Evaluation of WOMAC 20, 50, 70 response criteria in patients treated with hylan G-F 20 for knee osteoarthritis

Objective: A secondary analysis of a previously conducted one year randomised controlled trial to evaluate the capacity of responder criteria based on the WOMAC index to detect between treatment group differences. Methods: 255 patients with knee osteoarthritis were randomised to appropriate care with hylan G-F 20'' (AC+H) or appropriate care without hylan G-F 20'' (AC). In the original analysis, two definitions of patient response from baseline to month 12 were used: ( 1) at least a 20% reduction in WOMAC pain score ( WOMAC 20P); ( 2) at least a 20% reduction in WOMAC pain score and at least a 20% reduction in either WOMAC function or stiffness score ( WOMAC 20PFS). For this analysis, a responder was identified using 50% and 70% minimum clinically important response levels to investigate how increasing response affects the ability to detect treatment group differences. Results: The hylan G- F 20 group had numerically more responders using all patient responder criteria. Increasing the response level from 20% to 50% detected similar differences between treatment groups (25% to 29%). Increasing the response level to 70% reduced the differences between treatment groups (11% to 12%) to a point where the differences were not significant after Bonferroni adjustment. Conclusions: These results provide evidence for incorporating response levels ( WOMAC 50) in clinical trials. While differences at the highest threshold ( WOMAC 70) were not statistically detectable, an appropriately powered study may be capable of detecting differences even at this very high level of improvement.

HFE genotyping demonstrates a significant incidence of hemochromatosis in up differentiated arthritis

Objective Hereditary hemochromatosis is a common autosomal recessive disorder of iron metabolism. Among Northern Europeans the carrier frequency is estimated to be I in 10, while up to 1 in 200 is affected by the disease. Arthropathy is one early clinical manifestation of this disease, but the articular features are often misdiagnosed. In this study the two frequent mutations of the HLA-linked hemochromatosis gene (HFE) were investigated, in a rheumatology clinic population. Methods Two hundred and six consecutive patients (mean age 57.7 years; 38 male/168 female) attending a rheumatology clinic over a period of 14 months were screened for HFE mutations (C282Y and H63D). All standard diagnostic procedures were used to identify the aetiology: of the arthropathy. Mutations were evaluated by separation on PAGE of digested PCR amplificates of DNA (by SnapI and Bcl-I, for C282Y and H63D, respectively) obtained from PBMCs. Results The C282Y and H63D allele frequencies were 4.5 and 12.8 inpatients with rheumatic diseases. Five patients were homozygote for H63D (2.4%), and one,for C282Y (0.5%). Five patients were compound heterozygous (2.4%). The observed C282Y allele frequency in rheumatic patients with undifferentiated arthritis was 12.9 and exceeded that of healthy subjects (p = 0.01). Conclusions Determination of the HFE genotype is clinically useful in patients with arthritis of unknown origin, to allow early diagnosis of hemochromatosis.

Tumour necrosis factor inhibitors

The cytokine, tumour necrosis factor-alpha (TNF-alpha) plays a key role in the pathogenesis of many chronic inflammatory and rheumatic diseases, in particular, Crohn's disease, rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. Controlled trials have shown that the TNF inhibitors (etanercept, infliximab and adalimumab) significantly reduce symptoms and signs, improve function and quality of life, and reduce radiologically evident damage in patients with rheumatoid diseases. For reasons that are not entirely clear, etanercept does not work in Crohn's disease. Injection site and intravenous reactions and increased risk of infection (in particular, reactivation of tuberculosis) are associated with the use of these agents. Increased risk of lymphoproliferative disease, the development of lupus-like syndromes and demyelination, including optic neuritis and reactivation of multiple sclerosis, are under evaluation in long-term follow-up studies. The TNF inhibitors are expensive (about $18000 per year), and in some patients need to be given continuously to maintain benefit, even in the presence of other immunosuppressive therapy.

TRAP220 is modulated by the antineoplastic agent 6-Mercaptopurine, and mediates the activation of the NR4A subgroup of nuclear receptors

The NR4A1-3 (Nur77, NURR1 and NOR-1) subfamily of nuclear hormone receptors (NRs) has been implicated in Parkinson's disease, schizophrenia, manic depression, atherogenesis, Alzheimer's disease, rheumatoid arthritis, cancer and apoptosis. This has driven investigations into the mechanism of action, and the identification of small molecule regulators, that may provide the platform for pharmaceutical and therapeutic exploitation. Recently, we found that the purine antimetabolite 6-Mercaptopurine (6-MP), which is widely used as an anti-neoplastic and anti-inflammatory drug, modulated the NR4A1-3 subfamily. Interestingly, the agonist-mediated activation did not involve modulation of primary coactivators' (e.g. p300 and SRC-2/GRIP-1) activity and/or recruitment. However, the role of the subsequently recruited coactivators, for example CARM-1 and TRAP220, in 6-MP-mediated activation of the NR4A1-3 subfamily remains obscure. In this study we demonstrate that 6-MP modulates the activity of the coactivator TRAP220 in a dose-dependent manner. Moreover, we demonstrate that TRAP220 potentiates NOR-1-mediated transactivation, and interacts with the NR4A1-3 subgroup in an AF-1-dependent manner in a cellular context. The region of TRAP220 that mediated 6-MP activation and NR4A interaction was delimited to amino acids 1-800, and operates independently of the critical PKC and PKA phosphorylation sites. Interestingly, TRAP220 expression does not increase the relative induction by 6-MP, however the absolute level of NOR-1-mediated trans-activation is increased. This study demonstrates that 6-MP modulates the activity of the NR4A subgroup, and the coactivator TRAP220.

