Etanercept: a pharmacoeconomic review of its use in rheumatoid arthritis

Etanercept (Enbrel), which inhibits the activity of tumour necrosis factor-alpha, is indicated in the treatment of patients with active rheumatoid arthritis (RA). A lifetime cost-utility analysis in patients with severe disease-modifying antirheumatic drug (DMARD)-resistant RA in the UK suggested that etanercept is associated with acceptable cost-utility ratios relative to traditional nonbiological DMARDs. In a 12-month cost-utility study in Spain, etanercept was predicted to be dominant over infliximab plus methotrexate in patients with active, refractory RA with regards to the cost per QALY gained and cost per American College of Rheumatology (ACR) 20 response achieved. In short-term cost-effectiveness analyses conducted in the US, the cost effectiveness of etanercept relative to other treatments in patients with methotrexate-naive or -resistant RA depends on whether predicted incremental cost-effectiveness ratios of at least USD 41,900 per ACR 20 response or USD 34,800 per ACR 70 weighted response over a 6-month period are considered acceptable (1999 values). The relative efficacy and cost effectiveness of etanercept and other biological DMARDs will be clarified when appropriate data from directly comparative clinical and/or long-term pharmacoeconomic studies become available. Etanercept may prevent or delay disability, which may produce reductions in nondrug costs that could help offset its acquisition cost.     

Etanercept: a review of its use in the management of rheumatoid arthritis

Etanercept (Enbrel), a soluble fusion protein that binds specifically to the cytokine human tumour necrosis factor (TNF), is approved for subcutaneous use in the treatment of patients with moderate to severe active rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing arthritis and plaque psoriasis in the US, Italy, the rest of the EU and other countries worldwide. Subcutaneous etanercept was efficacious and generally well tolerated in several large, well designed, clinical trials and in the clinical-practice setting in adult patients with rheumatoid arthritis, including methotrexate-naive patients with early disease and those with long-standing, treatment-resistant active disease. Etanercept plus methotrexate combination therapy was generally superior to either monotherapy in reducing disease activity and structural joint damage, as well as improving health-related quality of life (HR-QOL). Furthermore, etanercept monotherapy was superior to placebo and at least as effective as methotrexate therapy in reducing disease activity and improving HR-QOL in patients with early or refractory disease. The beneficial effects of etanercept monotherapy or combination therapy were sustained in the long term (< or =9 years). Some pharmaco-economic analyses suggest that etanercept is a cost-effective option in the treatment of patients with rheumatoid arthritis. Direct head-to-head comparisons with other biological agents would help to definitively position etanercept with respect to these agents. Nevertheless, extensive clinical experience indicates that etanercept is a valuable treatment option in adult patients with long-standing moderate to severe active rheumatoid arthritis and an emerging option in those with early disease.     

Etanercept: an updated review of its use in rheumatoid arthritis,psoriatic arthritis and juvenile rheumatoid arthritis

Etanercept is a subcutaneously administered biological response modifier that binds and inactivates tumour necrosis factor-alpha, a proinflammatory cytokine. In patients with early active rheumatoid arthritis, etanercept 25mg twice weekly was associated with a more rapid improvement in disease activity and a significantly greater cumulative response than methotrexate over 12 months of treatment in a randomised, double-blind trial. In addition, etanercept recipients showed a slower rate of radiographic progression and a more rapid improvement in quality of life than methotrexate recipients. The efficacy of etanercept was maintained at 3 years' follow-up. Etanercept was also significantly better than placebo at reducing disease activity in patients who had an inadequate response to previous treatment with disease-modifying antirheumatic drugs (DMARDs) in several well controlled trials. At study end (after 3 or 6 months' treatment), the percentage of patients achieving an American College of Rheumatology 20% (ACR20) response with etanercept (25mg or 16 mg/m(2) twice weekly) was 59 to 75% as monotherapy and 71% in combination with methotrexate; corresponding placebo response rates were 11 to 14% and 27%, respectively. Response has been maintained in patients who continued treatment for up to 5 years. In patients with psoriatic arthritis, etanercept 25mg twice weekly significantly reduced disease activity and improved skin lesions in two double-blind, placebo-controlled, 12- to 24-week trials. In the 24-week study, ACR20 response rates (50 vs 13%), psoriatic arthritis response rates (70 vs 23%) and the median improvement in skin lesions (33 vs 0%) were significantly greater in etanercept than in placebo recipients. In patients with polyarticular-course juvenile rheumatoid arthritis, etanercept resulted in improvements in all measures of disease activity and was significantly more effective than placebo at reducing disease flare. Eighty percent of patients receiving etanercept achieved a >or=30% reduction in disease activity over 7 months of treatment, and this was maintained for up to 2 years in a trial extension. Etanercept was generally well tolerated in children and adults in clinical trials; the most commonly occurring adverse effects included injection site reactions, infection, headache, rhinitis and dizziness. In conclusion, etanercept has emerged as an important new treatment option in inflammatory arthritis. Etanercept provides rapid and sustained improvements in disease activity in patients with early and DMARD-refractory rheumatoid arthritis and has been shown to inhibit radiographic progression in those with early disease. Well controlled studies have also demonstrated the efficacy of etanercept in patients with psoriatic arthritis or polyarticular-course juvenile rheumatoid arthritis.     

