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Rheumatology
WHAT'S NEW IN RHEUMATOLOGY Published with Volume 33:11 2005
What’s new in ... Rheumatology
Medicine
Steve Young Min and Ian D Griffiths
Use of COX-2 inhibitors is controversial, as doctors struggle to interpret the trials and balance gastrointestinal safety against concerns of increased cardiovascular risk. There have been improvements in immunological testing for rheumatoid arthritis (RA), with the advent of highly specific anticyclic citrullinated peptide antibodies. This article also looks at novel treatments for ankylosing spondylitis – intravenous pamidronate and antitumour necrosis factor (TNF) therapy.
COX-2 controversy The rise and fall of rofecoxib Traditional non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen, ibuprofen and diclofenac are used in the treatment of arthritis. They act by inhibiting the enzyme cyclo-oxygenase. In the late 1980s, two isoforms of cyclo-oxygenase (COX-1, COX-2) were identified and found to have distinct patterns of expression and regulation. The COX-1 isoform appeared to be constitutively expressed, with a role in gastric cytoprotection and haemostasis, whereas COX-2 was induced by inflammatory stimuli. It was believed that selective inhibition of COX-2 would provide effective anti-inflammatory and analgesic effects without the gastrointestinal complications of NSAIDs. These predictions were borne out in the VIGOR trial, published in 2000, which
showed that a selective COX-2 inhibitor (rofecoxib, 50 mg daily) had greater gastrointestinal tolerability and safety than a traditional NSAID (naproxen, 500 mg b.d.) in 8076 patients with RA. This study revealed a reduction in the relative risk of gastrointestinal ulcer complications (perforation, obstruction, bleeding) to 0.4 (CI 0.2–0.8, p = 0.005) in the rofecoxib group. Worryingly, however, there was also an increase in the relative risk of myocardial infarction (MI) to 5.00 (CI 1.72–14.29). This study precluded use of aspirin, excluded patients with recent cardiovascular events and lacked a placebo arm. These features allowed speculation that the cardiovascular risks observed might result from a cardioprotective effect of naproxen rather than rofecoxib itself. It was proposed that naproxen, like other NSAIDs and aspirin, inhibits platelet COX-1 activity, prevents production of
Steve Young Min PhD MRCP is Specialist Registrar in Rheumatology at the Freeman Hospital, Newcastle upon Tyne, UK. Ian D Griffiths FRCP is Consultant Rheumatologist at the Freeman Hospital, Newcastle upon Tyne, UK, and Senior Clinical Lecturer at the University of Newcastle upon Tyne.
MEDICINE
1
thromboxane A2 and thereby inhibits platelet aggregation. A meta-analysis of randomized rofecoxib trials in 2001 and three case-control studies of naproxen and MI seemed to support this supposition. In September 2004, however, the manufacturer of rofecoxib, Merck, announced withdrawal of the drug because of cardiovascular toxicity seen in the results of the APPROVe trial. In this study, 2586 patients with a history of colorectal adenoma were randomized to rofecoxib, 25 mg daily, or placebo. Patients were allowed to take aspirin in doses of up to 325 mg daily. In the rofecoxib group, there was an increased risk of MI or cerebrovascular events after 18 months of treatment (relative risk 1.92, CI 1.19–3.11, p = 0.008). 1 There was also an increased incidence of congestive cardiac failure in the rofecoxib group. The findings of increased cardiovascular risk were also supported by two large casecontrol studies. Are all coxibs the same? There have also been reports of adverse cardiovascular events with the other COX-2 inhibitors. Valdecoxib and its intravenous prodrug parecoxib have been shown to increase the risk of adverse cardiovascular events following coronary artery bypass surgery. In an adenoma prevention study, celecoxib has been shown to cause a dose-related increase in cardiovascular death compared with placebo.2 However, a trial involving 18,325 osteoarthritis