Psoriatic arthritis: epidemiology, clinical features, course, and outcome

Psoriatic arthritis (PsA) has been defined as a unique inflammatory arthritis associated with psoriasis. Its exact prevalence is unknown, but estimates vary from 0.3% to 1% of the population. The clinical features described initially are recognised by most experienced clinicians, although they are most distinct in early disease. Initially, PsA typically presents as an oligoarticular and mild disease. However, with time PsA becomes polyarticular, and it is a severe disease in at least 20% of patients. Patients with PsA who present with polyarticular disease are at risk for disease progression. In addition to progression of clinical and radiological damage, health related quality of life is reduced among patients with PsA. It important to note that patients included in recent drug trials resemble patients followed prospectively in a clinic.

NF-gamma B - a target in the inflammation of bone destruction

NF-kappaB activation is associatied with the inflammation of bone destruction and certain cancers. The NEMO (NF-kB essential modulator)-binding domain (NBD) protein inhibits the activation of NF-kappaB. Cellular studies have shown that the NBD protein inhibits osteoclastogenesis. Mimicking infection with a lipopolysaccharide injection in mice resulted in activated osteoclasts and reduced bone mineral density. These responses are inhibited with the NBD peptide. In a mouse model of rheumatoid arthritis, collagen-induced arthritis, treatment with the NBD protein delayed the onset, lowered the incidence and decreased the severity of the arthritis. NF-kappaB is a target in the inflammation associated with bone destruction. A key issue is whether or not this important transcription factor can be inhibited without causing excessive adverse effects and/or toxicity.

Prostanoids as friends, not foes: Further evidence from the interference by cycloxygenase-inhibitory drugs when inducing tolerance to experimental arthritigens in rats

Pharmacologists have generally been prejudiced against prostanoids, uncritically accepting their suppression as desirable therapy, especially for ‘quick-fix’ analgesia. This myopic perception for a long time ignored (a) the essentiality of prostanoid precursors in nutrition, (b) the physiological protective functions of natural prostaglandins (PGs) (vasculature, stomach, kidney), (c) resolution of inflammation after the expression of COX-2 and (d) increasing therapeutic use of either synthetic PGs (for erectile dysfunction, opthalmic disorders, inducing parturition, etc) or their natural precursors, e.g., ω3-rich polyunsaturated oils, to treat arthritis. Experimental studies in rats have indicated that prostaglandins (E series) are (i) useful, perhaps auto-regulators of established immunoreactivity and (ii) able to amplify (or even induce) anti-inflammatory activity with other agents. Furthermore, anti-prostanoid therapy (APT) can be arthritigenic!!, interfering with the acquisition of tolerance to some arthritigens. For patients with rheumatoid arthritis this additional side-effect of APT, barely recognised to date, may actually perpetuate their arthritis by impairing prostanoid-mediated remission processes. Hopefully, recent adverse publicity about COX-2 inhibitory drugs might stimulate serious re-assessment of some traditional anti-inflammatory therapies with low APT activity for the management of both acute pain (non-addictive cannabinoids, celery seed, etc.) and chronic inflammation, e.g., Lyprinol® (a mussel lipid extract).

Attributes and skills of an effective musculoskeletal consumer

The OMERACT 7 Effective Musculoskeletal Consumer Workshop brought together people with rheumatoid arthritis, healthcare professionals, and researchers to discuss what they thought made a musculoskeletal consumer effective at managing their disease. Preliminary work before OMERACT provided a draft list of potential characteristics of an effective consumer. Participants at the workshop provided feedback about the list including relevance, missing items, format, and language. The feedback provided was useful and will be incorporated into a revised list to aid in the development of an instrument to measure health consumer effectiveness.

