Rheumatology 2001; 40: 603-606
© 2001 British Society for Rheumatology
Editorials |
Arthritis therapy: a better time, a better day
At a time when our arthritis armamentarium has clearly expanded beyond anything we have experienced in our previous medical lifetime, it behoves us to pause and reflect. How different are the new COX-2 non-steroidal anti-inflammatory drugs (NSAIDs) from their predecessors? Does their aggressive marketing distract from a balanced therapeutic approach to pain, suffering and deadly disease? We face a new challenge in our responsibility to respect and utilize unique advances in the international pain community.
We are still trying to sort out a rational approach to combinations of our potent but toxic disease-modifying drugs. How do the incredibly effective biologicals fit into this schema? What changes in timing and choices do these immunomodulating advances, and even an ‘arthritis machine’, portend for our structured attempts to create rational algorithms for our treatment efforts? The new additions are as impressive as they are varied. This editorial is an attempt to sort them out and put them in the perspective of our previous choices. Just as important, in our world of disparate resources, will be the issue of how they may be used. How they should be used reflects our grave responsibilities in dealing with the lifelong ravages of diseases that are amongst the most painful, disabling, destructive and deadly in all of medicine.
At the time that these new therapies were receiving regulatory approval, we had just celebrated the centennial anniversary of the use of aspirin, at one time the most-used drug in the world—certainly for arthritis. It is telling that this potent agent is now largely relegated to once daily use for the prevention of thrombotic events. Aspirin was the prototype for NSAIDs, but never in many decades of clinical evaluation of up to 100 NSAIDs has any of them shown superior efficacy, either analgesic or anti-inflammatory, to aspirin itself on a head-to-head equivalent dose basis [1]. The history of NSAIDs has been a star-crossed one at best. Yet despite significant toxicities of indomethacin and phenylbutazone a number of remarkable NSAIDs have emerged from the pack [2]. Benoxyprofen was approved as an NSAID that appeared to have potential for disease-modifying effects in rheumatoid arthritis (RA) that had never previously been expected from NSAIDs [3]. It was shortly withdrawn in a clamour of medical–legal lawsuits when significant numbers of very elderly patients died from hepatorenal complications. This had not been seen in over a decade of previous NSAID research, in which regulatory requirements excluded the very elderly.
The pharmacokinetics of each of our drugs must always be evaluated against the pharmacodynamics of representative at-risk populations. The long half-life of benoxyprofen was even longer in the very elderly, in whom excretion could take 80 h [4]. Thus, with prolonged use, benoxyprofen glucuronate crystals, previously cleared by healthy kidneys, accumulated in the bile canuliculi, producing liver failure and death. Rather than limit this most useful agent to a younger, healthier population, the manufacturer voluntarily withdrew the agent because of the storm of lawsuits.
Carprofen was the next NSAID to follow. As a consequence of the recent benoxyprofen disaster, carprofen was only approved as ‘not for primary use’. This was in the wake of anxiety about similar adverse events (though not serious this time), consisting of rashes and occasional liver enzyme abnormalities [4]. The manufacturer simply could not accept this limitation for marketing reasons, and withdrew it. Carprofen was the first COX-2 drug; it lacks gastric mucosal toxicity and is limited to veterinary use, primarily in dogs, which are otherwise vulnerable to NSAID gastropathy [5].
Sudoxicam was the first oxicam introduced to clinical research. It has documented disease-modifying effects in rheumatoid disease, as has benoxyprofen [6]. But sudoxicam was withdrawn after its idiosyncratic hepatonecrotic potential was noted (rarely), and a number of related deaths ended all clinical testing.
Piroxicam, an analogue of sudoxicam, succeeded it. This approved NSAID was to lead to more deaths from gastrointestinal bleeding than had been documented with any other NSAID to date [7].
In contrast to the symptomatic role of NSAIDs, immunomodulating therapies were evolving. Corticosteroids, introduced in the 1940s, are still used today, but in an ever-changing role. Because of the potential for abuse and the skills required in their use, they must be used with care if they are to be reliable in induction therapy. They are also invaluable for serious complications of non-articular rheumatic disease, such as vasculitis, and they have been used more recently in low doses in combination with disease-modifying anti-rheumatic drugs (DMARDs) to reduce erosions in RA [8].
