SARAH RYAN, SUSAN OLIVER AND ANN BROWNFIELD
Objectives
After reading this chapter you should be able to:
• Explain the mechanism of pain.
• Describe the purpose and mode of action of analgesia, NSAIDs, DMARDs, biologic therapies and steroids.
• Discuss the drug management of a patient with inflammatory arthritis.
• Debate the advantages and disadvantages of introducing a self-medication programme in the clinical area.
• Discuss the role of complementary therapies in the management of arthritis.
The treatment of rheumatological disorders will involve many components including education, exercise, adaptation and drug therapy. The main objectives of drug intervention will be to:
• Reduce or alleviate symptoms such as pain and stiffness.
• Suppress disease activity in chronic disorders such as RA.
The experience of pain can only be defined in terms of human consciousness. As with all sensory experience there is no way of being certain that one person’s experience of pain is the same as another’s (Jones, 1997). Pain is a paradox while being an accepted phenomenon experienced by everyone at some time during their life. It is also a unique, subjective and unverifiable personal experience (Turk and Melzack, 1992). Pain is one of the cardial symptoms of rheumatoid arthritis and will affect both physical and psychological aspects of functioning. It is the major contributor to the morbidity, disability and socioeconomic cost of musculoskeletal disorders (Cohen, 1994).
There are a number of evidence-based guidelines which can support the clinician in the managment of pain (ARMA, 2005; Australian Acute Musculoskeletal Pain Guidelines Group, 2004; Koes, Van Tulder and Osteso, 2001; Pain Society, 2005; Turk, Dworkin and Allan, 2003).
Acute pain is a transient experience where the source of pain is usually identifiable. Here pharmacological interventions are able to suppress the pain stimuli (Pearce and Wardle, 1989). In comparison chronic pain is an ongoing experience; often patients may demonstrate an array of associated disorders such as anxiety, depression and insomnia.
Drug Therapy in Rheumatology Nursing: Second Edition. Edited by Sarah Ryan. © 2007 John Wiley & Sons, Ltd.
The successful pharmacological control of pain dictates that nurses possess a comprehensive pharmacological knowledge and effective interpersonal skills to enable the assessment, planning, implementation and evaluation of pharmacological interventions in the management of pain (Lubkin, 1990).
PHYSIOLOGY OF PAIN
The Gate Control Theory of Pain
The gate control theory originates from Melzack and Wall (1982). It has been most influential in developing our present understanding of the mechanism of pain. Occasionally viewed as oversimplified or too rigid it has provided a framework which demonstrates the complexity of the pain response (Jackson, 1995).
The theory is founded on two main concepts (see Figure 2.1).
• The transmission of pain messages can be modulated within the spinal cord. This occurs via descending messages from the brain, which inhibit sensations from peripheral and internal sources being experienced as pain. Two neurotransmitters appear to be involved in this process. The release of enkephalin at the spinal cord inhibits the uptake of calcium ions by the spinal cord neurones. This prevents further transmission of the pain message. Serotonin (the second neurotransmitter) is involved in the transmission of pain messages between the raphe magnus and the cord.
• The transmission of pain messages to the brain can be altered by activating another source of sensory receptor.
When pain impulses enter the dorsal horn of the spinal cord the gate control mechanism is either opened or closed. A number of laminae within the dorsal horn form the gate control mechanism and this specialized area enabled the pain impulses to be modulated (Jackson, 1995).
Figure 2.1 Influences on the pain gate.
The primary sensory neurones involved in pain transmission are:
• Type A delta fibres. These are small myelinated fibres capable of transporting messages at speeds of 6-30 metres per second.
• Type C fibres. These are very small and have no myelin insulation. Therefore messages are transmitted a lot slower at speeds of 0.5-2 metres per second (Guyton, 1991). Type C fibres transmit slower chronic pain.
Impulses from A delta and C fibres are excitary in nature and promote the release of an exitory neurotransmitter Substance P, which opens the gate facilitating the perception of pain.
The opening of the gate allows the transmission of pain impulses along the spinoreticular and reticular thalamic tracts through various junctions into the sensory cortex (Fordham, 1986).
Studies of the thalamus and somatosensory cortex show that in arthritis some cells have an abnormally large response to joint stimulation causing changes in the way impulses are transmitted (Newman et al., 1996).
• Type A beta fibres. These are larger fibres than other sensory neurones and electrical impulses travel along them at a greater speed. Therefore, the pain stimulus conducted along type A beta fibres will be quicker and faster than transmission along the other fibres. If activated, type A beta fibres will occupy the secondary neurones first thereby blocking other pain messages. These fibres can be activated by rubbing or vibration of the skin and their activation will close the ‘pain gate’. This theory has been instrumental in the development of treatment inter- ventations such as transcutaneous electrical nerve stimulation machines (TENS).
PAIN RECEPTORS
Sensory receptors are situated in the tissues of the body, especially in the skin, synovium of joints and in the walls of arteries. These receptors are referred to as nociceptors as they respond to noxious stimuli. Such receptors can be divided into three categories.
• Mechanical changes in the receptor. In active inflammatory conditions such as RA, increased synovial fluid in the joint cavity and proliferation of the inflamed synovial tissues causes pain by distention and stretching of the capsule.
• Temperature changes. Exposure of the tissues to extremes of temperature can cause stimulation of the receptors.
• Inflammatory changes. The inflammatory response initiated by tissue damage will cause the release of prostaglandin, bradykinin, histamine and serotonin. This will stimulate a reaction in the receptors.
Some nociceptor receptors will respond to all the above stimulants. They terminate in the dorsal horn of the spinal cord and transmit their pain messages to secondary neurones. The destination for secondary neurones is the thalamus.
THE ROLE OF THE BRAIN
Pain signals terminate in the brain. Fast pain signals are relayed via the brain stem and the thalamus to areas of the cortex, especially the somatosensory area. This region of the cortex can differentiate the area of the origin of the pain message.
Slow pain messages are relayed over a wide area of the brain stem and thalamus. The reticuloactivitating system is situated in the brain stem; when it is stimulated it increases the excitability of the brain. This is why people with chronic pain conditions such as fibromyalgia report difficulty in sleeping, resting and relaxing. Also it provides us with a reason why chronic pain is difficult to locate because the pain messages are not relayed to the somatosensory areas.
Once stimulation of the receptor ceases so should the pain but pain pathways cannot explain all pain experiences and patients can continue to experience pain after the original cause of the pain has been removed.
Woolf (1994) offers a theory for the development of chronic pain states. He proposes that neurones in the dorsal horn of the spinal cord become hypersensitive and develop alternative synapses with neighbouring neurones. This causes pain messages to go astray.
Also, other substances released within the spinal cord can mediate the transmission of pain signals. N-Methyl-D aspartate (NMDA) and neurokinin (NK) cause the spinal cord neurones to become hypersensitive. This can cause the reproduction of hyperalgesia (severe pain to a stimulus that would normally only produce mild pain) and allodynia (pain in response to a stimulus that would not normally be painful - for example, stroking the skin - Woolf, 1994).
Additionally, many aspects of higher levels of processing will have a considerable effect on how unpleasant a pain stimulus is. The experience of pain is influenced by anxiety, cultural factors, the environment and past experiences (Gibson, 1994). Reassurances that a stimulus will be brief considerably reduces the unpleasantness rating (Jones, 1997). This assumes that there is an inevitable behavioural sequence that is initiated by a noxious stimulant referred to as the ‘bottom up approach’ (Jones, 1997). However the brain is quite capable of simply ignoring noxious stimuli altogether under conditions of severe stress (Melzack and Wall, 1982) and it is capable of selecting what sensory information is acted on; this is known as the ‘top down approach’. It is the balance between these ascending and decending processes that determines our perception of pain (Jones, 1997).
PHYSIOLOGICAL EFFECTS OF ACUTE PAIN
Once the acute pain impulse has passed the gate control mechanism it enters the reticular activating system, and sympathetic nervous system activity increases aiding the body’s flight of fight mechanism (Jordan, 1992).
This activity includes:
• An increase in hormonal activity. The anti-diuretic hormone increases the reabsorption from the renal tubules retaining water within the body (this can elevate blood pressure).
Aldosterone increases the reasorption of sodium from the renal tubules;
Adrenaline causes increased consciousness and emotion;
Cortisol increases blood glucose levels and the secretion of hydrochloric acid and pepsinogen.
• An increase in cardiovascular activity. Tachycardia and increased cardiac output.
• An increase in gastric activity. This leads to a reduction in gastric emptying.
The major pharmacological interventions for the management of pain include the following categories of drug therapy:
• Non-opioid analgesia
• Compound analgesia
• Opioid analgesia
• Antidepressant drugs
• Non-steroidal anti-inflammatory drugs (NSAIDs).
NON-OPIOID ANALGESIA
These medications are administered to treat mild-moderate pain.
Acetaminophen — Paracetamol
Paracetamol is an undervalued effective analgesic agent (Cohen, 1994). Its mechanism of action remains poorly understood although there is evidence of direct effect on the central nervous system (CNS) rather than on peripheral tissue. It blocks the synthesis and secretion of prostaglandin preventing nociceptor sensitization (Speight, 1987). It has both analgesic and anti-pyretic properties.
Pharmacokinetics
Taken orally paracetamol is well absorbed from the gastrointestinal tract and inactivated in the liver. A major advantage is the lack of upper gastrointestinal toxicity, especially ulceration and bleeding.
Adverse Effects
The well-known hazard of hepatoxicity is virtually only seen in conjunction with a drug overdose and is increased with liver disease and alcoholism. The daily dose should be closely monitored in these situations. The risk of nephrotoxicity with chronic dosing remains uncertain but is probably very small (Cohen, 1994).
COMPOUND ANALGESIA
Compound analgesia are fixed ratio combinations of non-opioid (aspirin or paracetamol) and opioid analgesia (dextropropoxyphene or codeine) preparations.
Compound analgesia contain either a low dose or full dose of opioid analgesic. Thus this range of analgesia is able to bridge the therapeutic gap between nonopioid and opioid analgesia. However it is worth noting that the compound or combined analgesic effect may also result in a combination of the side effects of both analgesia. Examples of these drugs include Co-Codamol and Codydramol. Adverse effects are shown in Table 2.1.
OPIOIDS
This group of drugs is classified in terms of its efficacy into two categories - low and high efficacy opioids (See Table 2.2). Their role in the management of moderate to severe musculoskeletal pain is controversial (Cohen, 1994). Although certain patients may benefit without experiencing adverse effects and addiction, the question of true efficacy has not yet been answered (Davis, 2000; Jamison, 1996).
