The folate antagonist methotrexate (MTX) has become established as the most commonly used disease-modifying anti-rheumatic drug (DMARD) in the treatment of rheumatoid arthritis (RA) but is commonly discontinued due to adverse effects. Adverse effects are thought to be mediated via folate antagonism. In this paper we summarize the current data on the use of folates as a supplement to MTX use in RA for the prevention of adverse effects and as a potential modulator of cardiovascular risk, and propose guidelines for standard practice.

We aimed to obtain an estimate of the prevalence and demographics of systemic sclerosis (SSc) and its subtypes at the turn of the millennium.

Licofelone, a competitive inhibitor of 5-lipoxygenase, cyclooxygenase (COX)-1 and COX-2, is currently in clinical development for the treatment of osteoarthritis (OA). Licofelone decreases the production of proinflammatory leukotrienes and prostaglandins-which are involved in the pathophysiology of OA and in gastrointestinal (GI) damage induced by NSAIDs-and has the potential to combine good analgesic and anti-inflammatory effects with excellent GI tolerability. Initial endoscopy data in healthy volunteers have demonstrated that licofelone is well tolerated and has a GI safety profile similar to placebo and significantly better than naproxen. These tolerability results were confirmed in patients with OA in two separate randomized studies. Furthermore, a long-term study (52 weeks) has shown that licofelone is at least as effective as naproxen in the treatment of OA. Licofelone also appears to be as effective as the selective COX-2 inhibitor celecoxib in the treatment of the signs and symptoms of OA. Licofelone has a GI safety profile similar to that of celecoxib, but may offer the advantage of fewer incidences or worsening of peripheral oedema. Preliminary data have also shown that licofelone coadministration with low-dose aspirin does not lead to increased GI toxicity. The emerging clinical data for licofelone indicate that it is an effective and well-tolerated therapy that could offer safety advantages over current treatment options, and that it could be suitable for the long-term treatment of a broad spectrum of patients with OA.

The development of osteoarthritis may be accompanied by increased production of leukotrienes (LTs) and prostaglandins (PGs) from arachidonic acid. These products contribute to joint damage, pain and inflammation. Cyclooxygenase (COX)-1 and COX-2 are responsible for the production of PGs. Inhibition of these enzymes by non-steroidal anti-inflammatory drugs and selective COX-2 inhibitors reduces the levels of PGs, resulting in a reduction in pain and inflammation. However, this inhibition can cause alternative processing of arachidonic acid via the 5-lipoxygenase (5-LOX) pathway, resulting in increased production of proinflammatory and gastrotoxic LTs. Licofelone is a competitive inhibitor of 5-LOX, COX-1 and COX-2 that is currently being developed for the treatment of osteoarthritis. Licofelone decreases the production of both LTs and PGs, and thereby reduces inflammation and pain with low gastrotoxicity. Unlike selective COX-2 inhibitors, coadministration of licofelone and aspirin does not appear to be associated with an increase in gastrointestinal adverse events, at least under experimental conditions. Furthermore, there is evidence from animal models to suggest that licofelone may stop disease progression.

Non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors are commonly used to control pain and inflammation in osteoarthritis. However, these agents have been associated with gastrointestinal, renal and cardiovascular adverse effects. Together, these complications indicate a clear unmet need in the safety of current treatment options for the management of osteoarthritis. NSAIDs are known to have adverse gastrointestinal effects, and more recently it has been suggested that some selective COX-2 inhibitors are also associated with serious gastrointestinal complications. Selective COX-2 inhibitors have a similar capacity to NSAIDs to delay ulcer healing, and may not significantly decrease the incidences of perforation, ulceration and bleeding (the most clinically relevant gastrointestinal endpoints) compared with NSAIDs. These effects may be due to overlapping roles of COX-1 and COX-2 in physiological and pathophysiological processes. Furthermore, as COX-2 is integrally involved in renal homeostasis, selective COX-2 inhibitors are associated with negative effects on kidney function similar to those seen with NSAIDs. Electrolyte disturbances, oedema and hypertension have been correlated with the use of both drug classes. Additionally, selective COX-2 inhibitors have the potential to increase cardiovascular events, although further research is required to clearly determine such a risk. With the current unmet needs in the treatment of osteoarthritis, the opportunity exists for the development of new therapies. Novel agents include the COX-inhibiting nitric oxide donors and the lipoxygenase (LOX)/COX inhibitor licofelone. Initial results suggest that these therapies may have tolerability advantages over the NSAIDs and selective COX-2 inhibitors.

