Credit for Learning: 2This article will form the basis of questions under the PJ/College of Pharmacy Practice Credit for Learning scheme |
In this article, the clinical presentation of rheumatoid arthritis is outlined, followed by discussion of the management of pain and inflammation with non-steroidal anti-inflammatory agents. The use of disease modifying anti-rheumatic drugs will be discussed in a later article
Rheumatoid arthritis is a chronic inflammatory disorder of the joints which is characterised by potentially deforming polyarthritis and a wide spectrum of extra-articular manifestations. It is the most common inflammatory arthritis and affects about 1 per cent of the adult population.
Rheumatoid arthritis is more common in women than men and is an important cause of disability and morbidity.1 There is also significant mortality associated with the disorder, with a reduction in life expectancy of approximately four years for men and 10 years for women.2 The mortality from other conditions including infection, cardiovascular disease, respiratory disease, renal disease and gastrointestinal problems is also increased.3 In this article the pathophysiology and clinical presentation of rheumatoid arthritis are described, followed by discussion of the management of pain and inflammation with non-steroidal anti- inflammatory drugs (NSAIDs). Management with disease modifying anti-rheumatic drugs (DMARDs) and potential new developments will be covered in a later article.
In the normal joint, the articulating surfaces are covered with hyaline cartilage and the joint is enclosed within a capsule. The latter is lined with synovium, a specialised tissue that produces synovial fluid to lubricate the joint. In early rheumatoid arthritis the synovium becomes inflamed (synovitis) and effusion into the joint space occurs which causes pain, stiffness and joint swelling. Once triggered, synovitis becomes self-sustaining. During later disease, polymorphonuclear leucocytes, lysosomal enzymes and other enzymes which are contained in the inflammatory effusion actively degrade the cartilage. Sustained inflammation of the synovium also leads to the formation of pannus, which is a granulation tissue. This tissue erodes the cartilage and eventually begins to erode the bone. Longstanding inflammation and effusion distend the joint capsule, causing the ligaments to become lax.
The combined effects of joint damage, muscle wasting, instability and continued use lead ultimately to joint deformity.
After a variable period, synovial inflammation may subside either spontaneously or as a result of treatment. If little structural damage has occurred, the joint may appear clinically or radiologically normal. If the joint has been damaged during the period of active inflammation, deformities will persist and may worsen as secondary degenerative changes follow.4
Rheumatoid arthritis is classified using the revised 1988 American Rheumatism Association (ARA) criteria, at least four of which must be present for at least six weeks for a positive diagnosis of rheumatoid arthritis. These criteria include:
The goals of management in rheumatoid arthritis are to relieve pain, stiffness and swelling, to prevent disease progression and deformities, to improve mobility and function of joints and, as far as possible, to maintain the patient's normal lifestyle. Drug treatment should not be considered as the only option. Management should involve a combination of interventions including rest, exercise, education, emotional support, occupational therapy and physiotherapy as well as drug treatment. The management plan can be individualised, based upon factors such as joint function, degree of disease activity, the patient's age, gender, occupation and response to previous therapy.
There are many general measures which can be used to help patients with rheumatoid arthritis. Education plays a vital role. Provision of information on the disease and its therapies gives patients a realistic outlook and allows them to be involved in therapeutic decisions. Education also emphasises the role of patients in controlling their own disease.
As much of the pain and stiffness associated with rheumatoid arthritis comes from peri-articular tissues, such as muscle and tendons, physiotherapists can advise on exercises and mobilisation techniques which can be tailored to the needs and capabilities of individual patients. Use of wax baths and hydrotherapy may also help to improve mobility and general fitness as well as maintaining muscle bulk around the joints.
Occupational therapists can provide appliances and devices to help patients with the activities of daily living. These include, for example, support rails and adaptors for keys and taps. In addition to educating patients on their drug therapy, pharmacists can provide a range of devices which may assist compliance, such as Haleraids and wing caps.
The role of the dietitian is also important. Some trials have suggested a consistent but modest benefit from the inclusion of fish oil, fish supplements or evening primrose oil in the diet. Various elimination diets have also been proposed.5,6 The Dong diet, which involves avoiding red meat, dairy products, fruit, herbs, additives and preservatives, is popular with patients.
Joint replacement has been one of the greatest advances in the management of rheumatoid arthritis. Other surgical procedures that are beneficial include tendon transfers (manipulation to reduce deformity) and synovectomy (removal of the synovial membrane, which is often undertaken in patients with RA of the knee). Function may be greatly improved after tendon transfer, particularly in the hand. Although used less frequently, synovectomy can usefully debulk a synovial mass, resulting in reduced pain.6
Unlike the treatment of osteoarthritis, simple analgesics provide only limited relief from the pain, stiffness and inflammation associated with rheumatoid arthritis. Therefore, although simple analgesics have a place in early disease when taken on an "as required" basis, greater benefit will be obtained from the use of non-steroidal anti-inflammatory drug (NSAIDs). In single doses, NSAIDs have analgesic activity comparable to paracetamol but in regular full dosage they have both a long lasting analgesic and an anti-inflammatory effect.