Etanercept in rheumatoid arthritis

Etanercept (Enbrel^?, Immunex Corporation, Seattle, Washington, USA) is a new biological disease-modifying antirheumatic drug (DMARD) for the treatment of active rheumatoid arthritis (RA). It is one of two TNF-α blockers to be licensed for the treatment of active RA and is classified as a recombinant human soluble TNF receptor. The drug competitively inhibits the binding of TNF to cell surface receptors and thus renders TNF biologically inactive. In doing so, etanercept inhibits the pro-inflammatory effects of TNF and results in a reduction of joint inflammation in patients with RA. Etanercept has shown a statistically significant reduction in swollen and inflamed joint counts, biochemical markers such as erythrocyte sedimentation rate and C-reactive protein and shown significant improvements in quality of life measures (HAQ and global assessment scores) in all studies. In early disease, etanercept has shown a reduction in joint space narrowing equal to methotrexate (MTX) and a reduction in the appearance of new erosions significantly better than MTX after 1 year of treatment. Etanercept has a rapid onset of action which is significantly faster than standard DMARDs. Etanercept was well-tolerated in clinical trials. The commonest side effects were injection site reactions and upper respiratory tract infections. Etanercept therapy has resulted in serious infections in some patients and should be used with caution in any patient with a history of recurring infections or with disease states that may predispose to infections. In summary, etanercept is an effective and well-tolerated agent that is a significant breakthrough in the treatment of this disabling condition.     

Etanercept in rheumatoid arthritis

Etanercept (Enbrel, Immunex Corporation, Seattle, Washington, USA) is a new biological disease-modifying antirheumatic drug (DMARD) for the treatment of active rheumatoid arthritis (RA). It is one of two TNF-alpha blockers to be licensed for the treatment of active RA and is classified as a recombinant human soluble TNF receptor. The drug competitively inhibits the binding of TNF to cell surface receptors and thus renders TNF biologically inactive. In doing so, etanercept inhibits the pro-inflammatory effects of TNF and results in a reduction of joint inflammation in patients with RA. Etanercept has shown a statistically significant reduction in swollen and inflamed joint counts, biochemical markers such as erythrocyte sedimentation rate and C-reactive protein and shown significant improvements in quality of life measures (HAQ and global assessment scores) in all studies. In early disease, etanercept has shown a reduction in joint space narrowing equal to methotrexate (MTX) and a reduction in the appearance of new erosions significantly better than MTX after 1 year of treatment. Etanercept has a rapid onset of action which is significantly faster than standard DMARDs. Etanercept was well-tolerated in clinical trials. The commonest side effects were injection site reactions and upper respiratory tract infections. Etanercept therapy has resulted in serious infections in some patients and should be used with caution in any patient with a history of recurring infections or with disease states that may predispose to infections. In summary, etanercept is an effective and well-tolerated agent that is a significant breakthrough in the treatment of this disabling condition.     