© 2005 The Medicine Publishing Company Ltd
WHAT'S NEW IN RHEUMATOLOGY
patients showed a non-significant increase in cardiovascular events in those taking lumiracoxib compared with those taking naproxen or ibuprofen. No data on the cardiovascular safety of etoricoxib have been published so far. The current hypothesis for the mechanism of cardiovascular toxicity arises from a reappraisal of the original COX-1/COX-2 hypothesis. It is now recognized that COX-2 may be constitutively expressed in various tissues, including vascular endothelium and the kidney. COX-2 activity is thought to be a significant physiological source of systemic levels of prostacyclin (PGI2), a potent platelet inhibitor. It is therefore proposed that specific COX-2 inhibition leads to decreased PGI2 levels, and COX-1-dependent thromboxane production is unopposed, resulting in increased platelet aggregation. It is possible that differences in COX-2/COX-1 selectivity may result in differing cardiovascular risk. Celecoxib: are traditional NSAIDs any safer? Celecoxib is currently the only available COX-2 inhibitor for which there are data from a large trial. The decision to prescribe this drug rather than a traditional NSAID rests on the balance between the individual patient’s gastrointestinal tolerability and safety, vs possibly increased cardiovascular risk. The gastrointestinal tolerability and safety of celecoxib were reported in the CLASS trial, in which 8059 patients with osteoarthritis or RA received celecoxib, 400 mg b.d. (twice the usual maximum dose), ibuprofen, 800 mg t.d.s., or diclofenac, 75 mg b.d. Results from the trial were published at 6 months. There was no significant reduction in the primary outcome measure of gastrointestinal ulcer complications, but when ulcer complications and symptomatic ulcers were considered together, the relative risk in the celecoxib group was reduced to 0.6 (p = 0.02) compared with NSAIDs. This benefit was not present in those taking aspirin. The CLASS trial was later challenged, because of discrepancies between the published 6-month data and the entire follow-up data (made available to the US Food and Drug Administration), which showed no significant differences between ulcer complication rates in the celecoxib, ibuprofen and diclofenac groups.
MEDICINE
Nevertheless, a subsequent meta-analysis concluded that celecoxib had significantly improved gastrointestinal safety and tolerability over standard NSAIDs. Regarding cardiovascular safety, the findings of the adenoma prevention study showed that celecoxib increased cardiovascular risk compared with placebo. Of greater importance, however, is whether celecoxib (and other COX-2 inhibitors) compare favourably with standard NSAIDs. The findings of a study of naproxen, celecoxib and placebo in Alzheimer’s disease prevention (the ADAPT trial) are also of interest. This study was stopped after 3 years, because of increased cardiovascular and cerebrovascular events in the naproxen arm compared with placebo. No such increase was demonstrated in the celecoxib arm. Aspirin was allowed in this study, and it has been suggested that naproxen therapy may have interfered with the antiplatelet action of aspirin. It is clear that further debate regarding COX-2 inhibitors and cardiotoxicity must also consider the cardiovascular safety of using standard NSAIDs long term. MHRA and EMEA advice Current advice from the Medicines and Healthcare products Regulatory Agency and the European Medicines Agency regarding COX-2-selective inhibitors is that they are contraindicated in patients with established ischaemic heart disease, cerebrovascular disease, peripheral arterial disease or moderate-to-severe heart failure (New York Heart Association class II–IV). Caution is required when prescribing to patients with risk factors for heart disease (hypertension, hyperlipidaemia, diabetes and smoking). The gastrointestinal benefit has not been clearly demonstrated in those also taking aspirin, and doctors are advised to prescribe the lowest effective dose for the shortest time.
