlled trial of motor control exercise. The results will inform best practice for treating chronic low back pain and prevent its occurrence.

Generation and maturation of dendritic cells for clinical application under serum-free conditions

Monocyte-derived dendritic cells (MoDCs) in clinical use for cancer immunotherapy are ideally generated in serum-free medium (SFM) with inclusion of a suitable maturation factor toward the end of the incubation period. Three good manfacturing practice (GMP) grade SFMs (AIM-V, X-VIVO 15, and X-VIVO 20) were compared with RPMI-1640, supplemented with 10% fetal bovine serum or 10% human serum. DCs generated for 7 days in SFM were less mature and secreted less interleukin (IL) 12p70 and IL-10 than DCs generated in 10% serum. DC yield was comparable in SFMs, and a greater proportion of cells was viable after maturation. Toll-like receptor (TLR) ligands were compared for their ability to induce cytokine secretion under serum-free conditions in the presence of interferon (IFN) gamma. With the exception of Poly I:C, TLR ligands stimulated high levels of IL-10 secretion. High levels of IL-12p70 were induced by two TLR4-mediated stimuli, lipopolysaccharide and Ribomunyl, a clinical-grade bacterial extract. When T-cell responses were compared in allogeneic mixed leukocyte reaction, DCs stimulated with Ribomunyl induced higher levels of IFN gamma than DCs stimulated with the cytokine cocktail: tumor necrosis factor-alpha, IL-1 beta, IL-6, and prostaglandin E-2. In the presence of IL-10 neutralizing antibodies, DC IL-12p70 production and T-cell IFN gamma were increased in vitro. Similarly, DCs stimulated with Ribomunyl, IFN gamma, and anti-IL-10 induced high levels of tetanus toxoid-specific T-cell proliferation and IFN gamma secretion. Thus, MoDCs generated ill SFM efficiently stimulate T-cell IFN gamma production after maturation in the presence of a clinical-grade TLR4 agonist and IL-10 neutralization.

Cytokine expanded myeloid precursors function as regulatory antigen-presenting cells and promote tolerance through IL-10-producing regulatory T cells

The initiation of graft-vs-host disease (GVHD) after stem cell transplantation is dependent on direct Ag presentation by host APCs, whereas the effect of donor APC populations is unclear. We studied the role of indirect Ag presentation in allogenic T cell responses by adding populations of cytokine-expanded donor APC to hemopoietic grafts that would otherwise induce lethal GVHD. Progenipoietin-1 (a synthetic G-CSF/Flt-3 ligand molecule) and G-CSF expanded myeloid dendritic cells (DC), plasmacytoid DC, and a novel granulocyte-monocyte precursor population (GM) that differentiate into class II+,CD80/CD86(+),CD40(-) APC during GVHD. Whereas addition of plasmacytoid and myeloid donor DC augmented GVHD, GM cells promoted transplant tolerance by MHC class II-restricted generation of IL-10-secreting, Ag-specific regulatory T cells. Importantly, although GM cells abrogated GVHD, graft-vs-leukemia effects were preserved. Thus, a population of cytokine-expanded GM precursors function as regulatory APCs, suggesting that G-CSF derivatives may have application in disorders characterized by a loss of self-tolerance.

Patient self-efficacy and health locus of control: relationships with health status and arthritis-related expenditure

Objective. To explore the relationship between measures of self-efficacy, health locus of control, health status and direct medical expenditure among community-dwelling subjects with rheumatoid arthritis (RA) and osteoarthritis (OA). Methods. This analysis is part of a larger ongoing study of the costs and outcomes of arthritis and its treatments. Community-dwelling RA and OA respondents completed questionnaires concerning arthritis-related expenditure, health status, arthritis related self-efficacy and health locus of control. Results. Data were obtained from 70 RA respondents and 223 OA respondents. The majority of respondents were female with a mean age of 63 yr for RA respondents and 68 yr for OA respondents. Among the RA respondents, those with higher self-efficacy reported better health status and lower overall costs. Health locus of control was not consistently correlated with health status. OA respondents with higher self-efficacy reported better health status and lower costs. Health locus of control had more influence. OA respondents with higher external locus of control reported worse pain and function. A higher belief in chance as a determinant of health was correlated with more visits to general practitioners and a higher cost to both the respondent and the health system. Conclusion. Higher self-efficacy, which is amenable to change through education programmes, was associated with better health status and lower costs to the respondent and the health system in this cross-sectional study. Locus of control had less of an influence; however, the tendency was for those with higher external locus of control to have higher costs and worse health status. As the measurement of these constructs is simple and the outcome potentially affects health status, these results have implications for future intervention studies to improve quality of life and reduce the financial impact of arthritis on both the health-care system and patients.