Leflunomide: a review of its use in active rheumatoid arthritis

A77 1726, the active metabolite of leflunomide, is an immunomodulator which inhibits cell proliferation in activated lymphocytes in patients with active rheumatoid arthritis. Because A77 1726 has a long half-life (approximately 2 weeks), treatment with oral leflunomide is initiated with a loading dose of 100mg once daily for 3 days and continued with 20mg once daily. Results of large randomised, double-blind, multicentre trials of up to 24 months' duration have shown that leflunomide is significantly superior to placebo and at least as effective as sulfasalazine in improving primary outcome measures, such as tender joint counts, swollen joint counts and physicians' and patients' global assessment, in adult patients with active rheumatoid arthritis. Whereas improvement in all primary outcome measures with leflunomide was similar to or significantly less than that with methotrexate after 12 months, the efficacy of both agents was similar after 24 months. The therapeutic effect of leflunomide appears earlier (at 4 weeks) than that of sulfasalazine or methotrexate, and reduction from baseline values in functional disability was significantly greater with leflunomide than with sulfasalazine, methotrexate or placebo at end-point. Leflunomide was at least as effective as sulfasalazine or methotrexate in delaying the rate of radiological progression of disease. The most common adverse events reported in patients receiving leflunomide in randomised double-blind, placebo-controlled trials were diarrhoea (27%), respiratory infections (21%), nausea (13%), headache (13%), rash (12%), increased serum hepatic aminotransferases (10%), dyspepsia (10%) and alopecia (9%). Leflunomide was as well tolerated as sulfasalazine or methotrexate in clinical trials. Monitoring of serum hepatic enzyme levels is recommended in patients receiving leflunomide. The drug is not recommended in female patients who are or may become pregnant. Drug treatment should be discontinued, and hastened drug elimination procedure should be considered, in male patients wishing to father a child. 16 potential cases of pancytopenia and 9 cases of serious skin reactions have been associated with the use of leflunomide in 76,000 patients to date. CONCLUSIONS: Leflunomide is a disease-modifying antirheumatic drug which reduces the signs and symptoms of inflammatory arthritis and delays the radiological progression of disease in adult patients with active rheumatoid arthritis. The drug appears to be as effective and as well tolerated as sulfasalazine or methotrexate, and represents a suitable alternative to these agents in adult patients with active rheumatoid arthritis. Benefits with leflunomide are evident within 4 weeks and efficacy is maintained for durations of up to 24 months.     

Infliximab: a pharmacoeconomic review of its use in rheumatoid arthritis

Infliximab (Remicade), a biological disease-modifying antirheumatic drug (DMARD), binds to and inhibits the activity of tumour necrosis factor-alpha, which is thought to play an important role in the pathophysiology of rheumatoid arthritis. Intravenous infliximab plus methotrexate is recommended in patients with rheumatoid arthritis who have not achieved satisfactory disease control with adequate courses of other DMARDs. Pharmacoeconomic analyses have been based on efficacy data from the pivotal placebo-controlled Anti-Tumour Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) trial in patients with active, refractory rheumatoid arthritis. Infliximab every 8 weeks plus methotrexate demonstrated rapid and sustainable improvements in clinical response, delayed radiographic progression, and/or improved functional status and health-related QOL compared with placebo plus methotrexate at weeks 30, 54 and 102. In cost-utility analyses of infliximab plus methotrexate conducted from a healthcare payer and/or societal perspective in the US, Europe, Portugal, Sweden and the UK, infliximab 3 mg/kg every 8 weeks plus methotrexate was associated with acceptable (<$US50,000 per discounted QALY gained) cost-utility ratios relative to methotrexate alone in patients with active, refractory rheumatoid arthritis. When only direct costs were considered, the lifetime incremental cost per discounted QALY gained with infliximab plus methotrexate relative to methotrexate alone was $US30,500-38,700 (year of costing 1998 or not reported; treatment duration 54 or 102 weeks or lifelong) in the US and Europe analyses, and euro39 500 (year of costing not reported; lifelong treatment) in the Portuguese analysis. The cost-utility ratios were more favourable when lost productivity costs or the additional benefit of infliximab on radiographic stabilisation were considered. In the Swedish and UK analyses with a 10-year time horizon, infliximab plus methotrexate for 1 or 2 years was associated with cost-utility ratios of euro28 600-56 100 (year of costing not reported) when direct costs were considered, and euro3440-48 200 when direct costs plus loss-of-productivity costs were considered. In conclusion, cost-utility analyses, which were based on modelling of data from the pivotal clinical trial of infliximab plus methotrexate, indicate that infliximab plus methotrexate is associated with acceptable cost-effectiveness ratios (<$US50,000 per discounted QALY gained) relative to methotrexate monotherapy in patients with active rheumatoid arthritis who have not responded to previous methotrexate or other DMARD therapy. The cost effectiveness of infliximab versus other DMARDs is at present unclear, but will be clarified when appropriate data from directly comparative clinical and/or pharmacoeconomic studies become available. In patients in whom adequate courses of other DMARDs have failed to achieve satisfactory disease control, infliximab plus methotrexate may prevent or delay disability, which may produce reductions in nondrug costs that can help offset its acquisition cost.     