Opioid analgesies work by fitting into the opioid receptors of the brain and spinal cord. These receptors are also used by endorphins, the body’s own opioid. Opioid analgesia inhibits the transmission of nociceptive messages to the higher centres or through activation of the decending anti-nociceptive pathways (Ferrante, 1983). Evidence from Stein (1991) highlights the peripheral analgesic action of these medications in conditions characterized by inflammatory hyperalgesia.
Table 2.1 Adverse effects of compound analgesia.
Dizziness
Sedation
Nausea/vomiting
Constipation
Abdominal pain
Rashes
Headaches
Weakness
Euphoria
Dysphoria
Hallucinations
Minor visual disturbances
Abnormal liver function tests
________
Table 2.2 Opioids.
Low efficacy
Codeine
Dihydrocoedeine
Dextropropoxyphene
Nalbuphine
Pentazocine
High efficacy
Buprenorphine
Dextromaramide
Diamorphine
Dipipanone
Meptazinal
Morphine
Papaveretum
Pethidine
Tramadol
______
Low Efficacy Opioids
Codeine Phosphate
Primarily prescribed as an analgesic but also used as an antidiarrhoeal drug and a cough suppressant, codeine has been in use for nearly 100 years. Although codeine’s analgesic properties are similar to morphine its analgesic action is equal to approximately only 10% of morphine.
Pharmacokinetics
Taken orally codeine is quickly absorbed within the gastrointestinal tract and metabolized within the liver. It has a half life of approximately two to three hours. Excretion of codeine is via the kidneys into the urine. The analgesic effect of 30 mg of codeine is suggested to equal 300-600 mg of aspirin.
Dihydrocodeine tartrate - this medication possesses a similar analgesic effect to codeine.
Dextropropoxyphene Hydrochloride
The analgesic effect of dextropropoxyphene is considerably less than that of codeine. Chemically it is structurally related to methadone but it possesses less analgesic, antitussive and dependency properties. The main use of dextropropoxyphene is as a compound analgesia with aspirin (doloxene).
Pharmacokinetics
Dextropropoxyphene is rapidly absorbed in the gastrointestinal tract and metabolized within the liver. In the event of an overdose the rapid absorption of dextropropoxyphene is able to produce respiratory arrest, hypotension and cardiac dysrhythmia within one hour.
High Efficacy Opioids
Buprenorphine (Temgesic)
This opioid can be useful because of the length (six hours) and strength of its analgesic properties. It also possesses both opioid agonist and antagonist qualities. It is therefore less likely to produce addiction, respiratory depression or affect cardiovascular function than other opioid analgesics.
Pharmacokinetics
Administered sublingually; if swallowed buprenorphine is metabolized within the liver and possesses a half life of five hours.
Dextromoramide (Palfium)
A derivative of the opium poppy, dextromoramide is a powerful quick acting analgesia which has been prescribed in Britain since the 1950s for severe and intractable pain. In relation to morphine it has a shorter duration of action and is less sedating. There fore it is able to produce pain relief without affecting consciousness, mental activity or inducing constipation unlike other opioids.
Concomitant administration of tranquillizers such as clopromazine produces a synergistic analgesic effect.
Pharmacokinetics
Taken orally dextromoromide is quickly absorbed and metabolized within the liver. It is short acting with a duration of approximately three hours.
Diamorphine Hydrochloride
Introduced 100 years ago diamorphine is indicated for both severe and chronic pain. It is a powerful opioid analgesia and is a derivative of the unripe seed pod of the opium poppy. Although diamorphine mirrors morphine in both its actions and uses it is able to produce enhanced pain relief with less adverse effects such as nausea or hypotension.
Pharmacokinetics
Following administration diamorphine is rapidly converted into monoacetyl morphine and more slowly metabolized into its main active metabolite morphine. Within 24 hours approximately 80% of the dose is excreted via the urine.
Fentanyl
Fentanyl is more efficacious than morphine. It is normally administered as an intra-operative analgesic. Fentanyl can also be used for chronic pain in the form of a patch for transdermal drug delivery (Durogesic). This mode of administration possesses the ability to maintain its efficacy for 72 hours.
Morphine
Derived from opium and in use since the last century morphine is prescribed for moderate to severe pain in both acute and chronic conditions. Morphine acts on the CNS to eliminate pain and it also possesses the ability to transform the unpleasant sensation of pain into a sense of euphoria. Morphine therefore has two major effects, one depressing, the other stimulating (Trouce and Gould, 1990).
The ‘depressing’ effects of morphine can include:
• Reduction of the appreciation of pain
• Suppression of respirations and the cough reflex
• Reduction of anxiety and inducing the feeling of euphoria
• Some levels of sedation (due to its mildly hypnotic properties)
• Reduction of the peristaltic activities of the bowel
• Urinary retention.
The stimulant effects of morphine can include:
• Increased arousal of the chemoreceptor trigger zone within the brain stem including nausea and vomiting.
• Increased arousal of the vagus nerve which may produce such effects as bradycardia and hypotension, owing to a parasympathic action in the cardiovascular system (Trouce and Gould, 1990)
Morphine works on specific opioid receptors situated throughout the body. Such receptors are divided into categories and include delta, kappa and mu receptors. It is the mu receptor on which morphine has its main effects. Mu receptors are associated with analgesia, respiratory depression, euphoria and dependance (Walker, 1994). The pharmacological effects of morphine on each individual will differ considerably (Rowbotham, 1993).
Pharmacokinetics
Following oral administration morphine is absorbed from the gastrointestional tract where is undergoes conjugation in the gut wall and liver with approximately 20% of the dose actually reaching the systemic circulation. Elimination of the majority of morphine is via the kidneys in the urine. Subcutaneous and intramuscular administration is quicker than oral administration. Drug interactions and adverse effects are shown in Tables 2.3 and 2.4.
Pethidine Hydrochloride
Akin to morphine, pethidine provides rapid pain relief for short durations of time. Prescribed inappropriately it can be addictive.
Tramadol Hydrochloride (Zydol)
Tramadol can enhance both serotonenergic and adrenergic pathways. It is considered equal to morphine regarding its efficacy when prescribed for moderate chronic pain but is less likely to cause respiratory depression, addiction or constipation than morphine. Tramadol has been shown to reduce NSAID consumption and relieve pain in osteoarthritis of the knee (Brant, 2004). It is also available in combination with paracetamol.
Table 2.3 Drug interactions of opioids.
Alcohol: enhances the sedative and hypotensive efects
Antidepressants: may result in CNS excitement or depression
Antipsychotics: enhance the sedative and hypotensive effects
Anxiolytics and hypnotics: enhance the sedative effect
Antihistamines; enhance the sedative effects
Cisparide: may antagonize the effect of gastrointestinal motility
Ulcer healing drugs: may increase plasma concentrations of opiods
Antiemetics: antagonize the effects of gastrointestinal activity
_________
Table 2.4 Adverse effects of opioids.
Nausea and vomiting
Constipation
Respiratory depression
Hypotension
Dry mouth
Micturition difficulties
Bradycardia/tachycardia
Hallucinations
Mood changes
Addition
Reduced libido
________
Pharmacokinetics
Administered orally tramadol is quickly absorbed from the gastrointestinal tract. It possesses a half life of six hours. Tramadol is excreted in the urine and approximately a third of the dose is excreted unchanged.
ANTIDEPRESSANT DRUGS
Antidepressant therapy may enhance the analgesic effect induced by other drugs. The presumed site of action is at the spinal cord level. Although there is a beneficial effect on sleep and mood, suggesting action elsewhere in the neuroaxis, debate continues over possible modes of action and whether or not these drugs induce analgesia in the absence of depression in chronic pain generally (Watson, 1994).
Serotonin uptake inhibitors: These drugs block the reuptake of serotonin. The commonest ones used in clinical practice are fluoxetine, paroxetine and sertraline. They should be avoided in patients with epilepsy, cardiac disease, diabetes mellitus and glaucoma. They may cause drowsiness and abrupt withdrawal can cause a variety of side effects (Bird, 2004).
Tricyclic drugs: The increased incidence of anxiety and depression amongst chronic pain sufferers is not the only justification put forward for the use of tricyclic drugs. They also appear to have a synergistic effect with centrally acting analgesia and the stimulation of endorphine production (Brown and Bottomley, 1990).
Amitriptyline is of proven efficacy (Carrette et al., 1994). It is taken in small incremential doses of 10-50 mg, two hours prior to settling at night to avoid the hypnotic effect. Sleep usually improves within two weeks whilst pain relief may take many months. Common side effects include dry mouth and palpitations. Dothiepin has been shown to be of comparable effect in controlled studies (Caruso, Sarzi Puttini and Bocassini, 1987).
Venlafaxine, an inhibitor of both serotonin and noradrenaline re-uptake, has been shown to be useful in the treatment of fibromyalgia (Dwight et al., 1998).
Pregabalin is of proven benefit in the treatment of neuropathic pain (Mease et al., 2003) and has also been shown to improve sleep quality and diminish fatigue.
NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
NSAIDs have become an integral part of the management of inflammatory conditions. The ultimate goal of NSAIDs therapy is to reduce the inflammation that is occurring. The decision to commence therapy will include consideration of the risks weighted against the potential for therapeutic benefit for the patient and will take into account the nature of the underlying condition and the severity of the patient’s symptoms.
The objective of commencing NSAIDs is to decrease the cardinal symptoms of inflammation which include pain, stiffness, swelling and warmth. These symptoms are not only unpleasant for the patient but also affect physical and psychological functioning. In addition to reducing inflammation this group of drugs also possesses analgesic and anti-pyretic properties, which are necessary to treat the associated features of inflammation. The effectiveness of NSAIDs should be evident within a few days and make an almost immediate impression on the patient’s symptoms. The therapy will continue to be effective as long as blood levels of the drug are maintained. If a patient stops taking this therapy for any reason, this action could result in a reoccurrence of the symptoms of inflammation. Although the patient will start to feel better once the features of inflammation are reduced this therapy will not influence the progression of conditions such as RA.
Classification of NSAIDs
The NSAIDs can be classified on the basis of their chemical structure. The older NSAIDs - for example, Indomethian - have excellent anti-inflammatory properties but commonly produce adverse side effects especially on the gastrointestinal system, whereas agents such as the propionic acid derivatives have less likelihood of causing side effects and are generally better tolerated. The chemical classification of the NSAIDs is shown in Table 2.5.
Which NSAIDs to Use?