Evidence-based medicine is affordable: The cost-effectiveness of current compared with optimal treatment in rheumatoid and osteoarthritis

Objective. To determine the cost-effectiveness of averting the burden of disease. We used secondary population data and metaanalyses of various government-funded services and interventions to investigate the costs and benefits of various levels of treatment for rheumatoid arthritis (RA) and osteoarthritis (OA) in adults using a burden of disease framework. Method. Population burden was calculated for both diseases in the absence of any treatment as years lived with disability (YLD), ignoring the years of life lost. We then estimated the proportion of burden averted with current interventions, the proportion that could be averted with optimally implemented cut-rent evidence-based guidelines, and the direct treatment cost-effectiveness ratio in dollars per YLD averted for both treatment levels. Results. The majority of people with arthritis sought medical treatment. Current treatment for RA averted 26% of the burden, with a cost-effectiveness ratio of $19,000 per YLD averted. Optimal, evidence-based treatment would avert 48% of the burden. with a cost-effectiveness ratio of $12,000 per YLD averted. Current treatment of OA in Australia averted 27% of the burden, with a cost-effectiveness ratio of $25,000 per YLD averted. Optimal, evidence-based treatment would avert 39% of the burden, with an unchanged cost-effectiveness ratio of $25,000 per YLD averted. Conclusion. While the precise dollar costs in each country will differ, the relativities at this level of coverage should remain the same. There is no evidence that closing the gap between evidence and practice would result in a drop in efficiency.

Early combination disease modifying antirheumatic drug treatment for rheumatoid arthritis

Most people presenting with rheumatoid arthritis today can expect to achieve disease suppression, can avoid or substantially delay joint damage and deformities, and can maintain a good quality of life. Optimal management requires early diagnosis and treatment, usually with combinations of conventional disease modifying antirheumatic drugs (DMARDs). If these do not effect remission, biological DMARDs may be beneficial. Lack of recognition of the early signs of rheumatoid arthritis, ignorance of the benefits of early application of modern treatment regimens, and avoidable delays in securing specialist appointments may hinder achievement of best outcomes for many patients. Triage for recognising possible early rheumatoid arthritis must begin in primary care settings with the following pattern of presentation as a guide: involvement of three or more joints; early-morning joint stiffness of greater than 30 minutes; or bilateral squeeze tenderness at metacarpophalangeal or metatarsophalangeal joints.

Leflunomide improves psoriasis in patients with psoriatic arthritis: An in-depth analysis of data from the TOPAS study

Background: Leflunomide has shown promise in the treatment of psoriasis. Objective: To provide an in-depth analysis of the effect of leflunomide on psoriasis in patients with psoriatic arthritis (PsA). Methods: 190 patients with plaque psoriasis (at least 3% skin involvement) and active PsA were randomized to double-blind treatment with leflunomide (100 mg/day loading dose for 3 days followed by 20 mg/day orally) or placebo for 24 weeks. Results: As previously reported, leflunomide resulted in a significantly higher Psoriatic Arthritis Response Criteria response rate than placebo (58.9 vs. 29.7%; p < 0.0001). Significant differences in favor of leflunomide were also observed in the Psoriasis Area and Severity Index (PASI 50 in 30.4% of patients vs. 18.9% for placebo; p = 0.05), target lesion response (46.4 vs. 25.3%; p = 0.0048), combined skin and joint response (27.2 vs. 8.9%; p < 0.0001), Dermatology Life Quality Index (improvement of 1.9 points vs. 0.2; p = 0.0173) and certain SF-36 subdomains. Dermatological responses were observed at the earliest examination (4 weeks) and increased throughout the 24-week study. Conclusion: Once-daily oral leflunomide is an effective and convenient treatment for PsA and plaque psoriasis. Copyright (c) 2006 S. Karger AG, Basel.