Diagnostic advances in RA Autoantibodies Rheumatoid factor (RhF) is part of the diagnostic criteria for RA and traditionally has been measured to help in the diagnosis and assessment of prognosis in patients with joint disease. IgM-RhF is generally found in 70–80% of RA patients. A wide variety of non-RhF autoantibodies have been studied, but advantages over RhF have not been shown. However, it was
2
recently recognized that many non-RhF autoantibodies recognize citrullinated peptide residues. An enzyme-linked immunosorbent assay based on synthetic cyclic citrullinated peptide (CCP) for the detection of anti-CCP antibodies was found to perform well in comparison with IgMRhF in RA patients.3 Anti-CCP antibodies perform better than RhF Multiple studies report that anti-CCP antibodies are more specific for RA than RhF, with specificities of 96–99%. Initial assays were relatively insensitive, but improved, second-generation anti-CCP2 assays may have sensitivities of 88%, and perform similarly to IgM-RhF. Anti-CCP assays are of particular diagnostic value in RhFnegative RA patients, almost 35% of whom are positive for anti-CCP antibodies. AntiCCP antibodies have also been studied in patients with early inflammatory arthritis.4 Like RhF, presence of anti-CCP antibodies appears to predict development of erosive radiographic progression and worsening disease activity. Most investigators report that combining anti-CCP and RhF status improves both diagnostic and prognostic performance. A role in the management of early inflammatory arthritis Rheumatologists now treat inflammatory arthritis early and aggressively, and there is increasing interest in the idea that the early phase of disease is a unique therapeutic window. Anti-CCP assays, in combination with IgM-RhF and imaging modalities such as musculoskeletal Doppler ultrasonography, are likely to be used increasingly to guide the management of early inflammatory arthritis.
Novel therapies for ankylosing spondylitis and psoriatic arthritis Treatment for ankylosing spondylitis has traditionally comprised NSAIDs and physiotherapy aimed at reducing pain and maintaining mobility. In general, diseasemodifying drugs such as methotrexate and sulfasalazine have little or no effect on the spinal disease in ankylosing spondylitis. In recent years, however, bisphosphonates have been reported as beneficial, and recently biological anti-TNFα-blocking agents have been licensed for the treatment of ankylosing spondylitis.
© 2005 The Medicine Publishing Company Ltd
WHAT'S NEW IN RHEUMATOLOGY
Intravenous pamidronate may be beneficial in patients with ankylosing spondylitis Bisphosphonates are widely used in the treatment of osteoporosis, in which they inhibit osteoclast activity. They have also been shown to suppress pro-inflammatory cytokines and have anti-inflammatory effects in arthritic conditions. Three open studies have suggested improvement in ankylosing spondylitis outcomes in patients treated with bisphosphonate therapy. There has also been a 6-month randomized, controlled, double-blind, dose–response comparison of monthly intravenous pamidronate (standard 60 mg vs low-dose 10 mg) in the treatment of NSAID-refractory ankylosing spondylitis. Disease activity as measured by the mean Bath Ankylosing Spondylitis Disease Activity Index had decreased by 34.5% in the 60-mg group and by 15% in the 10-mg group (p = 0.002). Differences in C-reactive protein and ESR were not significant. Although the measured benefits seen with intravenous pamidronate treatment were modest, particularly compared with those achieved with anti-TNF therapies, pamidronate is likely to remain a useful treatment option in ankylosing spondylitis.
REFERENCES 1 Bresalier R S et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352: 1092–102. 2 Solomon S D et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005; 352: 1071–80. 3 Schellekens G A et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 2000; 43: 155–63. 4 Raza K et al. Predictive value of antibodies to cyclic citrullinated peptide in patients with very early inflammatory arthritis. J Rheumatol 2005; 32: 231–8.
Anti-TNFα therapy in ankylosing spondylitis High levels of TNFα mRNA have been identified in inflamed synovium, including that in the sacroiliac joints of patients with ankylosing spondylitis or psoriatic arthritis. TNFα is believed to be the central cytokine in tissue inflammation and destruction within joints. Several anti-TNF agents are now licensed for the treatment of ankylosing spondylitis or psoriatic arthritis. All published open-label and randomized controlled trials have shown that anti-TNF therapies are effective in the treatment of patients with active ankylosing spondylitis or psoriatic arthritis when compared with those receiving placebo, but, particularly in ankylosing spondylitis, objective criteria of response are difficult to measure. In the UK, funding for these expensive regimens remains an issue. This situation is likely to continue until the National Institute for health and Clinical Excellence formally declares their eligibility.u
MEDICINE
3
© 2005 The Medicine Publishing Company Ltd
What’s new in ... Rheumatology
Medicine
Steve Young Min and Ian D Griffiths
Use of COX-2 inhibitors is controversial, as doctors struggle to interpret the trials and balance gastrointestinal safety against concerns of increased cardiovascular risk. There have been improvements in immunological testing for rheumatoid arthritis (RA), with the advent of highly specific anticyclic citrullinated peptide antibodies. This article also looks at novel treatments for ankylosing spondylitis – intravenous pamidronate and antitumour necrosis factor (TNF) therapy.