The choice between the various NSAIDs is largely empirical (Schlegal, 1987). There is a wide individual variability of response (Thompson and Dunne, 1995). The cause for this variability is not known. If a patient experiences a poor response to one NSAID another agent should be tried. There can be a variation in response even when the NSAID is from the same chemical family. Once a NSAID is commenced the patient should be maintained on it for two weeks before an assessment of its efficacy is made, unless the patient experiences an adverse reaction. The ultimate goal of NSAIDs intervention is to choose a preparation that combines the greatest effectiveness with the least toxicity for each individual patient (Schlegal, 1987). There is significant co-morbidity associated with NSAID use (Moore, 2003) and the clinician needs to balance the benefits against the risks proir to prescribing NSAID therapy.
Table 2.5 Chemical classification of NSAIDs.
|
Types of NSAID |
Examples |
|
Carboxylic acids |
aspirin, choline, salicylate, diflunisal |
|
Acetic acids |
indometacin, diclofenac, etodaloc |
|
Propionoc acids |
brufen, fluribiprofen, fenbrufen, fenoprofen, ketoprofen, tiaprofenic acid |
|
Fenamic acids |
piroxicam, phenylbutazone, azapropazone, tenoxicam |
|
Non-acidic compounds |
nabumetone |
|
COX 2 inhibitors |
rofecoxib, celecoxib |
NSAIDs can be divided into two groups according to their half life. Those drugs with a half life of greater than 12 hours - for example, piroxicam, tenoxicam and azapropazone - need only to be administered once or twice daily, which should aid concordance; although it should be noted that these medications with a long half life may build up excessively in the plasma of older patients increasing the potential for the occurrence of side effects. The majority of other NSAIDs are referred to as short half life drugs as their half life is usually less than six hours.
The Administration of NSAIDs
NSAIDs can be administered in many different ways, including by slow release compounds, topically, intramuscularly and in suppository form.
Topical preparations - These are only available for a few NSAIDs. They are more efficacious than placebo (Thompson and Dunne, 1995). Local skin sensitivity may occur and there is some absorption into the circulation leading to the rare occurrence of systemic side effects.
Suppositories are rarely used but do reduce the risk of gastric irritation by the direct effect of the drug on the mucosa. However, there is still a risk (although reduced) of gastric ulceration mediated via the circulation. NSAIDs given in suppository form can also cause local irritation in the rectum. Patients can also find them difficult to administer especially if they have reduced manual dexterity.
Patients at Risk from Gastrointestinal Problems
In patients with peptic ulcers disease NSAIDs are contraindicated. If a patient is at risk from GI symptoms the clinician will often prescribing gastric cytoprotection in the form of proton pump inhibitors for example, omeprazole and lansoprazole. These drugs inhibit the gastric acid by blocking the hydrogen-potassium adenosine triphosphatase enzyme system (the proton pump) of the gastric parietal cell. They are the treatment of choice for stricturing and erosive oesophagititis and are effective in the short-term treatments of gastric and duodenal ulcers.
Indicators for the Use of NSAIDs
In chronic inflammatory rheumatology conditions such as RA, ankylosing spondylitis, psoriatic arthritis and connective tissue disorders (with polyarthritis), patients may well have to take NSAIDs on a regular basis to provide symptomatic relief from the effects of ongoing inflammation. If the patient experiences a reduction in disease activity they may no longer need regular administration of the NSAID therapy and a trial will establish whether this is the case.
Patients with OA are better managed on simple analgesia. In the older patient the risk of side effects can outweigh the potential therapeutic effects of a NSAID, although their use may be considered if they experience a flare of inflammatory symptoms. Here the use of NSAID would be considered short term for symptom relief. Other conditions where it may be appropriate to use NSAIDs on a short-term basis include: gout, pseudogout and certain sport injuries.
Mode of Action of NSAIDs
NSAIDs appear to be involved in many of the pathways that are influential in the production of inflammatory mediators as well as actively involved in the interactions between inflammatory cells. NSAIDs are known to play a role in the suppression of prostaglandin synthesis partly by inhibiting the enzyme prostaglandin synthetase H (also known as cyclo-oxygenase). Prostaglandins are synthesized from membrane phospholipids; when induced they act to produce many of the features of inflammation including warmth, erythema and oedema. NSAIDs have effects on various other aspects of the inflammatory response including leukotriene synthesis, superoxide production and cytokine production (see Figure 2.2).
The suppression of prostaglandins by NSAIDs may help relieve the symptoms of inflammation but this suppression is also responsible for the major adverse effects of NSAIDs including gastrointestinal disturbances and effects on kidney functioning (Brooks, 1994; Flowers, 1996).
Figure 2.2 Pathways influenced by NSAIDs.
Pharmacokinetics
Most NSAIDs are completely absorbed from the gastrointestinal tract. They bind strongly to plasma proteins and are predominately cleared by the liver. The metabolites are excreted in the urine. Some NSAIDs are absorbed in the active form whilst others, referred to as pro-drugs, are converted by hepatic metabolism to active drugs.
Cyclo-Oxygenase 2 Inhibitors
Cyclo-oxygenase-2 (COX-2) inhibitors are a selective type of non-steroidal antiinflammatory drug (NSAID). They were developed to reduce the gastrointestinal side effects of traditional NSAIDs. Although COX-2 inhibitors are as effective as traditional NSAIDs in relieving pain (Bombardier et al., 2000) serious concerns about their cardiovascular safety have arisen. COX-2 plays a beneficial role in vascular health and its inhibition may create an imbalance between thromboxane and prostacyclin. Thromboxane is critical for platelet aggregation and vasoconstriction, and prostacyclin dampens the effects of thromboxane through fibrinolysis and vasodilation (Solomon, 2005). Other mechanisms linking coxibs (or NSAIDs) to cardiovascular events include hypertension from inhibition of prostagalandin- dependent counterregulatory mechanisms and COX-independent oxidative stress.
Concerns with trials regarding the safety of COX-2 inhibitors:
• Most trials have excluded patients with coronary heart disease (Topol and Falk 2004), and patients taking aspirin, and there has been no consensus regarding cardiovascular outcomes/endpoints.
• Trials have been of short duration and not included enough people to observe the incident of cardiovascular events and consequently studies have been unable to demonstrate whether the risk of cardiovascular events associated with coxibs is concentrated in certain subgroups of patients (Solomon, 2005).
Research Findings
• The Adenomatous Polyp Prevention on Vioxx trial examined rofecoxib 25 mg daily against placebo among 2586 patients with a prior adenomatous polyp (Bresalier et al., 2005). Seventeen per cent were taking daily aspirin at the commencement of the study. Patients taking rofecoxib experienced a 4.61 increase in the risk of congestive cardiac failure. Severe thrombotic cardiovascular events including acute myocardial infarction, peripheral arterial thrombosis, peripheral venous thromboisis and pulmonary embolus occurred twice as often in patients taking rofecoxib compared to patients on placebo. In 2005 rofecoxib was withdrawn because of its adverse cardiovascualar profile.
• The Adenoma Prevention with Celecoxib trial demonstrated that high dose longterm celecoxib use was associated with an increase in the risk of thrombotic events. The aspirin user subgroup did not experience a lower risk of cardiovascular events than those not using aspirin. Also patients taking aspirin do not experience a reduced risk of GI toxicity while taking coxibs compared with nonselective NSAIDs (Farkouh et al., 2004). The FDA has requested that the manufacturers of all NSAIDs including celecoxib include a warning highlighting the potential cardiovascular risks of these agents.
• Trials of patients receiving valdecoxib undergoing coronary artery bypass grafting (Nussmeier et al., 2005; Ott et al., 2003) have shown an increased risk of cardiovascular events. The risk ratio for confirmed cardiovascular events was 3.7 when the valdecoxib group was compared with the double placebo group (Nussmeier et al., 2005). In April 2005 the FDA requested that valdecoxib’s manufacturer withdraw the drug from the US market based on insufficient longterm cardiovascular safety data, evidence of an increased cardiovascular risk in short-term studies amongst patients undergoing heart surgery, the risk of life-threatening skin reactions and no proven advantages over other NSAIDs (Solomon, 2005).
Prescribing Advice Regarding the Use of COX-2 Inhibitors
• COX-2 inhibitors must not be used in patients with established ischaemic heart disease and /or cerebrovascular disease (stroke) or in patients with peripheral arterial disease.
• Healthcare professionals should exercise caution when presecribing COX-2 inhibitors to patients with risk factors for heart disease such as hypertension, hyperlipidaemia, diabetes and smoking.
• Given the association between cardiovascular risk and exposure to COX-2 inhibitors, prescribers are advised to use the lowest effective dose for the shortest possible duration of treatment.
• Skin reactions can occur with all COX-2 inhibitors. In the majority of cases these occur in the first month of use and patients with a history of drug allergies may be at greatest risk.
Side Effects of NSAIDs
In general the NSAIDs share a common spectrum of side effects although the frequency of particular side effects varies between different compounds. Mild adverse effects are relatively common, occurring in approximately 10-15% of users. Due to the fact that these drugs are prescribed in large numbers worldwide, a significant number of people will experience more serious side effects. The major side effects occur in several organ systems. These include:
• the gastrointestinal tract
• the central nervous system
• cardiovascular
• the haematopoetic system
• the kidney
• the skin
• the liver.
Gastrointestinal Tract
The gastrointestinal tract is the system most commonly affected by NSAIDs and often necessitates discontinuation of therapy. Symptoms patients may experience include dyspepsia, epigastric pain, indigestion, nausea and vomiting. Gastrointestinal lesions may range from hypermia to diffuse gastritis, erosions or ulcers.
Factors associated with increased risk of ulceration include:
• Age (over 65 years)
• Previous peptic ulcer disease
• Concomitant steroid therapy
• Heart failure
• High dose NSAIDs.
Low dose ibuprofen appears to be associated with a low risk of upper gastrointestinal symptoms. Diclofenac, naproxen and indomethacin are associated with intermediate risk of adverse events and azapropazone is associated with the highest risk. If patients are experiencing adverse reactions it will be necessary to carry out an endoscopy to assess any irritation or ulceration in the tract. All patients are advised to take NSAIDs with food.
Kidney
The synthesis of renal prostaglandins is simulated by vasoconstrictor substances involved in circulating haemostasis such as angiotensin II, norepinephrine and vasopressin. By modulating the effects of these vasoconstrictor substances on the kidney, vasodilatory prostoglandin - especially prostaglandin E2 and prostacyclin - helps to maintain adequate renal blood flow and glomeruler filtration rate. This modulatory effect plays a minor role in controlling renal function in healthy individuals but under circumstances of circulating stress the prostaglandins become essential to the maintenance of adaquate renal function. In this situation treatment with cyclo-oxygenase inhibitors such as NSAIDs may precipitate acute renal failure.