Etanercept: a review of its use in the management of ankylosing spondylitis and psoriatic arthritis

Etanercept (Enbrel), a recombinant, dimeric, soluble tumour necrosis factor (TNF) receptor protein, is approved in various countries for the treatment of adult patients with ankylosing spondylitis or psoriatic arthritis.Monotherapy with subcutaneous etanercept 25mg twice weekly or 50mg once weekly was effective and generally well tolerated in patients with ankylosing spondylitis or psoriatic arthritis participating in several large, well designed clinical studies. Treatment with etanercept was more effective than placebo in reducing disease activity and improving health-related quality of life (HR-QOL) in both patient populations, and in delaying structural disease progression in patients with psoriatic arthritis. The beneficial response to etanercept achieved with shorter-term treatment was sustained in studies of up to 4 years' total duration. Randomised, well designed, head-to-head comparisons, including pharmacoeconomic analyses, with other anti-TNF biological modulators are required to accurately position etanercept and fully establish its cost effectiveness. In the meantime, etanercept is a valuable treatment option for patients with ankylosing spondylitis or psoriatic arthritis who are suitable candidates for therapy.     

Infliximab: a review of its use in the management of rheumatoid arthritis

Infliximab is a chimaeric monoclonal antibody to human tumour necrosis factor-alpha (TNFalpha). It binds to both soluble and transmembrane forms of TNFalpha at picomolar concentrations in vitro. Secondary to inhibition of TNFalpha, infliximab reduces serum levels of inflammatory mediators and vascular endothelial growth factor, decreases the expression of chemokines in the synovial tissue and reduces lymphocyte migration into the joints of patients with rheumatoid arthritis. In 2 multicentre randomised double-blind trials conducted over 26 and 30 weeks, infliximab plus methotrexate was significantly more effective than placebo plus methotrexate according to American College of Rheumatology response criteria in patients with active rheumatoid arthritis. A substantial response to infliximab-containing regimens was evident within 2 weeks. Extension phases of these studies indicate sustained clinical efficacy for up to 54 weeks. Of considerable importance are preliminary 1-year radiographic findings that show zero median progression of joint damage in infliximab plus methotrexate recipients compared with a 7 to 8% deterioration in placebo plus methotrexate recipients. Headache, nausea, upper respiratory tract infection and infusion-related reactions are the most commonly reported adverse events with infliximab. Serious events occurred in 4.4% of infliximab versus 1.8% of placebo recipients. In the largest clinical trial, 2 patients died from disseminated infection and 3 developed new or recurrent malignancies, although the exact relationship between infliximab and these events is unknown. To date, 2 patients with rheumatoid arthritis have developed drug-induced lupus. About 10% of patients may develop antibodies to infliximab, although the clinical significance of these is presently unknown. Conclusion: Infliximab represents an important advance in the treatment of rheumatoid arthritis, with tolerability concerns raised by early studies having been eased somewhat by more recent data in larger patient numbers. If preliminary results indicating that infliximab is able to arrest joint destruction in patients with rheumatoid arthritis are corroborated, the drug will likely become an integral component of future management strategies for this difficult-to-treat condition.     