NSAIDs work to suppress inflammation by preventing the production of prostaglandins through inhibition of the enzyme cyclo-oxygenase (COX) which is known to have two isoforms, COX-1 and COX-2. It has been proposed that the anti-inflammatory actions of NSAIDs are due to COX-2 inhibition whereas the side effects, which include gastrointestinal and renal toxicity, are related to inhibition of COX-1.
NSAIDs show a wide variation in toxicity which may relate to some extent to their selectivity for COX-2. For example, drugs with a better COX-2:COX-1 activity ratio may have anti-inflammatory activity with fewer systemic side effects.
In addition, NSAIDs have been shown to interfere with a variety of other processes which may contribute to their effects. These include leukotriene synthesis, superoxide generation, lysosomal enzyme release, neutrophil function, cell membrane and lymphocyte function and cartilage metabolism.7
There are over 20 different oral NSAIDs available, most of which can be classified into six different structural groups. These are aspirin and the salicylates, the propionic acid derivatives, the fenamic acids, the acetic acid derivatives, the enolic acids and the alkalones. The classification and pharmacokinetic parameters of selected NSAIDs are shown in Table 1.
The choice of an NSAID for a particular patient is based upon a number of factors, including relative efficacy, toxicity, concomitant drugs, concurrent disease states, the patient's age, renal function, cost and, to a certain extent, on the prescriber's preference.
Differences in anti-inflammatory activity between NSAIDs in different groups is small but there is a wide variation in the incidence of side effects and in individual patient response. About 60 per cent of patients will respond to any given NSAID; of the others, those who do not respond to one drug may well respond to another, but it may be necessary to try several drugs before the most suitable agent is found for a particular patient. In considering patient response it is important to give each NSAID an appropriate therapeutic trial before an alternative is tried. An analgesic effect should normally be obtained within one week of starting therapy whereas a full anti-inflammatory effect may not be achieved (or may not be clinically assessable) for up to three weeks.
| Table 1: Classification and pharmacokinetic parameters of selected NSAIDs | ||
| Drug | Half life (hours) | Elimination |
| Aspirin and salicylic acid derivatives | ||
| Aspirin | 0.25 | Dose-related hepatic metabolism and renal |
| excretion of free salicylate (pH dependent) | ||
| Diflunisal | 5 (250mg daily) | Glucuronide conjugation and renal excretion |
| 20 (500mg daily) | ||
| Propionic acid derivatives | ||
| Flurbiprofen | 4 | Hepatic metabolism and renal excretion |
| Ibuprofen | 2 | Hepatic metabolism |
| Ketoprofen | 2 | Hepatic metabolism |
| Naproxen | 14 | Hepatic metabolism and renal excretion |
| Enolic acids | ||
| Azapropazone | 15 | Renal excretion of unchanged drug; little |
| hepatic metabolism | ||
| Meloxicam | 20 | Hepatic metabolism |
| Piroxicam | 38 | Hepatic metabolism — undergoes |
| entero-hepatic circulation | ||
| Acetic acid derivatives | ||
| Diclofenac | 2 | Hepatic metabolism |
| Etodolac | 3 | Hepatic metabolism and renal excretion |
| Indomethacin | 4 | Hepatic metabolism — enterohepatic |
| circulation via bile and renal excretion | ||
| Sulindac | 7 | Metabolised to active sulphide and sulphone |
| 16 (active metabolite | metabolites; excreted in urine and faeces | |
| Undergoes enterohepatic circulation | ||
| Alkalones | ||
| Nabumetone | 26 | Hepatically metabolised to active metabolites |
| Undergoes renal excretion | ||
Historically, aspirin was the traditional first choice but now other NSAIDs are used because they are better tolerated and more convenient. Ibuprofen, a propionic acid derivative, is the most commonly used first-line agent as it combines good efficacy with a low incidence of side effects. However, its anti-inflammatory properties are weaker than those of other NSAIDs. Diclofenac, an acetic acid derivative, is a popular alternative as a first or second-line agent; indomethacin, which is felt to have a superior anti-inflammatory action, is associated with a higher incidence of side effects and is often reserved as a third-line agent.
