Patterns of biologic and targeted-synthetic disease-modifying antirheumatic drug use in rheumatoid arthritis in Australia.

OBJECTIVE: The aim of this study was to describe treatment patterns in RA, including the frequency and reasons for switching or stopping biologic and targeted synthetic DMARDs (b/tsDMARDs). METHODS: The reasons for switching or stopping b/tsDMARDs were extracted from the Australian Rheumatology Association Database (ARAD) from 2003 to 2018 for RA participants. Switching patterns for each b/tsDMARD and time on first-, second- and third-line b/tsDMARDs were evaluated using Sankey diagrams and survival methods. RESULTS: A total of 2839 participants were included in the analysis. The first-line b/tsDMARDs were etanercept (n = 1414), adalimumab (n = 1024), infliximab (n = 155), golimumab (n = 98), abatacept (n = 66), certolizumab (n = 38), tocilizumab (n = 21) and tofacitinib (n = 23). Of those starting first-, second- and third-line biologic therapy, 24.0%, 31.8% and 24.4% switched to another b/tsDMARD within 12 months, respectively. Inefficacy or adverse effects were the most common reasons for stopping therapy, irrespective of line of treatment. Compared with first-line etanercept, participants were more likely to stop adalimumab [Hazard ratio (HR) 1.16, 95% CI: 1.04, 1.29] and infliximab (HR 1.77, 95% CI: 1.46, 2.16). No differences were seen for other b/tsDMARDs. For second-line therapies compared with etanercept, the risk of stopping was lower for tocilizumab (HR 0.41, 95% CI: 0.25, 0.70), rituximab (HR 0.51, 95% CI: 0.30, 0.85) and tofacitinib (HR 0.29, 95% CI: 0.15, 0.57). Participants taking rituximab, tocilizumab and tofacitinib were also less likely to stop third-line therapy in comparison with participants taking etanercept. CONCLUSIONS: Switching between b/tsDMARDs was common among ARAD participants with RA, most commonly due to inefficacy or adverse effects. Durability of exposure and reasons for switching varied between b/tsDMARDs.

The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: results of a double-blind, randomized, placebo-controlled, repeated-measures trial.

OBJECTIVE: To determine the effectiveness of subsensory, pulsed electrical stimulation (PES) in the symptomatic management of osteoarthritis (OA) of the knee. METHODS: This was a double-blind, randomized, placebo-controlled, repeated-measures trial in 70 participants with clinical and radiographically diagnosed OA of the knee who were randomized to either PES or placebo. The primary outcome was change in pain score over 26 weeks measured on a 100-mm visual analog scale (VAS). Other measures included pain on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), function on the WOMAC, patient's global assessment of disease activity (on a 100-mm VAS), joint stiffness on the WOMAC, quality of life on the Medical Outcomes Study Short-Form 36 (SF-36) health survey, physical activity (using the Human Activity Profile and an accelerometer), and global perceived effect (on an 11-point scale). RESULTS: Thirty-four participants were randomized to PES and 36 to placebo. Intent-to-treat analysis showed a statistically significant improvement in VAS pain score over 26 weeks in both groups, but no difference between groups (mean change difference 0.9 mm [95% confidence interval -11.7, 13.4]). Similarly, there were no differences between groups for changes in WOMAC pain, function, and stiffness scores (-5.6 [95% confidence interval -14.9, 3.6], -1.9 [95% confidence interval -9.7, 5.9], and 3.7 [95% confidence interval -6.0, 13.5], respectively), SF-36 physical and mental component summary scores (1.7 [95% confidence interval -1.5, 4.8] and 1.2 [95% confidence interval -2.9, 5.4], respectively), patient's global assessment of disease activity (-2.8 [95% confidence interval -13.9, 8.4]), or activity measures. Fifty-six percent of the PES-treated group achieved a clinically relevant 20-mm improvement in VAS pain score at 26 weeks compared with 44% of controls (12% [95% confidence interval -11%, 33%]). CONCLUSION: In this sample of subjects with mild-to-moderate symptoms and moderate-to-severe radiographic OA of the knee, 26 weeks of PES was no more effective than placebo.

Long-term Clinical Outcomes in Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis Syndrome.