Infliximab: a review of its use in Crohn's disease and rheumatoid arthritis

Infliximab (Remicade) is a chimeric monoclonal antibody against tumour necrosis factor (TNF)-alpha that has shown efficacy in Crohn's disease and rheumatoid arthritis with a disease-modifying activity and rapid onset of action. It is administered intravenously, generally in a schedule with initial infusions at 0, 2 and 6 weeks, followed by administration once every 8 weeks.Infliximab is effective in the treatment of patients with moderately to severely active Crohn's disease with an inadequate response to other treatment options or those with fistulising disease. In combination with methotrexate, infliximab reduced signs and symptoms and delayed disease progression in patients with active, methotrexate-refractory rheumatoid arthritis and in those with early disease. The drug was generally well tolerated. Recrudescence of tuberculosis infection and worsening of heart failure and demyelinating disease are among some of the concerns with anti-TNFalpha therapy, requiring cautious use of these agents in high-risk patients.Current data suggest that infliximab may be cost effective, especially when long-term clinical outcomes and burden of the diseases are taken into account. More robust, prospective pharmaco-economic studies are required to better ascertain the cost effectiveness of infliximab.Direct head-to-head comparative trials of infliximab with other biological agents are not yet available and would be helpful in determining with greater certainty the place of infliximab in the management of these diseases. Nonetheless, infliximab, like other biological agents, is a valuable treatment option in patients with moderately to severely active Crohn's disease (including fistulising disease) or rheumatoid arthritis (including early disease).     

Sulfasalazine: a review of its use in the management of rheumatoid arthritis

Sulfasalazine (salazosulfapyridine) [Azulfidine, Salazopyrin] is a well established disease-modifying antirheumatic drug (DMARD) used in the treatment of patients with rheumatoid arthritis. Clinical trials with sulfasalazine have used an array of measures of disease activity, such as the number of tender and swollen joints, Ritchie articular index (RAI) and erythrocyte sedimentation rate (ESR). In randomised, double-blind, placebo-controlled trials, sulfasalazine was associated with statistically significant benefits for various measures of disease activity, according to results of individual trials and/or meta-analysis. Sulfasalazine was associated with broadly similar efficacy to that of various other DMARDs in several randomised, double-blind, comparative trials. Promising results have also been demonstrated with sulfasalazine in combination with other DMARDs (e.g. methotrexate and hydroxychloroquine) in patients with early rheumatoid arthritis and in those with more established disease. Sulfasalazine was generally well tolerated in clinical trials, the most frequently reported adverse effects being adverse gastrointestinal effects, headache, dizziness and rash; myelosuppression can also occur. Sulfasalazine has a relatively short lag time until its onset of action and is often considered to be among the more efficacious traditional DMARDs. Based on considerations of safety, convenience and cost, many rheumatologists (particularly outside of the US) select sulfasalazine as initial therapy, although preferred first-line treatment options vary between countries.     

Etanercept: long-term clinical experience in rheumatoid arthritis and other arthritis

Etanercept is a dimeric fusion protein based on the p75 TNF-alpha receptor. It binds to TNF-alpha and blocks its biologic activity. In randomized, double-blind, placebo-controlled trials, etanercept has therapeutic activity in rheumatoid arthritis, psoriatic arthritis, polyarticular-course juvenile idiopathic arthritis and ankylosing spondylitis. Etanercept improves joint inflammation, physical function and slows/halts structural damage, especially when combined with methotrexate. A sustained response is observed in a substantial percentage of patients. Although some safety issues should be considered before starting etanercept treatment, in general terms, etanercept is a well tolerated drug with an acceptable safety profile. The use of any TNF-alpha antagonist must be in agreement with the National Recommendations for Biologic Therapy, and in difficult clinical situations, a balance between risk/benefit needs to be obtained.     

Etanercept: long-term clinical experience in rheumatoid arthritis and other arthritis

Etanercept is a dimeric fusion protein based on the p75 TNF-α receptor. It binds to TNF-α and blocks its biologic activity. In randomized, double-blind, placebo-controlled trials, etanercept has therapeutic activity in rheumatoid arthritis, psoriatic arthritis, polyarticular-course juvenile idiophatic arthritis and ankylosing spondylitis. Etanercept improves joint inflammation, physical function and slows/halts structural damage, especially when combined with methotrexate. A sustained response is observed in a substantial percentage of patients. Although some safety issues should be considered before starting etanercept treatment, in general terms, etanercept is a well tolerated drug with an acceptable safety profile. The use of any TNF-α antagonist must be in agreement with the National Recommendations for Biologic Therapy, and in difficult clinical situations, a balance between risk/benefit needs to be obtained.     