National audit of post-operative management in spinal surgery

Background: There is some evidence from a Cochrane review that rehabilitation following spinal surgery may be beneficial. Methods: We conducted a survey of current post-operative practice amongst spinal surgeons in the United Kingdom in 2002 to determine whether such interventions are being included routinely in the post-operative management of spinal patients. The survey included all surgeons who were members of either the British Association of Spinal Surgeons ( BASS) or the Society for Back Pain Research. Data on the characteristics of each surgeon and his or her current pattern of practice and post-operative care were collected via a reply-paid postal questionnaire. Results: Usable responses were provided by 57% of the 89 surgeons included in the survey. Most surgeons (79%) had a routine post-operative management regime, but only 35% had a written set of instructions that they gave to their patients concerning this. Over half (55%) of surgeons do not send their patients for any physiotherapy after discharge, with an average of less than two sessions of treatment organised by those that refer for physiotherapy at all. Restrictions on lifting, sitting and driving showed considerable inconsistency both between surgeons and also within the recommendations given by individual surgeons. Conclusion: Demonstrable inconsistencies within and between spinal surgeons in their approaches to post-operative management can be interpreted as evidence of continuing and significant uncertainty across the sub-speciality as to what does constitute best care in these areas of practice. Conducting further large, rigorous, randomised controlled trials would be the best method for obtaining definitive answers to these questions.

IL10 and IL12B polymorphisms each influence IL-12p70 secretion by dendritic cells in response to LPS

Dendritic cells (DC) are the main producers of the cytokine IL-12p70, through which they play a direct role in the development of IFN-gamma-secreting Th1 cells, costimulation of CTL differentiation and NK-cell activation. In contrast, IL-10, which is also produced by DC, negatively regulates IL-12 production. IL-12p70 production varies widely between individuals, and several polymorphisms in the gene encoding IL-12p40 (IL12B) have been identified that influence susceptibility and severity of infectious, autoimmune and neoplastic disease. Here we show that polymorphisms not only of IL12B, but also in the IL10 promoter, influence IL-12p70 secretion by monocyte-derived DC in response to LPS. Although IL12B promoter homozygotes were prone to making more IL-12p70, presence of the IL10 high genotype restricted IL-12p70 production in these individuals. These observations provide a further genetic control of IL-12p70 regulation and emphasize the complexity of production of this cytokine. They also suggest genotypes that might influence the outcome of DC immunotherapy.

The burden of musculoskeletal disease - a global perspective

Musculoskeletal diseases are one of the major causes of disability around the world and have been a significant reason for the development of the Bone and Joint Decade. Rheumatoid arthritis, osteoarthritis and back pain are important causes of disability-adjusted-life years in both the developed and developing world. COPCORD studies in over 17 countries around the world have identified back and knee pain as common in the community and are likely to increase with the ageing population. Musculoskeletal conditions are an enormous cost to the community in economic terms, and these figures emphasise how governments need to invest in the future and look at ways of reducing the burden of musculoskeletal diseases by encouraging exercise and obesity prevention campaigns.

RANKL protein is expressed at the pannus-bone interface at sites of articular bone erosion in rheumatoid arthritis