OBJECTIVE: To assess the outcome of empirical therapeutic interventions for synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. METHODS: The clinical features and treatment outcomes of a cohort of 21 patients diagnosed with SAPHO in Western Australia were reviewed retrospectively. RESULTS: All 21 patients met published diagnostic criteria; 20 (95%) were Caucasian, and the median age was 47 years. The median follow-up was 6 years (range, 2 to 32 years). Three patients (14%) received no treatment; 18 (86%) required conventional synthetic disease-modifying antirheumatic drug (DMARDs). Thirteen (62%) had an initial good response to methotrexate; 8 relapsed and progressed to biologic DMARDs (bDMARDs) during a period of 14 years. Of the 13 recipients on a tumor necrosis factor inhibitor, 11 (85%) continued treatment for a median of 4 years (range, 1 to 14 years), whereas none of 3 recipients of interleukin 17/23 continued treatment (median, 4 months). Higher Physician Global Assessment scores (better outcomes) were observed in bDMARD recipients (mean, 7.06±2.24 [SD]) compared with non-bDMARD recipients (mean, 5.63±2.50; P=.1672) after a median of 3 years of therapy. CONCLUSION: This study describes the broad range of clinical manifestations in SAPHO, variable courses over time, and inconsistent outcomes with diverse empirical therapies. Moderately good long-term treatment outcomes were observed in most recipients of tumor necrosis factor inhibitor. Poorer outcomes were observed with bisphosphonates and interleukin 17/23 axis inhibitors; however, low numbers preclude robust comparison. Suboptimal treatment may be associated with poorer clinical outcomes and greater skeletal damage. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry: ACTRN12619000445178.

Self-management for osteoarthritis of the knee: does mode of delivery influence outcome?

BACKGROUND: Self-management has become increasingly popular in the management of chronic diseases. There are many different self-management models. Meta analyses of arthritis self-management have concluded that it is difficult to recommend any one program in preference to another due to inconsistencies in the study designs used to evaluate different programs.The Stanford Arthritis Self-Management Program (ASMP), most commonly delivered by trained lay leaders, is a generic program widely used for people with rheumatological disorders. We have developed a more specific program expressly for people with osteoarthritis of the knee (OAKP). It includes information designed to be delivered by health professionals and results in improvements in pain, function and quality of life. AIM: To determine whether, for people with osteoarthritis (OA) of the knee, the OAKP implemented in a primary health care setting can achieve and maintain clinically meaningful improvements in more participants than ASMP delivered in the same environment. METHODS/DESIGN: The effectiveness of the programs will be compared in a single-blind randomized study. PARTICIPANTS: 146 participants with established OA knee will be recruited. Volunteers with coexistent inflammatory joint disease or serious co-morbidities will be excluded. INTERVENTIONS: Participants will be randomised into either OAKP or ASMP groups and followed for 6 months. MEASUREMENTS: Assessments will be immediately before and after the intervention and at 6 months. Primary outcome measures will be WOMAC and SF-36 questionnaires and a VAS for pain. Secondary outcomes will include balance, tested using a timed single leg balance test and a timed step test and self-efficacy. Data will be analysed using repeated measures ANOVA. DISCUSSION: With an aging population the health care costs for people with arthritis are ever increasing. Although cost analysis is beyond the scope of this study, it is reasonable to expect that costs will be greater when health professionals deliver self-management programs as opposed to lay leaders. Consequently it is critical to examine the relative effectiveness of the primary care management strategies available for OA. TRIAL REGISTRATION: This study is registered with the Australian New Zealand Clinical Trials Registry: 12607000031460.

Oral Complementary Medicine Use among People with Inflammatory Arthritis: An Australian Rheumatology Association Database Analysis.