COX-2 controversy The rise and fall of rofecoxib Traditional non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen, ibuprofen and diclofenac are used in the treatment of arthritis. They act by inhibiting the enzyme cyclo-oxygenase. In the late 1980s, two isoforms of cyclo-oxygenase (COX-1, COX-2) were identified and found to have distinct patterns of expression and regulation. The COX-1 isoform appeared to be constitutively expressed, with a role in gastric cytoprotection and haemostasis, whereas COX-2 was induced by inflammatory stimuli. It was believed that selective inhibition of COX-2 would provide effective anti-inflammatory and analgesic effects without the gastrointestinal complications of NSAIDs. These predictions were borne out in the VIGOR trial, published in 2000, which
showed that a selective COX-2 inhibitor (rofecoxib, 50 mg daily) had greater gastrointestinal tolerability and safety than a traditional NSAID (naproxen, 500 mg b.d.) in 8076 patients with RA. This study revealed a reduction in the relative risk of gastrointestinal ulcer complications (perforation, obstruction, bleeding) to 0.4 (CI 0.2–0.8, p = 0.005) in the rofecoxib group. Worryingly, however, there was also an increase in the relative risk of myocardial infarction (MI) to 5.00 (CI 1.72–14.29). This study precluded use of aspirin, excluded patients with recent cardiovascular events and lacked a placebo arm. These features allowed speculation that the cardiovascular risks observed might result from a cardioprotective effect of naproxen rather than rofecoxib itself. It was proposed that naproxen, like other NSAIDs and aspirin, inhibits platelet COX-1 activity, prevents production of
Steve Young Min PhD MRCP is Specialist Registrar in Rheumatology at the Freeman Hospital, Newcastle upon Tyne, UK. Ian D Griffiths FRCP is Consultant Rheumatologist at the Freeman Hospital, Newcastle upon Tyne, UK, and Senior Clinical Lecturer at the University of Newcastle upon Tyne.
MEDICINE
1
thromboxane A2 and thereby inhibits platelet aggregation. A meta-analysis of randomized rofecoxib trials in 2001 and three case-control studies of naproxen and MI seemed to support this supposition. In September 2004, however, the manufacturer of rofecoxib, Merck, announced withdrawal of the drug because of cardiovascular toxicity seen in the results of the APPROVe trial. In this study, 2586 patients with a history of colorectal adenoma were randomized to rofecoxib, 25 mg daily, or placebo. Patients were allowed to take aspirin in doses of up to 325 mg daily. In the rofecoxib group, there was an increased risk of MI or cerebrovascular events after 18 months of treatment (relative risk 1.92, CI 1.19–3.11, p = 0.008). 1 There was also an increased incidence of congestive cardiac failure in the rofecoxib group. The findings of increased cardiovascular risk were also supported by two large casecontrol studies. Are all coxibs the same? There have also been reports of adverse cardiovascular events with the other COX-2 inhibitors. Valdecoxib and its intravenous prodrug parecoxib have been shown to increase the risk of adverse cardiovascular events following coronary artery bypass surgery. In an adenoma prevention study, celecoxib has been shown to cause a dose-related increase in cardiovascular death compared with placebo.2 However, a trial involving 18,325 osteoarthritis
© 2005 The Medicine Publishing Company Ltd
WHAT'S NEW IN RHEUMATOLOGY