Celecoxib: a review of its use in osteoarthritis, rheumatoid arthritis and acute pain

Celecoxib is a cyclo-oxygenase (COX) inhibitor that exhibits relative in vitro and ex vivo selectivity for COX-2 over COX-1. Results of randomised double-blind multicentre studies indicate that celecoxib is superior to placebo and has similar efficacy as conventional nonsteroidal anti-inflammatory drugs (NSAIDs) in improving the signs and symptoms of osteoarthritis and rheumatoid arthritis. Analgesic efficacy and improvements in functional status are apparent within 2 weeks of starting therapy and are maintained throughout treatment. Available data suggest that celecoxib has analgesic efficacy in patients with postsurgical dental pain, although this is yet to be confirmed. In patients with osteoarthritis of the knee, celecoxib 100 and 200 mg and naproxen 500 mg twice daily were similarly efficacious and superior to placebo. Once and twice daily celecoxib dosage regimens provided comparable efficacy. Improvements in physical function paralleled those in pain relief. Celecoxib also has efficacy in treating the signs and symptoms of osteoarthritis of the hip. The effects of celecoxib were not diminished in elderly patients with osteoarthritis of the hip or knee. All dosages of celecoxib (100 to 400 mg twice daily) and naproxen 500 mg twice daily produced significant anti-inflammatory and analgesic effects in patients with active rheumatoid arthritis. In patients with stable rheumatoid arthritis, celecoxib 200 mg twice daily showed sustained symptomatic improvements similar to those of twice daily slow-release diclofenac 75 mg over a 24-week period. Celecoxib was well tolerated in clinical trials. Upper gastrointestinal complications occurred in significantly fewer patients treated with twice daily celecoxib 25 to 400 mg than in those receiving comparator NSAIDs. There was no evidence of a dose relationship in endoscopic ulcer development and incidences in celecoxib and placebo recipients were lower than in those receiving twice daily naproxen 500 mg or ibuprofen 800 mg 3 times daily. Conclusions: Celecoxib is the first COX-2 specific inhibitor approved for use in osteoarthritis and rheumatoid arthritis. Celecoxib produces significant improvements in pain and inflammation and these effects are maintained during treatment for up 24 weeks in clinical trials. Studies indicate that celecoxib has similar efficacy to conventional NSAIDs in relieving pain and improving functional status, but is associated with a lower incidence of upper gastrointestinal ulceration and complications. This promising gastrointestinal safety profile, together with sustained symptomatic relief, places celecoxib as a useful alternative for the treatment of osteoarthritis and rheumatoid arthritis, particularly in patients at high risk of developing gastrointestinal events. Although data are encouraging, its place in acute pain states remains to be established.     

Etanercept and infliximab for rheumatoid arthritis

Etanercept (Enbrel--Wyeth) and infliximab (Remicade--Schering Plough) belong to a new class of drugs that block the effects of tumour necrosis factor-alpha (TNF-alpha), a mediator of inflammation. Both are licensed for the treatment of patients with active rheumatoid arthritis who have responded inadequately to disease-modifying antirheumatic drugs (DMARDs). Here, we consider whether etanercept and infliximab offer advantages.     

Auranofin. A preliminary review of its pharmacological properties and therapeutic use in rheumatoid arthritis

Auranofin is the first orally active gold compound for the treatment of rheumatoid arthritis. Like other chrysotherapeutic agents, its exact mechanism of action is unknown, but it probably acts via immunological mechanisms and alteration of lysosomal enzyme activity. Although long term clinical experience with auranofin is limited, its efficacy appears to approach that of sodium aurothiomalate. Further comparative studies with aurothioglucose, hydroxychloroquine and D-penicillamine are required before definitive statements can be made regarding the relative efficacy of auranofin and these agents. While patients have demonstrated clinical remission of rheumatoid arthritis in response to auranofin therapy, radiological studies have been inconclusive regarding its effect on the occurrence or progression of erosive lesions. Auranofin is relatively well tolerated in most patients, but diarrhoea, skin rash, and pruritus are sometimes troublesome, and thrombocytopenia and proteinuria are potentially serious side effects which may occur during therapy. Whereas mucocutaneous side effects are more frequent with injectable gold compounds, gastrointestinal reactions are the most common adverse effect seen with auranofin. The frequency of side effects has been similar with auranofin and sodium aurothiomalate, but they are generally less severe with auranofin. While some of the side effects are controlled by a reduction in dosage, temporary or permanent withdrawal of auranofin may be necessary. Auranofin is clearly a useful addition to the limited list of agents with disease-modifying potential presently available for the treatment of rheumatoid arthritis. It will doubtless generate much interest as its final place in therapy becomes better defined through additional well-designed studies and wider clinical experience.     