OBJECTIVES: To describe oral complementary medicine (CM) use in people with inflammatory arthritis, associations with use, and changes in use over time. METHODS: Demographic, clinical, and patient-reported outcome data from 5,630 participants with rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), and juvenile idiopathic arthritis (JIA) were extracted from the Australian Rheumatology Association Database (ARAD), a national observational database. CM use at entry into ARAD was ascertained for participants recruited between 2002 and 2018. CM was categorised according to the NIH/Cochrane schema (fatty acids, herbs, or supplements). Logistic regression was used to assess associations between demographic characteristics and CM use. Change in CM use between 2006 and 2016 was investigated using a nonparametric test for trend of rate by year. RESULTS: 2,156 (38.3%) ARAD participants were taking CM at enrolment (RA: 1,502/3,960 (37.9%), AS: 281/736 (38.2%), PsA: 334/749 (44.6%), and JIA: 39/185 (21.1%)). CM use was more prevalent in women (OR 1.3; 95% CI: 1.13-1.50), those with tertiary education (OR 1.32; 95% CI: 1.13-1.55), private health insurance (OR 1.26; (95% CI: 1.10-1.44), drinking alcohol sometimes (OR 1.22; 95% CI: 1.05-1.43), poorer function (HAQ) (OR 1.13; 95% CI: 1.02-1.24), use of NSAID (OR 1.32; 95% CI 1.17-1.50), weak (OR 1.21; 95% CI 1.05-1.41) but not strong opioids, and less prevalent in current smokers (OR 0.76; 95%: CI 0.63-0.91). CM use was not associated with pain, disease activity, or quality of life. The most common CMs were fish oils (N = 1,489 users) followed by glucosamine (N = 605). Both declined in use over time between 2006 and 2016 (27.5% to 21.4%, trend p = 0.85 and 15.5% to 6.4%, trend p < 0.01), respectively. CONCLUSION: Oral CM use is common among Australians with inflammatory arthritis. Its use is greater among women and those with tertiary education. Fish oil and glucosamine, the most common CMs, both declined in use over time.

Role of a LIF antagonist in LIF and OSM induced MMP-1, MMP-3, and TIMP-1 expression by primary articular chondrocytes.

Cartilage degradation is mediated by matrix metalloproteinases (MMPs) and their inhibitors, tissue metalloproteinases (TIMPs), which are transcriptionally regulated by a variety of growth factors and cytokines. The levels of various MMPs as well as TIMPs have been shown to increase in response to certain cytokines. These include leukaemia inhibitory factor (LIF) and Oncostatin M (OSM), both of which have been detected in the synovial fluids of patients with rheumatoid arthritis (RA). However, the role of LIF and OSM in the regulation of various MMPs and TIMPs is still incompletely understood. The aims of this study were to examine the effects of LIF and OSM on MMP-1, MMP-3, and TIMP-1 production. In addition, the capacity of the LIF antagonist, MH35-BD, to block LIF and OSM induced MMP expression was examined. Primary chondrocytes, isolated from porcine metacarpophalangeal cartilage, were cultured in the presence and absence of LIF and OSM, with and without a predetermined concentration of the LIF antagonist. We analysed the levels of MMP-1, MMP-3 and TIMP-1 expression using qRT-PCR, Northern blot, and ELISA assays. The results indicate that LIF and OSM increase the expression of MMP-1, MMP-3, and TIMP-1 several fold. Furthermore their expression is reduced to basal levels in the presence of the LIF antagonist MH35-BD.

Undetectable mannose binding lectin is associated with HRCT proven bronchiectasis in rheumatoid arthritis (RA).

AIM: The aim of this study was to ascertain whether mannose binding lectin deficiency is implicated in coexistent rheumatoid arthritis and bronchiectasis and to determine whether undetectable mannose binding lectin confers poorer long-term survival in coexistent rheumatoid arthritis and bronchiectasis or in rheumatoid arthritis in general. MATERIALS AND METHODS: A retrospective audit was conducted in a rheumatoid arthritis cohort in which mannose binding lectin had been measured by enzyme linked immunosorbent assay from 2007-11. Rheumatoid arthritis patients with physician diagnosed HRCT proven bronchiectasis were recruited during this time and compared to those with uncomplicated rheumatoid arthritis. Survival from disease onset was recorded in October 2018. Kaplan-Meier survival estimates were performed to assess mortality over time in the two groups. Log rank tests were used for equality of survivor functions. RESULTS: The two groups were demographically comparable. A higher frequency of undetectable mannose binding lectin was observed in coexistent rheumatoid arthritis and bronchiectasis (37.5%) compared to uncomplicated rheumatoid arthritis, (8.9%, P = 0.005). Undetectable mannose binding lectin correlated with a strong trend toward poor survival in rheumatoid arthritis overall (P = 0.057). Cox regression analysis however, showed no difference in the hazard ratio for survival between the two groups when corrected for age, gender, prednisolone use ever, rheumatoid factor status and the full range of MBL concentrations. CONCLUSION: In summary, undetectable mannose binding lectin is associated with coexistent rheumatoid arthritis and bronchiectasis and correlates with poor survival in rheumatoid arthritis overall. These findings further implicate immunodeficiency in the genesis of bronchiectasis in rheumatoid arthritis.