Azapropazone, an enolic acid, produces a similar effect to naproxen but is associated with a high incidence of gastrointestinal side effects. For this reason, its use is restricted to rheumatoid arthritis, ankylosing spondylitis and acute gout when other NSAIDs have been tried and failed. It is contraindicated in patients with a history of peptic ulcer disease and the maximum daily dose has been reduced to 600mg daily in patients over 60 years of age.
Piroxicam has a long half life which permits once daily administration. While this may encourage compliance and be useful for patients who experience problems with early morning stiffness, piroxicam has a higher risk of side effects than slow-release formulations of ibuprofen.
The most important adverse effects of NSAIDs are gastrointestinal bleeding and perforation which occur in approximately 1 per cent of patients taking the drug long term and result in significant morbidity and mortality. About 60 per cent of patients taking NSAIDs for extended periods complain of symptoms such as nausea, dyspepsia, heartburn and/or epigastric pain, and active gastro-duodenal lesions occur in 30 to 50 per cent of these cases. However, some patients who present with bleeding or perforation have no history of dyspepsia or peptic ulceration.
The potential for serious adverse effects in the absence of warning signs is of great concern, especially as NSAID-induced gastrointestinal side effects are more prevalent among elderly patients.8 This has led to a number of strategies being proposed to reduce the gastrointestinal toxicity associated with NSAIDs. These include synthesis of pro-drugs, the development COX-2 selective and COX-2 specific agents, manufacture of different formulations and use of alternative routes of delivery, as well as co-prescription of gastrointestinal prophylaxis with H2 antagonists, proton pump inhibitors and synthetic prostaglandins.
Pro-drugs were developed with the aim of allowing absorption of inactive drug across the gastrointestinal mucosa without affecting prostaglandin synthesis until subsequent activation in the liver.
Nabumetone is a COX-2 selective, non-acidic pro-drug which is a member of a group called the alkalones. It is well absorbed after oral administration and is converted in the liver to its active metabolite 6-methoxy-2-naphthylacetic acid (6-MNA), which is a potent inhibitor of prostaglandin synthesis. 6-MNA is metabolised to inactive metabolites which are excreted via the kidney. There is no enterohepatic recirculation. The combination of COX-2 selectivity, non-acid pro-drug properties and the absence of biliary excretion of the active metabolite of nabumetone theoretically reduce the likelihood of gastrointestinal adverse drug reactions. In several studies, nabumetone appears to have comparable efficacy to naproxen but less gastrointestinal toxicity.9
Sulindac is a pro-drug which is structurally related to indomethacin. It is converted to a highly active sulphide metabolite in the liver. One theoretical advantage of sulindac is that adverse effects on the kidney are less likely as the active sulphide metabolite appears not to inhibit renal prostaglandin synthesis.10 However, sulindac does not appear to offer any particular advantages over other NSAIDs and it is not commonly used in clinical practice.
One of the COX-2 preferential agents is meloxicam, an enol-carboxamide which is related to piroxicam. It has limited selectivity for COX-2. At a dose of 7.5mg daily, meloxicam has been shown to cause no more mucosal injury than placebo in the short term. At a dose of 15mg daily, symptomatic gastrointestinal side effects appear to be intermediate between placebo and piroxicam 20mg daily.
This is consistent with the reduction in COX-2 selectivity which is known to occur at higher doses. In trials, meloxicam has been well tolerated at a dose of 7.5mg daily and caused significantly fewer symptomatic gastrointestinal side effects than either diclofenac 100mg daily or piroxicam 20mg daily over a period of one month. Whether a safety advantage persists with 15mg is not known.11,12 The main criticism of meloxicam is the absence of a large body of evidence from endoscopic studies in patients to confirm its relative safety,9 the fact that its effect on COX-1 remains considerable and its high cost compared with some of the "traditional" agents.
Two other well tolerated NSAIDs which have been marketed in the UK for a number of years are etodolac and nabumetone (which also has pro-drug properties, as discussed above). Like meloxicam, both these agents are reported to have some COX-2 selectivity.
The first of the new COX-2 selective agents, celecoxib, was approved by the US Food and Drug Administration (FDA) in 1998 for use to treat inflammation related to rheumatoid and osteoarthritis but not for analgesia. Rofecoxib is likely to become available in the US later this year for osteoarthritis and broad pain management, but not for rheumatoid arthritis. Rofecoxib was launched in the UK last week but the current licence does not include use in RA.
It has been suggested that these two agents may become the first cyclo-oxygenase inhibitors convincingly to break the prostaglandin-dependent link between efficacy and gastrointestinal toxicity.13 Both have been reported to have a similar ulcer incidence to placebo and a lower incidence than naproxen and diclofenac (in celecoxibrials) and ibuprofen (in rofecoxib trials).