Scoring poorly on the health assessment questionnaire (HAQ) has recently been shown to be a strong predictor of morbidity and mortality in rheumatoid arthritis (RA), while a good HAQ score is predictive of a better outcome. In patients presenting with early diffuse scleroderma prognosis is variable. Our goal was to determine possible baseline predictors of future good outcomes.

The increasing costs of health-care and the need for cost containment have resulted in a 'fourth hurdle' in the establishment of drug approval and reimbursement policies. This hurdle is the demonstration of a drug's cost-effectiveness through the process of economic evaluation. The role of models in the economic evaluation of pharmaceuticals is becoming increasingly accepted with the recent trend towards developing models with greater transparency and clinical relevance. However, health-care decisions do not, and should not, rely solely on the cost-effectiveness of a drug or intervention. Factors such as disease severity, availability of alternative treatment strategies, cost of drugs to patients, compliance with therapy and patients' satisfaction with overall treatment effectiveness should also be considered, and in some cases can be incorporated into economic evaluation. The Arthritis Cost Consequences Evaluation System (ACCES) is provided as an example of the attributes and limitations that should be considered in determining the usefulness of a model for economic evaluations with the purpose of determining reimbursement policy decisions.

Pain has been recognized as a problem of global proportions, and postoperative pain is one of the most common types of pain. Postoperative pain is acute and, although it is preventable and/or treatable, it is often undertreated. Lack of appropriate analgesic management has significant impact on clinical and economic outcomes. Negative clinical outcomes of inadequately managed acute postoperative pain include extended hospitalization, compromised prognosis, higher morbidity and mortality, and the development of a chronic pain state as a result of neuronal plasticity. Although estimating the economic burden of postoperative pain is difficult, this burden is considerable and results from direct costs due to excess health-care resource use, as well as indirect costs due to reduced patient functionality and productivity. These latter factors also have a significant adverse impact on patients' quality of life and may be associated with the development of depression and anxiety. Thus, improved clinical outcomes are dependent not only on the availability of effective drugs but also on their appropriate utilization. A multimodal approach incorporating different drugs and techniques is effective in reducing postoperative pain but is limited by the currently available therapies. The efficacy of opioids is well established, but there are concerns about dependency, respiratory depression and side-effects, which patients often find intolerable. Non-steroidal anti-inflammatory drugs (NSAIDs) are effective as adjunctive medication in a multimodal regimen but are associated with side-effects, such as platelet dysfunction and renal and gastrointestinal toxicity, that have special clinical significance in patients undergoing surgical procedures. Cyclooxygenase-2-specific inhibitors such as celecoxib, rofecoxib and valdecoxib, were developed to provide the efficacy of non-specific NSAIDs while limiting associated toxicity. These agents have demonstrated analgesic efficacy and an opioid-sparing effect in a variety of surgical procedures, suggesting their value as an alternative to non-specific NSAIDs. Further studies are needed to determine the impact of these drugs on clinical and economic outcomes when used in a programme of postsurgical pain management.

Azathioprine (AZA) is widely used in the management of rheumatological diseases. Despite its efficacy, AZA can often cause bone marrow suppression, notably leucopenia, which has been recorded in up to 17% of patients taking AZA for rheumatoid arthritis, though this can be considered clinically significant in about 3% overall. Severe myelosuppression, associated with abnormal AZA metabolism, is linked to the thiopurine methyltransferase (TPMT) genetic polymorphism. TPMT status can be assessed prior to AZA treatment by measuring enzyme activity or genotyping techniques. Analysis of recent data suggests that by optimizing the AZA dose on the basis of TPMT status testing (with a substantial reduction in dose for patients homozygous for mutant TPMT alleles), a reduction in drug-induced morbidity and cost savings can be made by avoiding hospitalization and rescue therapy for leucopenic events. In this article we review the pharmacogenetic and clinical implications of the TPMT polymorphism, emphasizing its relevance to rheumatologists managing diseases with AZA.

To devise new tools to assess activity and damage in patients with idiopathic myopathies (IIM).