Patients at risk from NSAID-induced renal insufficiency include those with:
• congestive heart failure
• cirrhosis with ascites
• neprotic syndrome
• age (over 60 yrs)
• concurrent diuretic therapy (that causes potassium retension).
Renal side effects from NSAIDs appear to be dose-related and occur more often in older people (Thompson and Dunne, 1995). NSAIDs can also affect the salt and water balance causing sodium retension which may result in hypertension, oedema or heart failure in predisposed individuals.
Drugs such as tiaprofenic acid have also been associated with cystitis. Acute interstial nephritis and nephrotic syndrome have been linked with naproxen, indomethacin, phenylbutazone, fenoprofen and diflunisal. The pathogenesis is unknown.
Hypersensitivity phenomena may also be present with nephrotic syndrome including fever, skin rash and eosinophilia.
Central Nervous System
Cognitive dysfunction, memory loss, inability to concentrate, confusion, personality change, forgetfulness, depression, sleeplessness and paranoid thoughts have all been reported in older patients treated with naproxen and ibuprofen (Goodwin and Regan, 1982).
Headaches and dizziness may occur with indomethacin. Aspirin can affect hearing and cause tinnitus.
Several of the NSAIDs have been associated with aseptic meningitis - for example, ibuprofen and sulindec (Schlegal, 1987). Patients with collagen diseases seem to be at the highest risk from the complication.
Cardiovascular
An increased risk of myocardial infarction was found in patients taking diclofenac and ibuprofen in an observational study (Hippisley-Cox and Coupland, 2005). For ibuprofen, one additional myocardial infarction would happen for every 1005 patients aged 65 and over, and for diclofenac one additional myocardial infarction for every 521 treated patients (Hippisley-Cox and Coupland, 2005). Ray et al. (2002) reported an increased risk of acute myocardial infarction associated with the use of ibuprofen in a high risk population over the age of 50. Patients taking diclofenac had a 55% increased risk of myocardial infarction, which is similar to that reported in a much smaller study of non-selective NSAIDs in patients with RA from the general practice database (Watson et al., 2002). There have been suggestions that naproxen has a protective cardiovascular effect but this has not been shown in a meta analysis (Juni et al., 2004). The potential for NSAIDs to cause other cardiovascular events including hypertension is well recognized (Solomon, 2005). At present the Committee on the Safety of Medicines has concluded that there is insufficient evidence to change practice on non-selective non-steroid antiinflammatory drugs. It advises that prescribing should be based on the overall safety profiles of NSAIDs and individual risk factors. Patients should take the lowest effective dose of NSAIDs or COX-2 inhibitors for the shortest time necessary.
Haematological Reactions
The most common reaction is iron deficiency anaemia as a result of gastrointestinal blood loss that occurs secondary to erosion or ulceration. Blood dyscracies associated with NSAIDs therapy are rare but among the major causes of death with this therapy. Agranulocytosis, thrombocytopenia, neutropenia and aplastic anaemia have all been reported. The latter is very rare except with phenylbutazone, the administration of which is limited to hospital prescriptions in the United Kingdom.
Inhibitors of platelet aggregation by NSAIDs may cause a mild prolongation of the bleeding time in patients. This becomes a particular concern for those patients receiving anticoagulation therapy or those who have hereditory clotting factor deficiencies.
Liver
NSAIDs can cause a transient rise in liver enzymes and more rarely a hepatic illness such as hepatitis. Older patients with a reduced renal function and receiving high dose NSAID therapy are at greatest risk of adverse liver reactions.
Respiratory System
NSAIDs may precipitate asthmatic attacks in predisposed individuals. In some patients with bronchial asthma the inhibitor of cyclo-oxygenase may reduce bronchodilatory prostaglandins. This diverts arachidonic acid metabolism towards lipoxygenase products (leukotrienes). This activity may precipitate bronchospasm.
Pulmonary effects including effusions have been reported with ibuprofen, naproxen and phenylbutazone therapy.
Skin
All NSAIDs can provoke skin reactions including photosensitivity, vesiculobullous eruptions, serum sickness and exfoliative erythroderma. Urticaria has been reported with aspirin, ibuprofen and indomethacin.
Phenylbutazone and oxyphenbutazone are the NSAIDs that have the highest incidence of serious or fatal skin reactions including erythema multiforme, exofoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal reaction.
Cultaneous vasculitis is a rare occurrence but has been related to the use of indomethacin, fenbrufen and naproxen.
Pregnancy
The inhibitor of prostaglandins synthesis by NSAIDs during pregnancy may cause prolongation of gestation and increase post-partum and neonatal bleeding. NSAIDs should be avoided during pregnancy especially as they may promote premature closure of the ductus arteriosus and impair fetal circulation.
Drug Interactions
The major interactions that occur with the administration of NSAIDs are shown below. For safe practice, consult the manufacturer’s guidelines before advocating usage.
• Anticoagulant therapy may be enhanced.
• Antidepressant therapy - for example, moclobemide - can acclerate the absorption of NSAIDs.
• Cardioglycosides. The plasma concentration of cardiac glycoside can be increased, exacerbating heart failure.
• Diuretics. There is an increased risk of nephrotoxicity and a possible risk of hyperkalaemia associated with potassium sparing diuretics.
• Lithium. There is an increased risk of toxicity.
• Muscle relaxants - for example, baclofen. There is an increased risk of toxicity.
• ACE inhibitors. There is an increased risk of renal damage and an antagonistic hypotensive effect.
• Beta blockers. NSAIDS are antagonistic of hypotensive effects.
• Cytotoxic agents. There is a reduction in the excretion of these agents. The potential interaction between NSAIDs and low dose methotrexate is not a problem at the dose used in patients with RA (Thompson and Dunne, 1995).
• Uricosurics - for example, probenecid. These drugs increase the plasma concentration of many NSAIDs and delay their excretion.
• Anti-epileptic drugs may be enhanced.
Interactions with Specific NSAIDs
• Brufen - can increase digoxin levels.
• Fenoprofen - its half life may be reduced following the co-administration of barbiturates - for example, phenobarbitone.
• Ketoprofen - this may increase the level of sulfonamides in the blood.
• Indomethacin - increases the bioavailability of biophosphates.
• Diclofenac - the plasma concentration can be increased if taken with ciclosporin.
• Azapropazone - this may interfere with the action of oral hypoglycaemic drugs.
Also the plasma concentration of azapropazone may increase with the administration of cimetidine.
The administration of two or more NSAIDs will increase the risk of adverse effects occurring.
Appendix 2.A entitled ‘What happens next’ contains case scenarios of patients in whom it may or may not be appropriate to prescribe a NSAID. What would your decision be?
USE OF DMARDs
A number of agents can be used to control rheumatological disorders, particularly RA. Their terminology can be confusing as they are known as either slow-acting anti-rheumatic drugs (SAARDs), second line therapies or disease-modifying antirheumatic drugs (DMARDs). In this chapter they will be known as DMARDs.
EARLY TREATMENT OF RA
Historically the pharmacological interventions for patients with early RA were guided by the pyramidal approach.
This approach dictated that initial drug interventions were limited to NSAIDs and analgesics which aimed to modify the symptoms of the disease process; hence these drugs were referred to as either symptom modifying drugs or first line therapies, and only when radiological evidence of erosions had been confirmed were DMARDs introduced in the therapeutic regime.
However, within the past decade, a consensus of opinion has existed which challenges the traditional pyramidal approach and advocates that DMARDs should be prescribed earlier in the disease process and prior to, rather than following, any structural damage; thus minimizing the disease activity quickly and effectively. The following factors suggest therefore that the pyramidal approach should be inverted:
• There is evidence that joint destruction and concurrent functional disability occurs within the first 12 months of the disease process (Van de Heij de et al., 1992). Therefore it is suggested that irreversible destruction of both cartilage and bone, resulting in functional disability, rapidly occurs within the early stages of the disease process, despite the fact that RA is a chronic progressive disease. Consequently it is suggested that the optimum time to introduce DMARDs to gain control or modify the disease process is when the patient initially presents (Donnelly, Scott and Emery, 1992). Also, functional deterioration will occur if patients remain untreated (Deodhar et al., 1995; Gough et al., 1994).
• In comparison with the general population, patients with RA experience increased morbidity and reduced life-expectancy, which has implications not only for the individual patient (pain, disability and loss of self-esteem), but also on society in general relating to loss of earnings, state payments and healthcare costs.
The efficacy of DMARDs in RA proves difficult to validate due to:
• the inconsistency of the disease process;
• the individual response to DMARDs;
• the potential for concurrent toxic side effects.
The limited effectiveness of DMARDs may be attributed to the discontinuation of DMARD therapies because adverse effects are experienced by the patient, rather than inefficacy of the DMARD themselves.
COMBINATION THERAPY
Combination therapy (i.e. the use of more than one DMARD) has evolved due to several factors:
• The long-term efficacy of a single DMARD regimen has revealed disappointing results.
• The change in philosophy entailing a more aggressive treatment regimen in an attempt to gain disease remission as early as possible.
The aim of combination therapy is to achieve a synergistic effect using two or more DMARDs in order to arrest the disease process and to achieve disease remission with minimal adverse reactions. Combination therapy can be implemented either by:
• a step up regimen where one DMARD is initially prescribed and a second DMARD added if disease remission is not achieved;
• a step down approach may be prescribed; this entails the initial treatment regimen of multiple DMARDs until disease suppression is achieved, then the number of DMARDs can be reduced.
Initially combination therapy research studies have targeted patients with established aggressive uncontrolled RA. However, in order to achieve maximum benefits for the maximum of patients, research studies have been extended to include early RA patients (Haagsma, van de Putte and van Riel, 1995).
MODE OF ACTION AND PHARMACOKINETICES OF DMARDs
Although DMARDs have different chemical structures, they all possess common properties:
• To control the signs and symptoms of RA, which include certain blood parameters denoting inflammation, painful swollen inflamed joints and sometimes slowing down the progression of radiological damage (Donnelly, Scott and Emery, 1992).
• Their effectiveness is delayed, thus a therapeutic response tends to occur for approximately two to four months.
• All DMARDs (excluding the antimalarials) have the potential to cause adverse effects, which include serious haematological toxicity. Consequently the incidence of adverse effects, which may be major or minor, presents a major constraint on the continual use of these agents, so much so that approximately 20-50% of patients will have to stop their DMARD within one year of commencement. The safety monitoring required in the surveillance of DMARDs is discussed in depth in Chapter 3.