patients showed a non-significant increase in cardiovascular events in those taking lumiracoxib compared with those taking naproxen or ibuprofen. No data on the cardiovascular safety of etoricoxib have been published so far. The current hypothesis for the mechanism of cardiovascular toxicity arises from a reappraisal of the original COX-1/COX-2 hypothesis. It is now recognized that COX-2 may be constitutively expressed in various tissues, including vascular endothelium and the kidney. COX-2 activity is thought to be a significant physiological source of systemic levels of prostacyclin (PGI2), a potent platelet inhibitor. It is therefore proposed that specific COX-2 inhibition leads to decreased PGI2 levels, and COX-1-dependent thromboxane production is unopposed, resulting in increased platelet aggregation. It is possible that differences in COX-2/COX-1 selectivity may result in differing cardiovascular risk. Celecoxib: are traditional NSAIDs any safer? Celecoxib is currently the only available COX-2 inhibitor for which there are data from a large trial. The decision to prescribe this drug rather than a traditional NSAID rests on the balance between the individual patient’s gastrointestinal tolerability and safety, vs possibly increased cardiovascular risk. The gastrointestinal tolerability and safety of celecoxib were reported in the CLASS trial, in which 8059 patients with osteoarthritis or RA received celecoxib, 400 mg b.d. (twice the usual maximum dose), ibuprofen, 800 mg t.d.s., or diclofenac, 75 mg b.d. Results from the trial were published at 6 months. There was no significant reduction in the primary outcome measure of gastrointestinal ulcer complications, but when ulcer complications and symptomatic ulcers were considered together, the relative risk in the celecoxib group was reduced to 0.6 (p = 0.02) compared with NSAIDs. This benefit was not present in those taking aspirin. The CLASS trial was later challenged, because of discrepancies between the published 6-month data and the entire follow-up data (made available to the US Food and Drug Administration), which showed no significant differences between ulcer complication rates in the celecoxib, ibuprofen and diclofenac groups.
MEDICINE
Nevertheless, a subsequent meta-analysis concluded that celecoxib had significantly improved gastrointestinal safety and tolerability over standard NSAIDs. Regarding cardiovascular safety, the findings of the adenoma prevention study showed that celecoxib increased cardiovascular risk compared with placebo. Of greater importance, however, is whether celecoxib (and other COX-2 inhibitors) compare favourably with standard NSAIDs. The findings of a study of naproxen, celecoxib and placebo in Alzheimer’s disease prevention (the ADAPT trial) are also of interest. This study was stopped after 3 years, because of increased cardiovascular and cerebrovascular events in the naproxen arm compared with placebo. No such increase was demonstrated in the celecoxib arm. Aspirin was allowed in this study, and it has been suggested that naproxen therapy may have interfered with the antiplatelet action of aspirin. It is clear that further debate regarding COX-2 inhibitors and cardiotoxicity must also consider the cardiovascular safety of using standard NSAIDs long term. MHRA and EMEA advice Current advice from the Medicines and Healthcare products Regulatory Agency and the European Medicines Agency regarding COX-2-selective inhibitors is that they are contraindicated in patients with established ischaemic heart disease, cerebrovascular disease, peripheral arterial disease or moderate-to-severe heart failure (New York Heart Association class II–IV). Caution is required when prescribing to patients with risk factors for heart disease (hypertension, hyperlipidaemia, diabetes and smoking). The gastrointestinal benefit has not been clearly demonstrated in those also taking aspirin, and doctors are advised to prescribe the lowest effective dose for the shortest time.