Highly selective COX-2 inhibitors may have major advantages, although these will not become evident until after wider use in clinical practice. However, they may have some limitations as there are several circumstances where COX-2 may be important for homoeostasis and where use of these drugs could, in theory, be deleterious. For example, safety data are needed in patients with Helicobacter pylori and gastrointestinal inflammation (including inflammatory bowel disease) in which COX-2 may be an important source of protective prostaglandins. The extent to which COX-2 inhibitors share the effects of non-selective NSAIDs on renal function also needs to be established (because COX-2 is expressed in the kidney). Their effect on the incidence of vascular disease will also need to be investigated in view of a reported role of COX-2 in sustaining vascular prostacyclin production.13
While COX-2 selectivity increases the safety of NSAIDs it will also limit their therapeutic application as they will not have the cardioprotective effects of aspirin which are mediated through COX-1. There has also been some suggestion that COX-1 activity may be needed for analgesic potency. The development of COX-2 selective agents is an interesting area where further developments are expected over the next few years.13
Although the administration of enteric-coated tablets and use of topical formulations or suppositories decreases any direct irritant effect of NSAIDs on the gastric mucosa it will not eliminate the risk of serious gastrointestinal adverse effects since the drug still reaches the mucosa via the systemic circulation.
Nevertheless, a wide range of topical NSAIDs is available in a variety of formulations such as gels, foams, creams, ointments and sprays. These are popular with patients but are often expensive. The most favourable results with these agents has been in acute, self limiting soft tissue injuries; their application in chronic inflammatory conditions such as rheumatoid arthritis requires further study.
For those patients who are at particular risk of developing NSAID-related gastrointestinal damage, and where use of an NSAID is essential, prophylactic therapy should be considered with an H2 antagonist, proton pump inhibitor or misoprostol.
Elimination or reduction of gastric acid by H2 antagonists reduces the incidence of duodenal but not gastric ulceration, while proton pump inhibitors, such as omeprazole, reduce the incidence of both gastric and duodenal ulceration compared with placebo. Misoprostol, a prostaglandin analogue, given in doses of 200µg two to four times daily, has been shown successfully to reduce gastric and duodenal ulcers as well as their complications. However, side effects such as diarrhoea, which occur in up to 40 per cent of patients may limit its use, especially in elderly patients.8
Possible future alternatives to COX-2 selective inhibitors include nitric oxide (NO) NSAIDs. Like prostaglandins, nitric oxide protects the gastric mucosa. NO-NSAIDs have a nitric oxide moiety linked to a conventional NSAID. In theory, these drugs donate NO to the gastric mucosa to counterbalance the harmful effects of prostaglandin deficiency. Studies in animals have shown a good gastrointestinal safety profile. However further work is needed to show their clinical value and to determine if they offer any practical advantages over COX-2 selective agents.
When choosing NSAIDs for inclusion in a drug formulary, the logical approach, in view of the significant variation in individual patient response, would be to select a range of agents from different chemical classes to enable treatment to be optimised.
When selecting an agent for an individual, the chosen drug should be started at a low dose. The dose should be increased after three to four days if the drug has a short half-life (eg, less than 12 hours) and after seven days if it has a longer half-life (see Table 1). If the chosen agent is tolerated, the patient should be tried on the maximum dose for a period of three weeks before it is concluded that the NSAID in question is ineffective and another is tried. At this stage, selection of a drug from a different chemical class may be appropriate in a patient who has had little or no response, whereas in a patients who experiences a partial response, selection of a more potent agent from the same chemical class would be reasonable.
During this initial stage an analgesic such as paracetamol may be added to supplement analgesic activity.
In practice, ibuprofen should be recommended as first-line therapy in the majority of patients as it is effective, inexpensive and has the lowest reported incidence of side effects.
Finally, it is good practice to ensure that patients taking NSAIDs long term, especially those under the care of their general practitioner, are reviewed regularly and the continued need for NSAIDs critically assessed.
The use of these agents in patients whose joint pain is related to mechanical destruction, rather than active inflammation, is inappropriate. In this group, use of regular paracetamol and/or a more potent opioids analgesic is a safer alternative.
Rheumatoid arthritis is the most common inflammatory arthropathy. Early, accurate diagnosis and referral to a rheumatologist is essential. Although pain and inflammation can be minimised by judicious use of NSAIDs and exercise can maximise mobility, early initiation of disease modifying (DMARD) therapy is essential if progressive joint damage is to be minimised. The use of DMARDs will be discussed in the next article in this series.
Mrs Wood is deputy chief pharmacist at University Hospital, Liverpool
References1. Brooks PM. Rheumatoid arthritis: aetiology and clinical features. Medicine 1998;26:28-31.
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