• Their mechanism of action is poorly understood.
THE ANTI-MALARIALS
Chloroquine Sulfate/Hydroxychloroquine Sulfate
Hydroxychloroquine and chloroquine are two drugs that were principally prescribed for both the treatment and prophylaxis of malaria. However, since the 1950s, research studies have revealed the efficacy of both hydroxychloroquine and chloroquine as disease-modifying anti-rheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis and systemic lupus erythematosus (Brooks, 1990). Because of their low toxicity profiles, hydroxychloroquine sulfate and chloroquine sulfate are rated as milder DMARDs, which may be prescribed independently or in combination with other DMARDs when only partial efficacy is achieved. An interesting property of hydroxychloroquine, when used in combination with methotrexate, is its protective mechanism against methotrexate-induced hepatotoxicity.
Indications for Use
• active RA;
• juvenile arthritis;
• systemic and discoid lupus erythematosus.
Treatment Regime
Hydroxychloroquine orally 200-400 mg daily with food. The dosage may be reduced to 200 mg daily depending on the clinical response. Maximum dose should not exceed 6.5 mg/kg body weight per day.
Chloroquine orally 250 mg daily with food.
Cautions
• patients with renal and liver impairment;
• it may reduce the threshold for convulsions in patients with epilepsy;
• it may exacerbate psoriasis;
• avoid antacids within four hours of administration.
Contraindications
• breastfeeding;
• pre-existing maculopathy.
Retinal Effect
It is generally agreed that retinal toxicity is due not to the cumulative dose but to the daily dose. Therefore, the maximum prescription limit for adults should be 4mg/kg/day for chloroquine and 6 mg/kg/day for hydroxychloroquine (Day, 1994).
To prevent potential toxicity, individual physicians’ regimen may differ; therefore patients may be prescribed hydroxychloroquine or chloroquine for 5 days of the week or for 7 days a week for 11 months of the year with a 1-month ‘drug holiday’. The ‘drug holiday’ will also allow the clinician to test the efficacy of the drug.
Before commencing treatment the patient should be asked about visual impairment that is not corrected by glasses. The visual acuity of each eye should be recorded using a reading chart. Treatment should only be commenced if there is no abnormality.
The Royal College of Ophthamologists recommends annual review either by an optometrist or enquiring about visual symptoms, rechecking visual acuity and assessing for blurred vision using the reading chart. Patients should be advised to report any visual disturbance. The treatment should be stopped if there is any development of blurred visison or changes in visual acuity. If patients are requiring long-term treatment (more than five years) it should be discussed with an ophthalmologist.
Mode of Action
The mode of action of both hydroxychloroquine and chloroquine remains unknown, although research studies have suggested that antimalarials affect subcellular organelles such as polymorphs, lymphocytes and macrophages, which produce an anti-rheumatic and immunosuppressive reaction (Brooks, 1990).
Pharmacokinetics
To avoid gastrointestinal disturbances, hydroxychloroquine and chloroquine should be administered with food. Food is not thought to affect bioavailability.
Hydroxychloroquine and chloroquine accumulate extensively in tissues, and both white and red blood cells.
These medications possess above average half lives (approximately six weeks); steady concentrations are not achieved for approximately three to four months.
Metabolized primarily by dealkylation and thus high renal clearance, approximately 40% of chloroquine and 25% of hydroxychloroquine are excreted unchanged in the urine; therefore therapeutic regimens should be adjusted to accommodate those patients with renal impairment.
Adverse Effects
• nausea;
• diarrhoea;
• abdominal pain;
• headaches;
• dizziness;
• convulsions;
• blurred vision;
• irreversible retinal damage;
• skin reactions (rashes, pruritis);
• depigmentation or loss of hair;
• ECG changes;
• rarely blood disorders (thrombocytopenia, agranulocytosis, aplastic anaemia) (Brooks, 1990).
Contraindications
Psoriatic arthritis (may exacerbate psoriasis).
SULFASALAZINE
Prescribed for patients with early RA, and in combination with other DMARDs, sulfasalazine has also been found to have some efficacy when treating sero-negative spondyloarthropathies, juvenile arthritis and psoriatic arthritis (Day, 1994). Developed in the 1930s when RA was thought to possess an infective aetiology (Porter and Capell, 1990), sulfasalazine contains the combination of an anti-inflammatory agent (5-aminosalicylic acid) and an antibiotic (sulfapyridine). However, as a result of early conflicting reports regarding the efficacy of sulfasalazine, the drug was originally dismissed by rheumatologists until the 1970s when further studies revealed its efficacy.
Mode of Action
The precise mode of action of sulfasalazine is unknown but it is thought that sulfasalazine in some way suppresses relevant immunological processes in the large bowel and, in addition, sulfasalazine possesses the ability to scavenge pro- inflammatory oxygen species released from activated phagocytes (Day, 1994).
Pharmacokinetics
Following oral administration the majority of the dose is absorbed in the large bowel where it reacts with colonic bacteria and separates into 5-aminosalicylic acid and sulfapyridine. Elimination is via the kidneys in the urine.
D-PENICILLAMINE
Used in the treatment of RA for 25 years, D-penicillamine has also been useful in treating progressive systemic sclerosis as well as unrelated rheumatological conditions such as Wilson’s disease, heavy metal poisoning and cystinuria.
Studies have revealed D-penicillamine to be effective in the reduction of joint inflammation, joint pain, early morning stiffness, laboratory inflammation indices and the improvements of rheumatoid nodules (Joyce, 1990). However, due to a lack of controlled studies, it has not been possible to determine if D-penicillamine is able to slow progressive radiological damage (Joyce, 1990).
Mode of Action
For the past 25 years the precise mode of action and toxicilogy of D-penicillamine has remained elusive, although it is thought to suppress the immune system (Joyce, 1990).
Pharmacokinetics
D-penicillamine is taken orally one to two hours before food; following absorption, peak plasma levels are present within one to four hours.
MYOCRISIN
Initially introduced and prescribed earlier in the twentieth century for the treatment of tuberculosis, gold salts were found to be of little value but were found to be efficacious for the treatment of RA. In the treatment of RA, myocrisin (injectable gold) has been shown to impede progressive radiological damage and concomitant fuctional impairment in both short- and medium-term treatment.
Mode of Action
To date there is no consensus regarding the precise mode of action of intramuscular gold although it is known to regulate gene transcription and affect polymorphonuclear and synovial cells, monocytes, lymphocytes and immunoglobins (Champion, Graham and Ziegler, 1990; Day, 1994).
Pharmacokinetics
Intramuscular gold is polymeric and water soluble and therefore not absorbed orally. Following intramuscular injection, absorption takes place quickly and gold travels to synovial tissue where it binds to inflamed synovial tissues; consequently the majority of gold is located in the synovial lining cells. Elimination of gold is initially rapid and largely in the urine. However, gold has been detected in tissues some 20 years after therapy.
AURANOFIN
Introduced in the last decade auranofin is a gold-based drug that can be taken orally. Although considered less efficacious than sodium aurothiomalate, auranofin possesses fewer serious side effects. The same is true when auranofin has been compared with D-penicillamine and methotrexate (Champion, Graham and Ziegler, 1990).
Mode of Action
Akin to sodium aurothiomalate, precise mode of action remains elusive.
Pharmacokinetics
Following oral administration of auranofin absorption is rapid but incomplete as only 20-25% of the gold is absorbed (Blocka et al. 1982), approximately 15% is then excreted via the kidneys but the majority of gold is excreted in the faeces and consists of both unabsorbed gold and gold that has been absorbed in the gastrointestinal tract and bound to gastric epithelium (Champion, Graham and Ziegler, 1990, Day, 1994).
METHOTREXATE
Initially introduced 50 years ago for the treatment of acute leukaemia, methotrexate is classed as one of the first antimetabolites. The introduction of methotrexate as a treatment for RA took place in the 1950s. However, it was to be some 30 years later, in the 1980s, before methotrexate was used widely by rheumatologists for the treatment of RA and psoriatic arthritis. It is now the commonest DMARD used in the treatment of RA (Cronstein, 1996). It is prescribed as monotherapy and in combination with other DMARDs and biological agents.
Mode of Action
Methotrexate is a cytotoxic drug which acts as a folate antagonist to cause cell death by affecting the synthesis of DNA. However, its precise mode of action in the treatment RA is not entirely understood.
Pharmacokinetics
Following administration (oral or intramuscular), methotrexate is absorbed rapidly and almost entirely, taking one to two hours before a peak concentration is achieved. The majority of methotrexate is excreted via the kidneys, and biliary elimination is suggested to account for approximately 10-30% of methotrexate (Songsiridej and Furst, 1990).
LEFLUNOMIDE
Leflunomide is one of the newer DMARDs that has proven efficacy and safety in randomized controlled trials (Smolen et al., 1999). It appears as effective as sulfasalazine and methotrexate as a monotherapy and can also be used as combination therapy usually with methotrexate or infliximab (Flendrie et al., 2005). It may have a faster onset of action in reducing synovial vascularity (Maddison et al., 2005).
Mode of Action
It is an isoxazole derivate and its active metabolite inhibits de novo pyrimidine synthesis, resulting in inhibition of T cell proliferation.
Pharmacokinetics
Leflunomide has a long elimination half life of 15-18 days, which results from low hepatic clearance and enterohepatic cycling (Flendrie et al., 2005). Its active metabolite is detectable in plasma up to two years after discontinuation of the drug. If a severe adverse event occurs a washout of the drug may need to be considered using oral cholestyramine, 8 mg three times daily for 11 days.
AZATHIOPRINE
Azathioprine is a cytotoxic immunosuppressant drug, originally prescribed to prevent the rejection of transplanted organs. It has also proved to be efficacious in the treatment of RA, vasculitis, systemic lupus erythematosus, polymyalgia rheumatica/giant cell arteritis, Behcet's disease, polymyositis, dermatomyositis, myasthenia gravis and chronic inflammatory bowel disease.
Mode of Action
The precise mode of action of azathioprine is unclear but, as an immunosuppressant, azathioprine interferes with DNA synthesis by either inhibiting cell division or causing cell death in relation to RA. This results in fewer circulating B and T lymphocytes (Furst and Clements, 1994, Luqmani, Palmer and Bacon, 1990). Azathioprine is also administered as a steroid sparing agent.
Pharmacokinetics
Following oral administration, azathioprine remains inactive until it is metabolized in the liver into 6-thioinosinic acid and 6-thioguanylic acid. Elimination is via the kidneys.