The use of gold salts was the first disease-modifying therapy to come into use. This treatment was discovered serendipitously in the 1930s and is still in use despite serious toxicity and the limited responder population.
Chemotherapeutic agents were first recognized for rheumatoid disease in the 1950s. Methotrexate has separated from the pack as the most used of this group for RA, through to the present [9]. Combination therapies using these agents were to become popular towards the end of the last decade [10].
It is against this historical background of our armamentarium that the approval of a host of disparate but important new therapies confronts us. Dozens of other high-tech agents are now in various stages of clinical testing as we enter our new therapeutic millennium.
After decades of new NSAIDs and their continuing toxicity concerns (gastropathy, renal disfunction, etc.), a number of selective COX-2 agents have been introduced and are among the most successful entries to the market in medical history [11]. Yet, although these agents have the same efficacy profile as NSAIDs and the same analgesic limitations, they are therapeutic agents distinct from the NSAIDs [12]. Indeed, their COX-1-sparing properties do constitute an important distinction. This is primarily in relation to NSAID gastropathy, gastrointestinal bleeding and the associated deaths that plague the use of the older NSAIDs and are the most frequent dangerous adverse events reported to regulatory agencies worldwide [13, 14]. The direct and indirect costs of this may be greater than those for all other therapies [15].
Data to date support the selective gastrosparing safety of the COX-2 agents [16]. However, older, non-acetylated salicylates from the last century have always been prostaglandin-sparing and therefore gastrosparing [1]; however, they have been faulted as providing limited analgesia.
This brings us to an entirely different group of agents that have always been superior to aspirin and NSAIDs for more serious or severe pain: the opioids. The World Health Organization has recently given its imprimatur to opioids for sustained use in serious non-malignant pain (primarily arthritis and musculoskeletal pain) [17]. Because of this, a world pain community, separate from the rheumatology community, has endorsed such use through newer long-acting release systems that allow 24-h pain control with opioids [18]. This approach has recently been reported to be safer, and to allow pain relief with opioids at lower doses [19]. This is part of a recent literature that deals with the problems of pseudo-addictive behaviour, breakthrough pain and poor dosage control with the older pattern of ad libitum/add-on use of opioids. This latter practice has been common in clinical rheumatology [17–19]. Opioids, when properly and skilfully employed, often at moderate doses in arthritis, are virtually free of end-organ toxicity [20]. This is in marked contrast to the arthritis armamentarium that we use to treat a high-risk, chronically ill, elderly population.
Methotrexate is still the cornerstone of rheumatoid disease-modifying therapy. But for patients who do not respond to or cannot tolerate methotrexate, leflunomide has emerged as a viable new alternative [21]. In head-to-head comparisons it holds up well as an effective DMARD, with a therapeutic toxicity ratio approximately equivalent to that of methotrexate. However, it will be many years until we are able to compare leflunomide against methotrexate for long-term sustained therapy. Methotrexate has by far the most persuasive record of continuing efficacy of over a decade or more compared with other DMARDs [9]. Methotrexate in combination with leflunomide will also require long-term observation. Early results suggest that there may be concern with this combination, in that in some patients it may amplify the liver enzyme abnormalities common to both agents [22].
Combinations of three or more DMARDs have become the vogue in recent years [10]. However, none of these combinations has had a clearcut, specifically defined and corroborated advantage in efficacy in rheumatoid disease over the use of one or two agents alone [23]. Studies of the long-term outcome of the use of these combinations were faulted epidemiologically because of the varying disease stages and responses of the individual host subpopulations. In truth, these ever-changing combinations had all the scientific elegance of cluster bombing.
Biologicals, in contrast, have entered the new millennium with the introduction of highly targeted molecules created to exploit the wonders of recombinant DNA. Now, with laser-like precision, new agents directed against tumour necrosis factor (TNF), interleukin 1 and CD4 have been tested successfully in RA [24]. Unfortunately anti-CD4 therapy has shown the terrifying potential of a man-made AIDS agent, with potential for seriously depleting the number of T cells [25].