Rofecoxib: a review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis

Rofecoxib is a selective cyclo-oxygenase (COX)-2 inhibitor which has little or no effect on the COX-1 isoenzyme at doses up to 1000 mg/day. Rofecoxib has greater selectivity for COX-2 than celecoxib, meloxicam, diclofenac and indomethacin. In well-controlled clinical trials, rofecoxib 12.5 to 500 mg/day has been evaluated for its efficacy in the treatment of osteoarthritis, acute pain and rheumatoid arthritis [lower dosages (5 to 125 mg/day) were generally used in the chronic pain indications]. In the treatment of patients with osteoarthritis, rofecoxib was more effective in providing symptomatic relief than placebo, paracetamol (acetaminophen) and celecoxib and was similar in efficacy to ibuprofen, diclofenac, naproxen and nabumetone. Overall, both the physician's assessment of disease status and the patient's assessment of response to therapy tended to favour rofecoxib. In patients with postsurgical dental pain, pain after spinal fusion or orthopaedic surgery, or primary dysmenorrhoea, rofecoxib provided more rapid and more sustained pain relief and reduced requirements for supplemental morphine use after surgery than placebo. Rofecoxib was more efficacious than celecoxib in patients with acute dental pain and pain after spinal fusion surgery, although celecoxib may have been used at a subtherapeutic dose. In comparison with traditional nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, diclofenac and naproxen sodium, rofecoxib was similar in efficacy in the treatment of acute pain. Although naproxen sodium provided more rapid pain relief than rofecoxib in patients with primary dysmenorrhoea, the reverse was true after orthopaedic surgery: rofecoxib provided more rapid pain relief and less supplemental morphine was needed. Rofecoxib was as effective as naproxen in providing symptomatic relief for over 8700 patients with rheumatoid arthritis. Compared with traditional NSAID therapy, rofecoxib had a significantly lower incidence of endoscopically confirmed gastroduodenal ulceration and, in approximately 13,000 patients with osteoarthritis and rheumatoid arthritis, a lower incidence of gastrointestinal (GI) adverse events. Rofecoxib was generally well tolerated in all indications with an overall tolerability profile similar to traditional NSAIDs. The most common adverse events in rofecoxib recipients were nausea, dizziness and headache. In conclusion, rofecoxib is at least as effective as traditional NSAID therapy in providing pain relief for both chronic and acute pain conditions. Rofecoxib provides an alternative treatment option to traditional NSAID therapy in the management of symptomatic pain relief in patients with osteoarthritis. Initial data from patients with primary dysmenorrhoea and postoperative pain are promising and further trials may confirm its place in the treatment of these indications. Rofecoxib has also shown promising results in patients with rheumatoid arthritis and is likely to become a valuable addition to current drug therapy for this patient population. Importantly, rofecoxib is associated with a lower incidence of GI adverse events than traditional NSAIDs making it a primary treatment option in patients at risk of developing GI complications or patients with chronic conditions requiring long term treatment.     

Valdecoxib: a review of its use in the management of osteoarthritis, rheumatoid arthritis, dysmenorrhoea and acute pain