CYCLOPHOSPHAMIDE
Cyclophosphamide, a derivative of nitrogen mustard, is an alkylating agent which was developed 50 years ago as an anticancer drug. Cyclophosphamide has been shown to possess both immunosuppressive and immunostimulatory effects (Miller and North, 1981; Turk and Parker, 1979). Its use by rheumatologists for the treatment of RA began in the late 1960s even though research studies revealed conflicting results regarding its efficacy in controlling or slowing down radiographic changes. Cyclophosphamide has proved to be an effective in the treatment of the systemic complications of RA, such as vasculitis, and it has also proved to be effective treatment of systemic lupus erythematosus (Austin et al., 1986).
Mode of Action
The mode of action of cyclophosphamide is not entirely understood. It is known to cross link DNA and possess properties that act to stop DNA replication and halt cell division. Additionally, it has a toxic effect on resting cells. This is said to account for its quick action, which is accompanied with increased toxicity in comparison with azathioprine (Brooks, 1990, Furst and Clements, 1994).
Pharmacokinetics
Cyclophosphamide may be administered orally or intravenously. Although metabolized to some extent in both the kidneys and lungs, cyclophosphamide is predominately metabolized in the liver (Bagley, Bostick and De Vita, 1973). Cyclophosphamide is excreted via the faeces, expiration, spinal fluid, perspiration, breast milk, saliva and synovial fluid (Furst and Clements, 1994). The majority however is excreted by the kidneys unchanged (less than 20%) and as metabolites in the urine (65%), the dominant metabolite of cyclophosphamide (acrolein) having been highlighted as the major source of bladder toxicity (Mouridsen and Jacobsen, 1975). Hence an increased fluid intake is essential when administering this drug.
CICLOSPORIN
Ciclosporin is an immunosuppressant initially developed to suppress the rejection of organ transplantation. Its anti-arthritis properties were initially identified in the mid-1970s (Borel et al., 1976). Further studies have demonstrated that it is able to reduce bone and cartilage destruction (Del Pozo et al., 1990) and also to restore T-helper and T-suppressor subsets (Bersani-Amado et al., 1990; Yocum et al., 1986). Ciclosporin has been used in the treatment of RA and retinal vasculitis including that witnessed in Behcet.’s syndrome.
Mode of Action
Ciclosporin is able to inhibit T cell response and interaction by blocking IL-2 and other pro-inflammatory cytokines.
Pharmacokinetics
Taken orally, absorption is noted to be both incomplete and erratic (Kowal, Carstens and Schinitzer, 1990) with distribution taking place outside rather than inside the blood volume; hence ciclosporin has been detected in the body fat, liver, lungs, kidneys, adrenal glands, spleen and lymph nodes. Consequently elimination is mainly via the biliary system and, to a much lesser extent, via the urine (Furst and Clements, 1994).
CHLORAMBUCIL
Although generally out of vogue for the past 20 years, chlorambucil has maintained its popularity in both France and North America for the treatment of most connective tissue disease and associated inflammatory eye diseases (Luqmani, Palmer and Bacon, 1990).
Mode of Action
Chlorambucil is a cytotoxic drug (a nitrogen mustard derivative) and belongs to the group of drugs known as alkylating agents. Alkylating agents are chemically very active substances which bind with DNA within the cell nucleus resulting in cell death at the point of cell division.
Pharmacokinetics
Administered orally, chlorambucil is rapidly absorbed and then both chlorambucil and its metabolites are excreted in the urine.
PHENYLBUTAZONE
Introduced in 1949 for the treatment of arthritis and gout, phenylbutazone is said to be one of the oldest and strongest non-steroidal anti-inflammatory drugs and is often prescribed for its suppressive properties. However, because of reported toxic side effects, phenylbutazone is currently only prescribed for ankylosing spondylitis under hospital specialist supervision.
Mode of Action
Phenylbutazone acts to inhibit the biosynthesis of prostaglandins (Moll, 1983).
Pharmacokinetics
Administered orally with food (because of gastric irritation), like other NSAIDs, phenylbutazone is almost entirely absorbed from the gastrointestinal tract (as it is not bound irretrievably by food). Elimination is via the kidneys following conversion by the liver into glucuronides and/or additional metabolites (Hart and Klinenberg, 1985).
DAPSONE
Known principally as an antileprotic drug, it has also proved effective as an anti- malarial drug, and in the treatment of both RA and psoriatic arthritis.
Mode of Action
Related to sulfonamide antibacterials, dapsone produces a depressant effect on the immune system.
Pharmacokinetics
Taken orally, dapsone is absorbed rapidly, with excretion via the kidneys in the urine.
MINOCYCLINE
Minocycline is a broad spectrum antibiotic, prescribed for the treatment of tetracycline-sensitive organisms, certain strains of meningitis, acne and for the treatment of RA.
Mode of Action
The mode of action of minocycline is unclear but it is thought to inhibit pro- inflammatory enzymes.
Pharmacokinetics
Following absorption, minocycline spreads widely throughout the body, including a variable penetration across the meningeal barrier into the cerebrospinal fluid. Excretion of the greater part of the drug is slowly via the kidneys.
MYCOPHENOLATE MOFETIL
Mycophenolate mofetil (MMF) is a pro drug of the active metabolite of mycophenolic acid. It is a suppressor of T and B cell proliferation and adhesion and inhibits monophosphate dehydrogenase that eventually blocks the progression to DNA synthesis and proliferation.
Susan Oliver
INTRODUCTION
This section will focus on the new therapies (biologic therapies) that have been introduced over the last five years and are usually prescribed when traditional DMARDs have failed to adequately control the disease process in inflammatory joint disease.
DMARDs have been recognized as playing an essential part in controlling inflammatory joint diseases and are the first line treatment for RA and other inflammatory joint diseases (for example, PsA and AS). DMARDs control the disease by suppressing the autoimmune response and reducing the potential for joint erosions and long-term damage. However it is clear that maintaining control of the disease and reducing joint damage remain suboptimal for many patients despite treatment with DMARDs.
There are now a number of new medications that have a specific and more targeted action on the cell-to-cell interactions of the immune response. These include therapies such as anti-interleukin 1 receptor antagonist (IL-1ra), anti-tumour necrosis factor alpha (anti-TNFa) and more recently anti-cluster differentiation 20 (CD 20) B cell depletion (B cell depletion). A general term frequently used to refer to all of these new biologically engineered therapies is ‘biologic therapies’.
Biologic therapies follow DMARDs in the treatment pathway and are advocated as appropriate treatment when traditional DMARDs (usually at least two DMARDs) have failed to control the disease (Ledinghan and Deighton, 2005). The initial rationale for placing such therapies at this point in the treatment pathway reflects the need for clinicians to gain a greater insight into using these therapies in routine clinical practice, enabling them to develop a sound knowledge of risks and benefits of such therapies, but also related to the costs of treatment, which can range from approximately £8,000-10,000 per annum per patient. However, more recently there has been an increasing recognition that these therapies are effective in methotrexate naive patients and early aggressive treatment may improve long-term outcomes (Furst et al., 2005).
Biologic therapies have improved the quality of life for many individuals with moderate to severe RA (Maini et al., 2004). Studies also reveal that not only is progressive joint damage halted, but there is early evidence that repair of joint erosions can be seen; something not experienced with traditional therapies and a factor that adds a very important dimension in treatment for those with RA (Furst et al., 2005). Optimal treatment benefits are achieved when biologic therapies are co-prescribed with methotrexate (Furst et al., 2005).
However, for the practitioners caring for individuals treated with these therapies there are important issues that need to be considered in pre-screening and monitoring of patients receiving biologic therapies (RCN, 2003). This section will outline the key issues that need to be considered.
BIOLOGICALLY ENGINEERED THERAPIES (BIOLOGICS)
The use of biotechnology has enabled scientific knowledge to manipulate and redesign key aspects of the body’s own cell-to-cell communications and interactions. A range of new therapies have been, and continue to be, developed for inflammatory joint diseases as a result of this work. A key component of these specifically designed therapies is that of disarming pro-inflammatory cytokines responsible for driving autoimmune responses (Oliver and Mooney, 2002). Cytokines are proteins or glycoproteins that act as important intercellular messengers travelling through blood and the lymphatic systems to communicate important pro- or antiinflammatory responses.
Therapeutic targets have been identified for the cytokines interleukin 1 (IL-1) and tumour necrosis factor alpha (TNFa) and more recently B cell depletion of CD20 B cells. Further specific cell-to-cell interactions have identified new therapeutic pathways that are currently being researched and it is likely that some of these will be licensed within the next few years.
The reader should refer to other key documents in the management of patients receiving biologic therapies. These include:
• Guidance on eligibility criteria, screening and management of those being treated with anti-TNFa prepared by the British Society for Rheumatology (BSR, 2002, 2005).
• Guidelines for the patient taking immunosuppressants, steroids and the new biologic therapies. Vaccinations in the immunocompromised person (BSR, 2002; DoH, 1996). Immunizations against infectious disease.
• The British Thoracic Society (BTS, 2005) guidelines for the assessment and treatment of tuberculosis in patients due to start anti-TNF therapy (BTS, 2005)
• The Royal College of Nursing Guidance on assessing, managing and monitoring biologic therapies for inflammatory arthritis (RCN, 2003)
• National Institute of Clinical Excellence (NICE) guidance for etanercept and infliximab for the treatment of RA.
• Background information on the use of rixutimab in the treatment of nonHodgkin’s lymphoma (NICE, 2002). NICE proposes to review rituximab for RA in their appraisal programme this year.
This section will give an overview of how these biologic therapies provide a new and more effective approach to treating conditions that are driven by a faulty immune response (autoimmunity). Autoimmune diseases can result in a range of conditions depending upon the tissues affected. Examples of inflammatory joint conditions include RA, PsA and AS.
CLASSIFICATIONS - BIOLOGIC THERAPIES
All biologic therapies have been developed using technology manipulating immunoglobulins. This technology involves designing immunoglobulins so that they can specifically disarm cytokines or their receptors and, as result, stop their normal mode of action. Biologically engineered immunoglobulins are made up of foreign proteins. These proteins may be made up using technology that incorporates either all human or part human/part animal immunoglobulins demonstrating the different components of three biologic therapies and their constituent parts.
Immunoglobulins (Antibodies)
Immunoglobulins belong to a family of large protein molecules also known as antibodies. Immunoglobulins are produced by B cells in response to a challenge to the immune system. B cells that have had no antigen/antibody reaction are called ‘naive’ B cells and therefore produce a good but not highly specific immunoglobulin response (or targeted bullet) on first contact or prior to clonal expansion. Immunoglobulins can become more specific with the ability to recognize an antigen following initial interaction with the antigen resulting in a more rapid and effective response in subsequent challenges to the immune system. When an immunoglobulin develops a specific targeted response it is said to have a ‘shared epitope’ - that is, a perfect match between the immunoglobulin and the antigen, matching in a similar way to a lock and key, with the lock being the antigen and the key being the immunoglobulin.