Objectives. Receptor activator of NF-kappa B ligand (RANKL) and osteoprotegerin (OPG) have been demonstrated to be critical regulators of osteoclast generation and activity. In addition, RANKL has been implicated as an important mediator of bone erosion in rheumatoid arthritis (RA). However, the expression of RANKL and OPG at sites of pannus invasion into bone has not been examined. The present study was undertaken to further elucidate the contribution of this cytokine system to osteoclastogenesis and subsequent bone erosion in RA by examining the pattern of protein expression for RANKL, OPG and the receptor activator of NF-kappa B (RANK) in RA at sites of articular bone erosion. Methods. Tissues from 20 surgical procedures from 17 patients with RA were collected as discarded materials. Six samples contained only synovium or tenosynovium remote from bone, four samples contained pannus-bone interface with adjacent synovium and 10 samples contained both synovium remote from bone and pannu-bone interface with adjacent synovium. Immunohistochemistry was used to characterize the cellular pattern of RANKL, RANK and OPG protein expression immediately adjacent to and remote from sites of bone erosion. Results. Cellular expression of RANKL protein was relatively restricted in the bone microenvironment; staining was focal and confined largely to sites of osteoclast-mediated erosion at the pannus-bone interface and at sites of subchondral bone erosion. RANK-expressing osteoclast precursor cells were also present in these sites. OPG protein expression was observed in numerous cells in synovium remote from bone but was more limited at sites of bone erosion, especially in regions associated with RANKL expression. Conclusions. The pattern of RANKL and OPG expression and the presence of RANK-expressing osteoclast precursor cells at sites of bone erosion in RA contributes to the generation of a local microenvironment that favours osteoclast differentiation and activity. These data provide further evidence implicating RANKL in the pathogenesis of arthritis-induced joint destruction.

The in vivo expression of actin/salt-resistant hyperactive DNase I inhibits the development of anti-ssDNA and anti-histone autoantibodies in a murine model of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is characterised by the production of autoantibodies against ubiquitous antigens, especially nuclear components. Evidence makes it clear that the development of these autoantibodies is an antigen-driven process and that immune complexes involving DNA-containing antigens play a key role in the disease process. In rodents, DNase I is the major endonuclease present in saliva, urine and plasma, where it catalyses the hydrolysis of DNA, and impaired DNase function has been implicated in the pathogenesis of SLE. In this study we have evaluated the effects of transgenic overexpression of murine DNase I endonucleases in vivo in a mouse model of lupus. We generated transgenic mice having T-cells that express either wild-type DNase I (wt. DNase I) or a mutant DNase I ( ash. DNase I), engineered for three new properties - resistance to inhibition by G-actin, resistance to inhibition by physiological saline and hyperactivity compared to wild type. By crossing these transgenic mice with a murine strain that develops SLE we found that, compared to control nontransgenic littermates or wt. DNase I transgenic mice, the ash. DNase I mutant provided significant protection from the development of anti-single-stranded DNA and anti-histone antibodies, but not of renal disease. In summary, this is the first study in vivo to directly test the effects of long-term increased expression of DNase I on the development of SLE. Our results are in line with previous reports on the possible clinical benefits of recombinant DNase I treatment in SLE, and extend them further to the use of engineered DNase I variants with increased activity and resistance to physiological inhibitors.

Replication of association of IL1 gene complex members with ankylosing spondylitis in Taiwanese Chinese

Objective: To test the association of interleukin 1 ( IL1) gene family members with ankylosing spondylitis ( AS), previously reported in Europid subjects, in an ethnically remote population. Methods: 200 Taiwanese Chinese AS patients and 200 ethnically matched healthy controls were genotyped for five single nucleotide polymorphisms ( SNPs) and the IL1RN. VNTR, markers previously associated with AS. Allele, genotype, and haplotype frequencies were compared between cases and controls. Results: Association of alleles and genotypes of the markers IL1F10.3, IL1RN. 4, and IL1RN. VNTR was observed with AS ( p < 0.05). Haplotypes of pairs of these markers and of the markers IL1RN.6/1 and IL1RN.6/2 were also significantly associated with AS. The strongest associations observed were with the marker IL1RN. 4, and with the two-marker haplotype IL1RN.4-IL1RN.VNTR ( both p = 0.004). Strong linkage disequilibrium was observed between all marker pairs except those involving IL1B-511 ( D' 0.4 to 0.9, p < 0.01). Conclusions: The IL1 gene cluster is associated with AS in Taiwanese Chinese. This finding provides strong statistical support that the previously observed association of this gene cluster with AS is a true positive finding.