Fc-based cytokines : prospects for engineering superior therapeutics.

The application of Fc (fragment crystallizable)-based cytokines (the fusion of the constant region of IgG to a cytokine of interest) as biotherapeutic agents to modulate inflammatory and immune responses has become increasingly popular in recent years. This is because in their monomeric form, cytokines are relatively small molecules with short serum half-lives, which necessitates frequent administration and thus limits their clinical utility. To rectify the problem, attempts have been made to improve the stability of these agents in vivo. This has been achieved through diverse strategies such as modification with polyethylene glycol (PEGylation) or by ligating the cytokine to protein moieties such as the constant heavy chain of IgG, known as the Fc fragment. The construction of Fc chimeric proteins has been shown to improve pharmacokinetics. However, since there is an inverse relationship between the size of molecules and the rate at which they diffuse through mucus, Fc fusion constructs potentially have a lower rate of diffusion. Consequently, a compromise is reached whereby Fc constructs are engineered to incorporate ligated cytokines in a monomeric form (one molecule of cytokine fused to a single Fc dimer) rather than in a dimeric form (two molecules of cytokine fused to a single Fc dimer). A recent and novel approach to improve stability in serum is a procedure that involves sheathing cytokines in protective protein covers called latency peptides. The enclosed cytokine is protected from degradation and allowed to act where needed when the outer peptide cover is removed. For some applications, a reduced serum half-life is desirable; for example, where there is a need to reduce IgG levels in antibody-mediated diseases. To achieve this goal, a strategy called AbDeg, which involves enhanced Ig degradation, has been devised. This article provides an overview of the design and construction of Fc-based cytokines, in both dimeric and monomeric forms. Several examples of recent applications of such constructs, which include cytokine antagonism, cytokine traps, gene therapy and drug delivery, are also discussed. Other antibody-engineered constructs such as Fab (fragment, antigen binding) and single chain Fv (fragment, variable) fusions are also briefly covered.

Short and medium-term effects of an education self-management program for individuals with osteoarthritis of the knee, designed and delivered by health professionals: a quality assurance study.

BACKGROUND: Self-management (SM) programs are effective for some chronic conditions, however the evidence for arthritis SM is inconclusive. The aim of this case series project was to determine whether a newly developed specific self-management program for people with osteoarthritis of the knee (OAK), implemented by health professionals could achieve and maintain clinically meaningful improvements. PARTICIPANTS: 79 participants enrolled; mean age 66, with established osteoarthritis of the knee. People with coexisting inflammatory joint disease or serious co-morbidities were excluded. INTERVENTION: 6-week disease (OA) and site (knee) specific self-management education program that included disease education, exercise advice, information on healthy lifestyle and relevant information within the constructs of self-management. This program was conducted in a community health care setting and was delivered by health professionals thereby utilising their knowledge and expertise. MEASUREMENTS: Pain, physical function and mental health scales were assessed at baseline, 8 weeks, 6 and 12 months using WOMAC and SF-36 questionnaires. Changes in pain during the 8-week intervention phase were monitored with VAS. RESULTS: Pain improved during the intervention phase: mean (95% CI) change 15 (8 to 22) mm. Improvements (0.3 to 0.5 standard deviation units) in indices of pain, mental health and physical functioning, assessed by SF-36 and WOMAC questionnaires were demonstrated from baseline to 12 months. CONCLUSION: This disease and site-specific self-management education program improved health status of people with osteoarthritis of the knee in the short and medium term.

The effectiveness of pulsed electrical stimulation (E-PES) in the management of osteoarthritis of the knee: a protocol for a randomised controlled trial.