MODE OF ACTION - GENERAL
The mechanism of action of traditional DMARDs is not fully understood but it is likely that their effect on immune suppression is suboptimal based upon the limited understanding of their non-specific actions on cytokine production and cell replication. Compared to DMARDs and corticosteroids, biologic therapies have a more specific and targeted effect at cell level. Biologic therapies act by mimicking the normal immune processes, effectively preventing or displacing a cytokine from ‘locking’ into its defined receptor. This has the consequence of preventing the activation of pro-inflammatory cytokines responsible for ensuring an ‘inflammatory cascade’. When activated an inflammatory cascade results in the classic signs of inflammation (heat, redness, swelling, loss of function and pain).
Biologics have a direct cell-to-cell effect on specific targeted cytokines but also have a less clearly mapped action on other closely related or possibly directly linked communicating cytokines that also have an effect on the inflammatory cascade and ultimately the effects that these responses have on other tissues as a consequence of the cytokine activation. (For further reading see Dinarello and Moldawer, 2002, Oliver, 2003, 2004.)
Knowledge of cytokines and their effects continues to be researched with well over 150 cytokines clearly identified. These cytokines are classified into families (for example anti-TNFa or interleukin 1) and are described as either pro- or antiinflammatory cytokines. Pro-inflammatory cytokines have been identified as playing an important part in driving an inflammatory response (Dinarello and Moldawer, 2002).
Research continues on key cytokines and chemokines (smaller molecules than a cytokines but playing a similar role in the immune response) as well as looking at different stages of the cell-to-cell interactions in the immune pathway as the focus for future therapeutic targets.
Biologic therapies and other key cells-to-cell interactions that might be amenable to therapeutic manipulation are the focus of research for a number of chronic autoimmune conditions. As research continues it is possible that current therapies will be identified as effective treatments for a number of other autoimmune conditions.
ADVERSE REACTIONS TO BIOLOGIC THERAPIES
As with all injected foreign proteins (e.g. blood transfusion) there is the potential for the body to develop antibodies to the protein and/or hypersensitivity reactions. The likelihood of an individual experiencing an anaphylactic reaction to an agent is influenced by age, gender, atopy, route of exposure and prior exposure as well as history of prior anaphylactic reactions (Winbery and Lieberman, 1995).
A detailed discussion on the incidence of infusion reactions and an algorithm to guide practitioners has been described by Cheifetz et al. (2003) in the management of Crohn’s disease. Table 2.6 provides an overview of management. Adverse responses for immediate and delayed reactions can be categorized as mild, moderate or severe (according to severity and signs of symptoms).
Immediate Reactions (Within the First 24 Hours)
Cheifetz (2003) suggests reactions should be categorized in simple terms such as immediate and delayed, but also considered based upon immune (antibody/antigen reactions) or non-immune mediated reactions (such as dose-dependent drug toxicity, secondary effects of drug or drug-drug interactions).
Severe anaphylaxis type reactions (antibody/antigen reaction) are considered to be driven by IgE-mediated acute hypersensitivity events although Cheifetz et al.’s study in the use of infliximab did not support this finding. However anaphylaxis type reactions do appear to occur more frequently in individuals with a history of atopy or previous history of infusion-related reactions. In these cases, retreatment should be commenced at a slower rate (usually slowing the normal rate by half) initially and then gradually increasing in line with normal treatment regimes if all observations are satisfactory (see Tables 2.7 and 2.8).
Delayed Reactions
Delayed reactions can occur after 24 hours and up to 14 days after treatment and often present in the form of arthralgia, myalgia, urticarial rash, fever or malaise.
Table 2.6 Biologic prescribing issues.
2) Adalimumab (Humira)
Table 2.6 (Continued).
Infliximab (Remicade)
Table 2.6 (Continued).
1) For full details please refer to: Summary of Product Characteristics Amgen (2005), British National Formulary (September, 2004).
BSR Guidelines for prescribing TNFa blockers in adults with rheumatoid arthritis (2005), British Thoracic Society (2005), British Society of Rheumatology vaccination guidelines (2002).
2) For full details please refer to: Summary of Product Characteristics Abbott Laboratories Ltd (2005), British National Formulary (September, 2004).
BSR Guidelines for prescribing TNFa blockers in adults with rheumatoid arthritis (2005), British Thoracic Society (2005), British Society of Rheumatology vaccination guidelines (2002).
3) For full details please refer to: Summary of Product Characteristics Schering Plough Ltd (2005), British National Formulary (September, 2004).
BSR Guidelines for prescribing TNFa blockers in adults with rheumatoid arthritis (2005), British Thoracic Society (2005), British Society of Rheumatology vaccination guidelines (2002).
4) References: Summary of Product Characteristics Rituximab (Roche Products Ltd, 2005), British National Formulary (September 2004).
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Table 2.7 Key issues in caring for individuals receiving biologic therapies.
Nurse/practitioner screening prior to starting treatment
Patient has had an opportunity to discuss their treatment options and has made an informed decision about starting therapy. Consent documented for treatment and data collection for BSR Biologics Register data.
Patients need to fulfil the eligibility criteria for treatment (National Institute of Clinical Excellence; NICE 2002) and the British Society for Rheumatology according to disease (RA, ankylosing spondylitis, psoriatic arthritis; BSR, 2005).
Screening for risks of tuberculosis should be undertaken for all patients receiving anti- TNFa therapies according to the BTS guidelines (BTS, 2005). Those who have risk factors should be referred to the prescribing physician for consideration of referral to respiratory or immunology physician.
If co-prescribed with a DMARD that they are continuing on this treatment and monitoring is satisfactory.
Confirmation that women of childbearing age are not pregnant and (both men and women) are aware they must use an effective contraceptive.
Patients should be free of infections or any potential foci of infection (such as chest infections, indwelling catheter or sepsis of prosthetic joint within the last 12 months). Also ensure there is no recent contact with chicken pox or herpes zoster.
Immunizations should be reviewed and if time allows and patient is well enough ensure immunizations are undertaken 4 weeks prior to starting treatment (BSR, 2002).
Ensure no malignancy or pre-malignancy state (excluding basal cell carcinoma or malignancies diagnosed and treated more than 10 years previously).
Exclude any history or new symptoms of heart failure or demyelinating disease.
Treatment issues general
Provide written information and contact details for support about their treatment and ensure they know when they should seek urgent advice.
Question to ensure there are no new symptoms or pending investigations awaited (e.g. for possible malignancy).
Training and competencies have been assessed in storage, administration and monitoring issues related to self-administration of subcutaneous therapy if treated with anakinra, etanercept or adalimumab.
Infusion issues (infliximab or rituximab): Ensure that
Full screening has been undertaken and patient has an opportunity to ask questions.
Assessment and disease activity criteria have been fulfilled for data collection (such as the BSR Biologics Register) and review of treatment benefits.
Pre-infusion monitoring has been carried out and these are with in normal range (vital signs — temperature, pulse, respirations, blood pressure) and urinalysis. Patient has been weighted if appropriate.
Have received appropriate prophylactic drug therapy prior to starting an infusion.
Clinical management plans or protocols for infusion regimes are adhered to and recorded.
All infusion-related reactions are monitored carefully and managed promptly according to local and national guidelines. If severe reactions occur (e.g. dyspnoea, hypotension) treatment should stop and appropriate treatment administered promptly.
Recommence infusions following a reaction are started slowly and appropriate medical support and full resuscitation equipment readily available.
Post-infusion: Ensure that
Post-infusion observations are satisfactory, the patient is asymptomatic and all details are recorded.
Information and contact numbers have been provided to the patient about follow-up care and what to do if an adverse event occurs.
_________________
Table 2.8 Screening and management of infusion-related reactions.
Baseline
General screening
Ensure the patient is free of infection and review any changes in health status (e.g. new investigations for suspected cardiac, neurological or malignancy issues). If of childbearing potential confirm effective contraceptive used.
Check any issues re venous access. The appropriate site for a cannular can sometimes be difficult with consideration required for poor skin integrity, bruising or painful joints.
Practitioners should review blood results before proceeding and check for any documentation of human anti-chimeric antibodies (HACA). The presence of HACA is an additional indicator of potential infusion-related reactions. The co-prescription of a DMARD reduces the risks of HACAs developing.
Check, if prescribed, that the patient is still taking their disease-modifying drugs (usually methotrexate). The risk of infusion-related reactions may be higher if not co-prescribed a DMARD. If stopped DMARD, check the time frame from stopping treatment and refer to prescribing physician.
Enquire on history of atopy or previous infusion-related reactions.
Review baseline blood results (check for any abnormalities and report to prescribing physician or review protocols/guidelines on treatment pathway).
Undertake any data collection and consent that is required (e.g. consent for treatment/or BSR Biologics Register or Disease Activity Assessments).
For individuals on anti-hypertensive agents who are treated with rituximab the prescribing physician may elect to withhold anti-hypertensive medications for 12 hours prior to the infusion.
Pre-administration
If prescribed administer pre-medication prior to starting infusion (e.g. paracetamol and/or antihistamine). If prescribed rituximab review concordance with between infusion oral steroid treatment and ensure 100mg intravenous methylprednisolone pre-treatment is administered.
Patients should have their general well-being (e.g. flushed or chest pain) and observations recorded prior to the infusion and every 30 minutes during the infusion (blood pressure and pulse).
Advise patient to report if they have unexplained/new symptoms such as breathlessness, pruritis, fever, chills or chest pain.
___________________
Infusion-related reactions (acute)
Mild to moderate
If patient experiences symptoms stop treatment and treat according to severity of reaction and according to local protocols. Mild or moderate infusion reactions usually occur within two hours of the initial infusion (although they may commence within a few seconds of commencing treatment). They may necessitate temporarily withholding the treatment but usually respond to reduction in the rate of infusion and possibly treatment with paracetamol and diphenhydramine. If observations are satisfactory and symptoms are mild (e.g. headache) and treatment is not required the physician may decide to re-start the infusion at a slower rate and with frequent monitoring. If the infusion then continues without event subsequent infusions can be undertaken with caution.