Valdecoxib is an orally administered, highly selective cyclo-oxygenase (COX)-2 inhibitor with anti-inflammatory and analgesic properties. In well designed trials, valdecoxib demonstrated efficacy versus placebo in patients with osteoarthritis (OA), rheumatoid arthritis (RA), primary dysmenorrhoea and postoperative pain. Initial results in patients with migraine headache were promising. The efficacy of valdecoxib appears dose dependent up to 40 mg/day. Valdecoxib 10 mg/day was as effective as naproxen and rofecoxib in improving signs and symptoms of OA. The American College of Rheumatology 20% response rate was similar in recipients of valdecoxib, naproxen and diclofenac in patients with RA. In patients with dysmenorrhoea, valdecoxib 20 or 40 mg up to twice daily provided as effective pain relief as naproxen sodium 550 mg twice daily. In acute post-surgical pain, single-dose valdecoxib 40 mg had a rapid onset of action, provided similar analgesia to oxycodone 10 mg plus paracetamol (acetaminophen) 1000 mg and provided a longer time to rescue medication than rofecoxib or oxycodone/paracetamol after oral surgery. Pre-emptive administration of valdecoxib 10-80 mg was particularly effective in dental pain. Valdecoxib had opioid-sparing effects after hip or knee arthroplasty and reduced pain after laparoscopic cholecystectomy. Valdecoxib is generally well tolerated. The incidence of gastroduodenal ulcers was generally lower than with nonselective NSAIDs (i.e. NSAIDs not specifically developed as selective COX-2 inhibitors). With concomitant aspirin, the ulcer rate in valdecoxib recipients increased significantly, but was still lower than that in recipients of aspirin plus nonselective NSAIDs. In conclusion, valdecoxib, a COX-2-selective inhibitor, is as efficacious in pain relief as nonselective NSAIDs, with better gastrointestinal tolerability. It was as effective in RA, OA and primary dysmenorrhoea (the approved indications) as nonselective NSAIDs and as effective as rofecoxib in RA flare. In acute post-surgical pain, valdecoxib provided similar pain relief to oxycodone/paracetamol, had a long duration of action, a rapid onset of analgesia and was opioid-sparing. Valdecoxib provides a valuable alternative in the treatment of chronic arthritis pain and acute pain.     

Cyclosporin a in rheumatoid arthritis: A critical review

Khawar K, Buchanan WW. Cyclosporin A in rheumatoid arthritis: a critical review. Inflammopharmacology. 1993;2:141–157. This paper reviews the current position of cyclosporin A in the therapeutic armamentarium of rheumatoid arthritis. The pharmacokinetic disposition, results of open and controlled trials, and toxicity will be reviewed.     

Celecoxib: a review of its use for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis

Celecoxib (Celebrex?) was the first cyclo-oxygenase (COX)-2 selective inhibitor (coxib) to be introduced into clinical practice. Coxibs were developed to provide anti-inflammatory/analgesic activity similar to that of nonselective NSAIDs, but without their upper gastrointestinal (GI) toxicity, which is thought to result largely from COX-1 inhibition. Celecoxib is indicated in the EU for the symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis in adults. This article reviews the clinical efficacy and tolerability of celecoxib in these EU-approved indications, as well as overviewing its pharmacological properties. In randomized controlled trials, celecoxib, at the recommended dosages of 200 or 400?mg/day, was significantly more effective than placebo, at least as effective as or more effective than paracetamol (acetaminophen) and as effective as nonselective NSAIDs and the coxibs etoricoxib and lumiracoxib for the symptomatic treatment of patients with active osteoarthritis, rheumatoid arthritis or ankylosing spondylitis. Celecoxib was generally well tolerated, with mild to moderate upper GI complaints being the most common body system adverse events. In meta-analyses and large safety studies, the incidence of upper GI ulcer complications with recommended dosages of celecoxib was significantly lower than that with nonselective NSAIDs and similar to that with paracetamol and other coxibs. However, concomitant administration of celecoxib with low-dose cardioprotective aspirin often appeared to negate the GI-sparing advantages of celecoxib over NSAIDs. Although one polyp prevention trial noted a dose-related increase in cardiovascular risk with celecoxib 400 and 800?mg/day, other trials have not found any significant difference in cardiovascular risk between celecoxib and placebo or nonselective NSAIDs. Meta-analyses and database-derived analyses are inconsistent regarding cardiovascular risk. At recommended dosages, the risks of increased thrombotic cardiovascular events, or renovascular, hepatic or hypersensitivity reactions with celecoxib would appear to be small and similar to those with NSAIDs. Celecoxib would appear to be a useful option for therapy in patients at high risk for NSAID-induced GI toxicity, or in those responding suboptimally to or intolerant of NSAIDs. To minimize any risk, particularly the cardiovascular risk, celecoxib, like all coxibs and NSAIDs, should be used at the lowest effective dosage for the shortest possible duration after a careful evaluation of the GI, cardiovascular and renal risks of the individual patient.