BACKGROUND: Osteoarthritis (OA) of the knee is one of the main causes of musculoskeletal disability in the western world. Current available management options provide symptomatic relief (exercise and self-management, medication and surgery) but do not, in general, address the disease process itself. Moreover, adverse effects and complications with some of these interventions (medication and surgery) and the presence of co-morbidities commonly restrict their use. There is clearly a need to investigate treatments that are more widely applicable for symptom management and which may also directly address the disease process itself. In two randomised controlled trials of four and 12 weeks duration, pulsed electrical stimulation was shown to be effective in managing the symptoms of OA of the knee. Laboratory and animal studies demonstrate the capacity of externally applied electric and electromagnetic fields to positively affect chondrocyte proliferation and extracellular matrix protein production. This latter evidence provides strong theoretical support for the use of electrical stimulation to maintain and repair cartilage in the clinical setting and highlights its potential as a disease-modifying modality. METHODS/DESIGN: A double-blind, randomised, placebo-controlled, repeated measures trial to examine the effectiveness of pulsed electrical stimulation in providing symptomatic relief for people with OA of the knee over 26 weeks. Seventy people will be recruited and information regarding age, gender, body mass index and medication use will be recorded. The population will be stratified for age, gender and baseline pain levels. Outcome measures will include pain (100 mm VAS and WOMAC 3.1), function (WOMAC 3.1), stiffness (WOMAC 3.1), patient global assessment (100 mm VAS) and quality of life (SF-36). These outcomes will be measured at baseline, four, 16 and 26 weeks. Activity levels will be measured at baseline and 16 weeks using accelerometers and the Human Activity Profile questionnaire. A patient global perceived effect scale (11-point Likert) will be completed at 16 and 26 weeks. DISCUSSION: This paper describes the protocol for a randomised, double-blind, placebo-controlled trial that will contribute to the evidence regarding the use of sub-sensory pulsed electrical stimulation in the management of OA of the knee. TRIAL REGISTRATION: Australian Clinical Trials Registry ACTRN12607000492459.

In vitro evaluation of leukemia inhibitory factor receptor antagonists as candidate therapeutics for inflammatory arthritis.

Leukemia inhibitory factor (LIF) and oncostatin M (OSM) are found in appreciable concentrations in synovial fluid from patients with rheumatoid arthritis (RA) but not osteoarthritis. Accordingly, both are potential therapeutic targets in inflammatory diseases of the joints. Several LIF antagonists have been developed. They have the capacity to inhibit the biologic activities of not only LIF but also other interleukin-6 (IL-6) subfamily cytokines, including OSM. Both LIF and OSM share the same receptor, which is part of a cytokine receptor super family in which the glycoprotein 130 (gp130) subunit is a common constituent. The aim of this study was to evaluate the antagonistic potentials of two LIF mutants, LIF05 and MH35-BD. Both are mutant forms of human LIF with reduced affinity for gp130 and greater LIF receptor (LIFR) binding affinity. The results, using Ba/F3 cell proliferation assay, acute-phase protein (haptoglobin) induction analysis in HepG2 human hepatoma cells, a porcine cartilage glycosaminoglycan release assessment for proteoglycan degradation, and a collagen release assay, show that these antagonists inhibit relevant LIF, OSM, and other IL-6 subfamily cytokines in vitro albeit with differential potencies and have, therefore, therapeutic potential for treatment of RA and perhaps other diseases.

Generation of mutant leukaemia inhibitory factor (LIF)-IgG heavy chain fusion proteins as bivalent antagonists of LIF.

Two leukaemia inhibitory factor (LIF) mutants, designated MH35-BD and LIF05, have been shown to have a capacity to inhibit the biological activities of not only human LIF (hLIF) but also other interleukin-6 (IL-6) subfamily cytokines such as human oncostatin M (hOSM). These cytokines share the same receptor complex in which the glycoprotein 130 (gp130) subunit is a common constituent. However, at low concentrations and in their monomeric forms, such molecules have a relatively short plasma half-life due to rapid clearance from the kidneys. Here, to prolong their serum half-lives, we have used a multi-step polymerase chain reaction (PCR) to fuse each of the LIF05 and MH35-BD cDNA fragments to a sequence encoding the Fc portion, and the hinge region, of the human immunoglobulin G (hIgG) heavy chain. The linking was achieved through an oligomer encoding a thrombin-sensitive peptide linker thus generating MH35-BD:Fc and LIF05:Fc, respectively. Both Fc fusion constructs were expressed in insect cell Sf21 and the proteins were purified by two successive affinity chromatography steps using nickel-nitrilotriacetic acid (Ni-NTA) agarose and protein A beads. The Ba/F3 cell-based proliferation assay was used to confirm that the proteins were biologically active. In addition, preliminary pharmacokinetics indicates that the Fc fusion constructs have a longer serum half-life compared to their non-fusion counterparts.

Undetectable Mannose Binding Lectin and Corticosteroids Increase Serious Infection Risk in Rheumatoid Arthritis.