Changes in use of disease-modifying anti-rheumatic drugs in Australia over the period 1992-2004

Purpose Evidence is growing that early use of disease-modifying anti-rheumatic drugs (DMARDs) and combinations of these drugs provide optimal care for people with rheumatoid arthirits. The aim of this study was to describe objectively the pattern of consumption of DMARDs in the Australian community (community-based prescribing, specialist and general practitioner) 1992-2004, and to compare this with prescribing patterns reported in other countries. Method Dispensing statistics from the Pharmaceutical Benefit Scheme (PBS-Australia's universal prescription subsidy scheme) were analysed and temporal trends evaluated. Drug consumption was calculated as the number of dispensed defined daily doses (DDD)/1000 inhabitants/day (WHO ATC/DDD classification 2005). Results The consumption of DMARDs in the Australian community increased steadily from 2.6 DDD/1000 inhabitants/ day in 1992 to 5.5 DDD/1000 inhabitants/day. Over the period 1992-2004, methotrexate (MTX) was the most commonly used DMARD (from 0.6 to 3.0 DDD/1000 inhabitants/day). Consumption of gold (parentcral and oral) and penicillamine declined during this time. The inclusion of leflunomide on the PBS in 2000 contributed to the increase in DMARD usage. Conclusion Use of DMARDs within the Australian community has increased in recent years, coinciding with the change in guidelines for therapy for rheumatoid arthritis (RA) to earlier use of DMARDs and the more common use of combinations. This study used DDD methodology to quantify trends for DMARD consumption and these trends are broadly consistent with international prescribing patterns assessed using different methodologies. Copyright (c) 2006 John Wiley & Sons, Ltd.

Complement factor 5a as a therapeutic target

The complement system is an innate immune defense mechanism that protects the host from infection and injury. Complement activation results in the formation of anaphylatoxins, including the biologically active protein C5a. This anaphylatoxin is a potent chemotactic agent for immune and inflammatory cells and induces cell activation. In situations of excessive or uncontrolled complement activation, the overproduction of C5a can cause deleterious effects to the host, and this process is implicated in the pathogenesis of numerous immunoinflammatory disease states, including rheumatoid arthritis, psoriasis, inflammatory bowel disease, ischemia-reperfusion injuries and others. The presence of C5a in a wide variety of condition's has prompted many groups to examine the potential of inhibiting this complement activation product, with the aim of controlling these diseases and reducing the pathologic process. However, to date there is no clinically available specific C5a inhibitor and development of this new drug class is still in a relatively early stage, although limited phase I and phase II human clinical trials have been undertaken in the last few years with selected agents. In this review, examination of the current evidence supporting a specific role of C5a in selected disease states and an overview of potential therapeutic C5a inhibitors will enable the critical evaluation of the potential for C5a as a therapeutic target.

How is leflunomide prescribed and used in Australia? analysis of prescribing and adverse effect reporting

Purpose To evaluate the use of leflunomide in the Australian community since introduction in 2000. Trends in adverse drug reaction (ADR) reporting were also studied. Methods Annual Australian prescription and dispensing statistics were analysed. Drug utilisation was estimated as defined daily doses (DDD)/1000 inhabitants/day. ADR data from the Therapeutic Goods Administration's Adverse Drug Reactions Advisory Committee (ADRAC) national monitoring system were compared with the World Health Organisation (WHO) Vigibase records. Results Leflunomide use in Australia (dispensing data) increased from 0.2 in 2000 to 0.4 DDD/1000 inhabitants/day in 2002. The same overall pattern was observed in the 'authority to prescribe' data. From 2000-2002, prescribing of the starter pack (3 x 100 mg loading dose plus 30 x 20 mg tablets) declined (down 74%); likewise for the 20mg (30 tablets) pack. Gradual increases were noted for the 10 mg (30 tablets) pack (up 40%). Approximately 135 reports, detailing about 370 individual ADR, were generated annually. Gastro-intestinal disorders predominated, accounting for 24% of reactions reported to ADRAC. Skin and appendages disorders constituted 14% of reported reactions. Deaths in leflunomide users were attributed to a combination of haematological and gastro-intestinal complications, but it was not possible to ascertain other medication usage or contributing factors. Trends observed with the ADRAC reports were consistent with the WHO database. Conclusions Leflunomide was the first registered DMARD in Australia in over a decade and its use has increased within the community. The ADR reports might have contributed to Australian rheumatologists gradually abandoning loading patients with high doses of leflunomide in favour of starting therapy at lower doses. Copyright (c) 2006 John Wiley & Sons, Ltd.

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.

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.

Recent developments in C5/C5a inhibitors

Complement factor 5a (C5a) is formed upon complement system activation in response to infection, injury or disease. Whilst C5a is a potent mediator of immune and inflammatory processes, excessive production or inadequate regulation of C5a has been implicated in the pathogenesis of numerous immuno-inflammatory diseases, predominantly through experimental studies utilising animal models of disease. Both acute and chronic conditions may benefit from C5a inhibition, including rheumatoid arthritis, inflammatory bowel disease, asthma, psoriasis, haemorrhagic shock and neurodegenerative conditions. The potentially broad clinical application for treatments that inhibit the activity of C5a at C5a receptors and the large global market for anti-inflammatory therapeutics have made C5a and the C5a receptor attractive targets for academic and commercial drug development programmes. in the past 5 years, interest in C5a as a drug target has grown substantially, and this activity has resulted in a collection of patents and scientific papers reporting novel C5a and C5a receptor inhibitors and antagonists, and generated a secondary stream of patent applications broadly claiming the use of C5/C5a inhibitors as a method of treating various immune and inflammatory conditions. This paper will review the physiology and pathophysiology of C5a and discuss the development of C5a and C5a receptor inhibitors in light of the recent scientific and patent literature.