Now that this in biological therapy has been added to the archives, anti-interleukin therapies have emerged successfully. A number of anti-TNF therapies (infliximab and etanercept) have now been approved and are being used successfully in clinical practice. These potent early treatments, however, raise the issue of the risk of sustained specific suppression by interleukins of the steady-state, harmonized biological backup systems that are normally needed for the correct working of a healthy, reactive immune system [26, 27]. There is thus a long-term threat of potent specific immunosuppression. Therefore, the high risk of infections proceeding to sepsis, and even death, in more vulnerable, chronically ill or very elderly treated subpopulations becomes of immediate concern in prioritizing and making choices among these treatments [26, 27]. The possibility of a targeted immune surveillance system with potential for leading to lymphomas or death in more vulnerable chronically ill or very elderly treated subpopulations is of immediate concern [24, 26] and must be monitored closely. This is especially true for a disease already prone to a high incidence of neoplasia.
At present, the obvious alternative to the long-term maintenance of profound immunosuppression is spaced induction therapy. This model could be based on the spaced induction therapy intervals, with ‘rest periods’, that are commonly used in chemotherapy in oncology. It took a long period of trial and error to devise an acceptable, safe schedule for methotrexate in RA [9]. We may learn from this and other experiences, including our knowledge of the use of pulses of potent alkylating agents or of high-dose steroids alternating with less toxic long-term maintenance schedules [23].
In contrast, we also have a non-immunosuppressive therapy recently approved in the form of Prosorba column apheresis [28, 29]. This cumbersome intervention is invasive and expensive, and requires twelve 2-h sessions of extracorporeal therapy once weekly. In this intervention, adequate venous access is necessary, as is sustained compliance. Serum is separated from the cells and passed through a beer mug-sized container containing purified staphylococcal protein A. This activates complement and other biochemical changes yet to be clarified. More to the point, apheresis has led at times to impressive clinical efficacy in the face of unremitting rheumatoid disease [28, 29]. It is now clearly an alternative to our existing therapies. In the years of the pivotal protocol trial that led to the approval of this procedure, no DMARDs were allowed and an average of five or more DMARDs had failed. Yet even in these dire circumstances of advanced, unresponsive disease, 47% of Prosorba-treated patients (vs the sham group) demonstrated impressive disease modification [29]. Improvement often continued for up to a year or more after the initial induction phase. To date this therapy has been limited to more severe rheumatoid disease. But postmarketing experience now indicates that there is a larger potential RA responder population when Prosorba apheresis is used in combination with methotrexate or other DMARDs [30].
Other unique biologicals, and even a rheumatoid vaccine, are undergoing clinical testing. But in today's global system of rationed health-care delivery there are serious issues of availability and realistic cost concerns. These must be counterbalanced by postmarketing documentation of actual benefits weighed against the enormous expense of uncontrolled rheumatoid disease. For it is what we do to whom and under what risk circumstances that determines the ratio of therapeutic success to toxicity. In the absence of a cure, this long-term challenge is based upon approved, documented clinical research carried out as part of the regulatory process. But persuasive as those trials may be, they represent relatively small cohorts of patients compared with the humbling challenge of the use of such potent agents in what will become a huge postmarketing exposure.
NSAID therapy remains the most used form of medication in all countries in all arthritis populations of all ages [15]. The major advancement in this area is the recognition of the potential limitations of this ubiquitous therapy. NSAIDs have a therapeutic ceiling that is too often not able to control the chronic pain suffered by our patients [19]. NSAID treatment is too often too dangerous in our elderly and high risk patients [4, 13]. The new COX-2 NSAID agents offer an important measure of safety in the face of the all too frequent gastrointestinal catastrophes seen in the long-term treatment of typically older arthritics [16]. Twenty-four-hour pain control with properly regulated opioids is a new and important change in strategy [20]. In all countries, it requires special levels of skill and responsibility for monitoring opioid use.
Our choices among multiple disease-modifying agents can be resolved only on the basis of our skills and experience, applied one patient at a time. These choices should be based on the growing body of evidence-based data specific to the combinations used in RA and related rheumatic disorders.
The highly potent new biologicals seem ideally appropriate as induction therapy. Only time and experience will tell us whether open-ended, profound immunosuppression is justified in view of the severity of the diseases we are treating, in comparison with the rest pauses in biological therapy alternating with background DMARD combinations.
Totally new choices, such as Prosorba column apheresis and anti-idiotype or anti-sense vaccines, surely expand our therapeutic horizons and choices. So much pharmacotherapeutic opportunity heralds a better time in our fight against dreadful diseases. Our challenge is to master and apply effectively this cornucopia of opportunities to successfully open the door to a better day.
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