BACKGROUND: Infection is the leading cause of death in rheumatoid arthritis (RA). Corticosteroid (CS) use is a known and important risk factor for serious infections (SIs). Mannose binding lectin (MBL) is a genetically determined component of the innate immune system implicated in neonatal infections. OBJECTIVE: Our aim was to determine whether MBL deficiency is a risk factor for SIs in RA and to compare it with CS use and also synthetic and biologic disease-modifying antirheumatic drug (DMARD) therapy. METHODS: Data on 228 patients with RA were collected for up to 7 years (median = 5.9 years). Serum MBL concentrations were determined in all patients receiving synthetic (n = 96) or biologic (n = 132) DMARD therapy. RESULTS: High rates of SIs were observed in RA irrespective of treatment (17%). Similar rates of SIs were observed in synthetic and biologic DMARD users. The rates of single and multiple SIs were similar, irrespective of the use of a biologic agent. Undetectable MBL (<56 ng/mL) concentrations and maintenance prednisolone at 10 mg per day or higher were associated with an increased risk for an SI, with incident risk ratio of 4.67 (P = .001) and 4.70 (P < .001), respectively. CONCLUSIONS: Undetectable MBL and prednisolone confer a high risk for an SI. The use of biologic DMARDs did not confer substantial SI risk in this observational study. MBL deficiency is hitherto an unrecognized risk factor for an SI in RA.

Polyarticular osteoarthritis--two major phenotypes hypothesized.

Osteoarthritis is the commonest form of arthritis, at least amongst Caucasians and is frequently polyarticular. Genetic factors are now considered pivotal in the aetiopathogenesis of polyarticular osteoarthritis (POA). This document proposes a nexus between the gene most commonly mutated amongst Caucasian peoples, notably the HFE gene and an appreciable subset of POA patients who have a clinically recognisable OA phenotype. It is hypothesised that there are at least 2 major POA phenotypes each of which is associated with discrete genotypes. Type 1 POA characterized by Heberden's or Bouchard's nodes with prominent DIP, PIP, knee joint (medial compartment) and Great toe MTP joint involvement corresponds to the putative nodal generalized form of OA or NGOA (proposed Type 1 POA phenotype). As yet no genetic marker has been defined for this POA subset. The second is a hitherto less well recognized phenotype characterized by involvement of the index and/or middle finger metacarpophalangeal (MCP2,3) joints and the elbows, ankles and possibly the intertarsal and tarsometatarsal joints. The hip and knee joints may sometimes also be involved. This different joint distribution corresponds closely to the pattern observed in the arthropathy that often accompanies hereditary haemochromatosis. It is predicted that mutations in the HFE gene will associate strongly with the proposed Type 2 POA phenotype and serve as a genetic marker for this clinically recognisable subset.

Efficacy of patient information concerning casts applied post-fracture.

INTRODUCTION: Serious complications can result when casts are used for bone immobilization following fracture. Adequate patient information regarding cast care and possible complications is vital for prevention. This study examines the effectiveness of verbal and written patient information regarding cast safety. METHODS: Patients (n= 109; age ≥18 years) from three Western Australian teaching hospitals were interviewed using a custom-designed questionnaire. Patients' understanding of cast care and possible complications were tested by recall of seven categories of information, notably: pain, swelling, cast care, itching, neural signs, vascular signs/symptoms, exercise/rest. A follow-up phone call (3-8 weeks after initial interview) was conducted to elicit complications and determine information recall. RESULTS: Written information was received by 62% of patients; however, overall, only 35% claimed to have read the information provided. Of these, the highest recall was in four of seven information categories. A high proportion of those given only verbal information had poor recall (≤2 categories, defined a priori). In contrast, patients who also received written information had better recall (three or more categories, defined a priori, P= 0.031). Four of the 109 patients developed complications attributable to the cast (three had pressure ulcers and one had a deep vein thrombosis). CONCLUSION: Patient recall of information concerning cast care and possible complications was no more than 60%. The provision of written information was associated with a significantly higher awareness of possible complications. The results indicate that for fracture care, the delivery and use of information protocols can be greatly improved.

A randomised controlled trial of a self-management education program for osteoarthritis of the knee delivered by health care professionals.