Diagnostic advances in RA Autoantibodies Rheumatoid factor (RhF) is part of the diagnostic criteria for RA and traditionally has been measured to help in the diagnosis and assessment of prognosis in patients with joint disease. IgM-RhF is generally found in 70–80% of RA patients. A wide variety of non-RhF autoantibodies have been studied, but advantages over RhF have not been shown. However, it was
2
recently recognized that many non-RhF autoantibodies recognize citrullinated peptide residues. An enzyme-linked immunosorbent assay based on synthetic cyclic citrullinated peptide (CCP) for the detection of anti-CCP antibodies was found to perform well in comparison with IgMRhF in RA patients.3 Anti-CCP antibodies perform better than RhF Multiple studies report that anti-CCP antibodies are more specific for RA than RhF, with specificities of 96–99%. Initial assays were relatively insensitive, but improved, second-generation anti-CCP2 assays may have sensitivities of 88%, and perform similarly to IgM-RhF. Anti-CCP assays are of particular diagnostic value in RhFnegative RA patients, almost 35% of whom are positive for anti-CCP antibodies. AntiCCP antibodies have also been studied in patients with early inflammatory arthritis.4 Like RhF, presence of anti-CCP antibodies appears to predict development of erosive radiographic progression and worsening disease activity. Most investigators report that combining anti-CCP and RhF status improves both diagnostic and prognostic performance. A role in the management of early inflammatory arthritis Rheumatologists now treat inflammatory arthritis early and aggressively, and there is increasing interest in the idea that the early phase of disease is a unique therapeutic window. Anti-CCP assays, in combination with IgM-RhF and imaging modalities such as musculoskeletal Doppler ultrasonography, are likely to be used increasingly to guide the management of early inflammatory arthritis.
Novel therapies for ankylosing spondylitis and psoriatic arthritis Treatment for ankylosing spondylitis has traditionally comprised NSAIDs and physiotherapy aimed at reducing pain and maintaining mobility. In general, diseasemodifying drugs such as methotrexate and sulfasalazine have little or no effect on the spinal disease in ankylosing spondylitis. In recent years, however, bisphosphonates have been reported as beneficial, and recently biological anti-TNFα-blocking agents have been licensed for the treatment of ankylosing spondylitis.
© 2005 The Medicine Publishing Company Ltd
WHAT'S NEW IN RHEUMATOLOGY
Intravenous pamidronate may be beneficial in patients with ankylosing spondylitis Bisphosphonates are widely used in the treatment of osteoporosis, in which they inhibit osteoclast activity. They have also been shown to suppress pro-inflammatory cytokines and have anti-inflammatory effects in arthritic conditions. Three open studies have suggested improvement in ankylosing spondylitis outcomes in patients treated with bisphosphonate therapy. There has also been a 6-month randomized, controlled, double-blind, dose–response comparison of monthly intravenous pamidronate (standard 60 mg vs low-dose 10 mg) in the treatment of NSAID-refractory ankylosing spondylitis. Disease activity as measured by the mean Bath Ankylosing Spondylitis Disease Activity Index had decreased by 34.5% in the 60-mg group and by 15% in the 10-mg group (p = 0.002). Differences in C-reactive protein and ESR were not significant. Although the measured benefits seen with intravenous pamidronate treatment were modest, particularly compared with those achieved with anti-TNF therapies, pamidronate is likely to remain a useful treatment option in ankylosing spondylitis.
REFERENCES 1 Bresalier R S et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352: 1092–102. 2 Solomon S D et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005; 352: 1071–80. 3 Schellekens G A et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 2000; 43: 155–63. 4 Raza K et al. Predictive value of antibodies to cyclic citrullinated peptide in patients with very early inflammatory arthritis. J Rheumatol 2005; 32: 231–8.
Anti-TNFα therapy in ankylosing spondylitis High levels of TNFα mRNA have been identified in inflamed synovium, including that in the sacroiliac joints of patients with ankylosing spondylitis or psoriatic arthritis. TNFα is believed to be the central cytokine in tissue inflammation and destruction within joints. Several anti-TNF agents are now licensed for the treatment of ankylosing spondylitis or psoriatic arthritis. All published open-label and randomized controlled trials have shown that anti-TNF therapies are effective in the treatment of patients with active ankylosing spondylitis or psoriatic arthritis when compared with those receiving placebo, but, particularly in ankylosing spondylitis, objective criteria of response are difficult to measure. In the UK, funding for these expensive regimens remains an issue. This situation is likely to continue until the National Institute for health and Clinical Excellence formally declares their eligibility.u
MEDICINE
3
© 2005 The Medicine Publishing Company Ltd