INTRODUCTION: Our aim in the present study was to determine whether a disease-specific self-management program for primary care patients with osteoarthritis (OA) of the knee (the Osteoarthritis of the Knee Self-Management Program (OAK)) implemented by health care professionals would achieve and maintain clinically meaningful improvements in health-related outcomes compared with a control group. METHODS: Medical practitioners referred 146 primary care patients with OA of the knee. Volunteers with coexistent inflammatory joint disease or serious comorbidities were excluded. Randomisation was to either a control group or the OAK group. The OAK group completed a 6-week self-management program. The control group had a 6-month waiting period before entering the OAK program. Assessments were taken at baseline, 8 weeks and 6 months. The primary outcomes were the results measured using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) Pain and Function subscales on the Short Form 36 version 1 questionnaire (SF-36) Secondary outcomes were Visual Analogue Scale (VAS) pain, Timed Up & Go Test (TUG), knee range of motion and quadriceps and hamstring strength-isometric contraction. Responses to treatment (responders) and minimal clinically important improvements (MCIIs) were determined. RESULTS: In the OAK group, VAS pain improved from baseline to week 8 from mean (SEM) 5.21 (0.30) to 3.65 (0.29) (P ≤ 0.001). During this period, improvements in the OAK group compared with the control group and responses to treatment were demonstrated according to the following outcomes: WOMAC Pain, Physical Function and Total dimensions, as well as SF-36 Physical Function, Role Physical, Body Pain, Vitality and Social Functioning domains. In addition, from baseline to week 8, the proportion of MCIIs was greater among the OAK group than the control group for all outcomes. For the period between baseline and month 6, WOMAC Pain, Physical Function and Total dimensions significantly improved in the OAK group compared to the control group, as did the SF-36 Physical Function, Role Physical, Body Pain, Vitality and Social Functioning domains, as well as hamstring strength in both legs. During the same period, the TUG Test, range of motion extension and left-knee flexion improved compared with the control group, although these improvements had little clinical relevance. CONCLUSIONS: We recorded statistically significant improvements compared with a control group with regard to pain, quality of life and function for participants in the OAK program on the basis of WOMAC and SF-36 measures taken 8 weeks and 6 months from baseline.

Precocious bilateral hip joint osteoarthritis is a "form-fruste" of the arthropathy of hereditary haemochromatosis.

Osteoarthritis (OA) of the hip joint is a common disorder, especially in aging peoples of Caucasian descent. Hip OA like OA in other joints is heterogeneous and may manifest in early or late adult life. The aetiology of early onset (precocious) bilateral hip OA is poorly understood, but the clinical and radiological characteristics of this form of OA suggest that chondral resorption due to biochemical or metabolic factors is likely to be of pre-eminent importance. The hip arthropathy which occurs in Hereditary Haemochromatosis (HH) and the ostensibly idiopathic precocious bilateral concentric form of hip OA are virtually indistinguishable. Accordingly, the possibility exists that the causal factors for these conditions may be very similar. On the basis of this premise and in the light of the finding in a small observational study that HFE gene mutations are very common in precocious bilateral hip OA (100% amongst 8 sequentially collected patients), it is hypothesised that precocious bilateral hip OA is a "form-fruste" of the arthropathy of HH in which HFE gene mutation mediated articular iron deposition in hip joint tissues may be of pivotal pathogenetic importance. Confirmation of this hypothesis could have implications for the prevention and strategic medical management of this form of OA.

Interleukin-6 subfamily cytokines and rheumatoid arthritis: role of antagonists.

Many cytokines have been implicated in the inflammatory pathways that characterize rheumatoid arthritis (RA) and related inflammatory diseases of the joints. These include members of the interleukin-6 (IL-6) family of cytokines, several of which have been detected in excess in the synovial fluid from RA patients. What makes the IL-6 group of cytokines a family is their common use of the glycoprotein 130 (gp130) receptor subunit, to which they bind with different affinities. Several strategies have been developed to block the pro-inflammatory activities of IL-6 subfamily cytokines. These include the application of monoclonal antibodies, the creation of mutant form(s) of the cytokine with enhanced binding affinity to gp130 receptor and the generation of antagonists by selective mutagenesis of the specific cytokine/gp130 receptor-binding site(s). The rationale for the use of anti-cytokine therapy in inflammatory joint diseases is based on evidence from studies in vitro and in vivo, which implicate major cytokines such as interleukin-1 (IL-1), tumour necrosis factor (TNF)-alpha and IL-6 in RA pathogenesis. In particular, IL-6 subfamily antagonists have a wide range of potential therapeutic and research applications. This review focuses on the role of some of the IL-6 subfamily cytokines in the pathogenesis of the inflammatory diseases of the joints (IJDs), such as RA. In addition, an overview of the recently developed antagonists will be discussed.