Moderate to severe
If the patient experiences significant changes in vital signs (e.g. diastolic blood pressure decreases between 15-20mm Hg) or the patient experiences symptoms that indicate hypersensitivity or in the treatment of rituximab, severe cytokine release syndrome (e.g. severe dyspnoea, bronchospasm, urticaria, fever, hypotension), stop infusion. Treat aggressively according to local anaphylaxis protocol (usually would include pain relief, antihistamines, intravenous saline or brochodilators, corticosteroids and/or epinephrine, oxygen). For those treated with rituximab the infusion should not be recommenced until complete resolution of all symptoms and normalization of laboratory values and chest X-ray findings.
The infusion may be resumed (at the discretion of the physician and consent from the patient) but must recommence at no more than one half of the previous rate (Roche, 2005, personal communication). If a severe adverse reaction occurs for a second time the prescribing physician should review the decision to continue subsequent treatments on a case-by-case basis.
Recommencing treatment following an infusion-related reaction
For those patients attending for a subsequent infusion having had a previous serious infusion reaction a physician should be at hand for the next treatment, if the decision to re-treat has been taken.
Commence infusions at slower rate and ensure frequent observations of vital signs until patient stable (e.g. every 15 minutes). Gradually increase rate and maintain observations and observe carefully until patient stable.
If a further severe infusion-related reaction occurs, stop infusion and treat aggressively according to local protocols. Review with prescribing physician.
Delayed infusion reactions
Usually present with arthralgia, myalgia, urticarial rash, fever and malaise. These are usually managed by prescribing paracetamol, antihistamines and occasionally steroids if required.
References: Summary of product characteristics for infliximab (Schering Plough, 2005) and rituximab (Roche Products, 2005). For infliximab see also Cheifetz et al. (2003).
BIOLOGIC THERAPIES - TREATMENT OPTIONS
Interleukin-1 Receptor Antagonist (IL-1ra)
Anakinra (kineret)
Classification
Anakinra - a biologically engineered monoclonal antibody working as an interleukin-1 receptor antagonist. Anakinra is indicated for the treatment of RA in combination with methotrexate when there is an inadequate response to methotrexate alone.
Mode of Action
In normal joints interleukin-1 receptor antagonist (IL-1Ra) modifies the activity of interleukin 1 (IL-1; a pro-inflammatory cytokine). IL-1Ra binds to interleukin 1 receptors (IL-1R1) and by doing so competitively prevents binding of IL-1 into their receptors reducing the number of receptors available for IL-1 to lock into and cause an inflammatory response. This is the body’s normal response to maintain equilibrium and ensure an appropriate level of inflammatory response. The loss of self-tolerance (recognition and acceptance of tissues that belong to self) results in an autoimmunity condition upsetting the usual immunological balance. Anakinra is the only IL-1Ra therapy licensed for RA. Maximum plasma concentrations of anakinra occur three to seven hours following subcutaneous injection. The plasma half life ranges from four to six hours.
Anakinra has been shown to have limited value for the majority of RA patients, based upon current criteria for evaluating effectiveness of treatment using the Disease Activity Score (DAS 28) although research continues into the therapeutic benefits in other conditions (e.g. osteoarthritis). It has been suggested that in RA despite suboptimal DAS scores, there may be benefits in the reduction of longterm joint damage over time although further research will be needed (Strand and Kavanaugh, 2004).
Administration of Anakinra
Anakinra 100 mg daily is administered subcutaneously using a pre-filled syringe preferably at the same time each day, and should be co-prescribed with a once- weekly dose of methotrexate (weekly dose of methotrexate may vary according age, and renal and hepatic function).
Indication for Use
Anakinra should be prescribed for the treatment of RA in combination with methotrexate, where there is an inadequate response to methotrexate alone.
In theoretical terms the combined treatment of anakinra with an anti-TNFa was initially thought to be an ideal therapeutic option. However this has been shown to significantly increase risks of infections and therefore co-prescribing is not recommended (Amgen, 2005).
No dose adjustment is required for the elderly (more than 65 years of age), or those with hepatic or mild renal impairment. Caution is advised for those with moderate renal impairment.
Anakinra is contraindicated in severe renal impairment. Patients with persistent neutropenia (<1.5 x 109/l) should be excluded from treatment with anakinra (see Table 2.6 for additional guidance on screening and management).
The risks related to co-prescription of methotrexate need to be considered in the management of patients with hepatic or renal impairment (National Patient Safety Agency, 2005). Individuals who have hypersensitivity to E. coli should not be treated with anakinra.
Anakinra was reviewed by the National Institute of Clinical Excellence in 2003 and was not seen to be cost-effective based upon the evidence available at that time.
Side Effects
Allergic Reactions
The most frequently reported side effect (>10%) in all clinical trials has been that of mild to moderate injection site reactions (ISRs). These were usually mild and self-limiting urticarial or maculopapular rashes; however, if severe reactions occur, treatment should be discontinued and appropriate treatment given. Discontinuation due to ISR was seen in only 7% of patients (BSR, 2002). ISRs most frequently occurred within the first four weeks of treatment (see also section on infection and injection site reactions).
Blood disorders
Blood disorders (neutropenia) were seen in 1-10% of patients in clinical trials. It is recommended that pre-screening of white count should be undertaken, if neutropenic (below <1.5x109/L) treatment should not be initiated. Regular blood monitoring (monthly for the first six months and then quarterly thereafter) are advised. If neutrophils drop below (below < 1.5 x 109/L) treatment should be stopped (Amgen, 2005; BSR, 2002).
Infections
There is an increased risk of serious infections (particularly upper respiratory tract infections) (1.8% in treated group compared to placebo 0.7%). In clinical trials and post-marketing experience some opportunistic infections have been seen including fungal, mycobacterial and viral pathogens (Amgen, 2005). Infections are commonly bacterial infections; once treated and resolved anakinra can usually be restarted.
Anakinra has not been associated with reactivation of latent tuberculosis (Furst, et al., 2005). The risks of reactivation of TB appear to be greater for anti-TNFa treatments (BTS, 2005). The BTS guidance may be helpful in assessing general risk factors related to TB exposure although it is important to note the management guidelines are related to anti-TNFa therapies and not specifically for anakinra. However, the co-prescribing of methotrexate and the potential for patients who fail on anakinra to progress to anti-TNFa makes this a sensible principle to apply in assessing patients.
Lymphomas and Malignancy
As there is limited data on the impact of treatment on malignancies it is recommended that individuals with pre-existing malignancy should not be treated with anakinra (Amgen, 2005). Patients treated with anakinra have an increased risk of lymphoma compared to the general (non-RA) population; however, the rate for malignancy is comparable to the RA population (two- to threefold increase compared to the general non-RA population) (Amgen, 2005).
Drug Interactions
Drug interactions have not been extensively investigated although in clinical trials non-steroidal anti-inflammatory drugs, corticosteroids and disease-modifying drugs were co-prescribed and no interactions were observed (Amgen, 2005, Tesser et al., 2004). Studies observing toxic interactions related to methotrexate when co-administered with anakinra did not demonstrate any reductions in clearance rates (Amgen, 2002).
Pregnancy and Breastfeeding
As with all new therapies there is insufficient data on the use of anakinra in pregnant or breastfeeding women and therefore treatment should not be prescribed if the patient is at risk of pregnancy, pregnant or breastfeeding. Women of childbearing potential must be advised to use an effective means of contraception when treated with anakinra.
Immunization
There is limited data available on the effects of vaccinations in patients receiving anakinra (Amgen Ltd, 2005).
Live vaccines are contraindicated for both anakinra and methotrexate. Where possible it is helpful to ensure patients have their immune status reviewed for any vaccinations required at least four weeks before starting any biologic therapy. Readers should refer to additional guidance on management of patients who are immunosuppressed and/or are also co-prescribed methotrexate (DoH, 1996 and the BSR, 2002). There is no data on the secondary transmission of infection by live vaccines.
Anti-Tumour Necrosis Factor Alpha (Anti-TNFa)
Anti-TNFa therapies consist of the three currently licensed therapies. These are:
1. Adalimumab (Humira) licensed for:
(a) RA (severe, active and progressive)
(i) Dose range 40 mg every other week as a single dose (in combination with methotrexate)
(ii) Dose may be increased to 40 mg every week (for monotherapy)
(a) Psoriatic arthritis 40 mg every other week as a single dose.
2. Etanercept (Enbrel) licensed for:
(a) RA (severe, active and progressive)
(i) Dose of 50 mg once weekly either as combination therapy with methotrexate or as a monotherapy
(b) Plaque psoriasis
(i) 25 mg twice weekly or
(ii) 50 mg twice weekly for up to 12 weeks reducing to 25 mg twice weekly.
3. Infliximab (Remicade) licensed for:
(a) RA (severe, active and progressive)
(i) 3 mg/kg of body weight in combination with methotrexate (0-, 2-, 6- and 8-weekly thereafter)
(b) AS (severe axial symptoms and elevated serological markers)
(i) 5 mg/kg body weight 0-, 2- and 6-weekly - if no response after three doses no additional treatment.
(c) PsA (active progressive)
(i) 5 mg/kg body weight 0-, 2-, 6- and 8-weekly thereafter.
These three therapies will be discussed individually although the next section will refer to the key issues common to all three anti-TNFa therapies.
GENERAL ISSUES RELATED TO THE MODE OF ACTION - FOR ALL ANTI-TNFa THERAPIES
The release and activation of the cytokine TNFa triggers a cascade of responses from other pro-inflammatory cytokines. Tumour Necrosis Factor alpha (TNFa) is a pivotal cytokine in the inflammatory response. Activating inflammation is achieved when the TNFa cytokine is released and locks into a T Cell Receptor (TCR) for TNFa resulting in a cascade of responses from other pro-inflammatory cytokines.
There are two types of TCR for TNFa that bind with comparable affinity - p55 and p75. TCR for TNFa can be soluble or tissue-bound. Some anti-TNFa therapies can block soluble and tissue-bound receptors.
There are variations in the specific interactions with TNFa tissue and soluble receptors, as well as the structure and composition of each of the anti-TNFa therapies, plasma half lives and routes of administration. The variations between therapies may also explain some differing benefits in specific disease areas although the full significance of the differing therapeutic options is not completely understood and remains an area of close scrutiny and expert discussions. For example it has been suggested that the ability of etanercept to block lymphotoxin a may explain the benefits achieved in JIA as Lymphotoxin a is identified in inflamed joints of JIA patients.
SIDE EFFECTS THAT SHOULD BE CONSIDERED FOR ALL ANTI-TNFa
Table 2.7 provides an overview of the issues to consider for each of the biologic therapies (see also the details related to each therapy individually).
The common points that should be considered regularly are:
• The need to consider all possible opportunistic infections.
• Awareness of allergic reactions related to the injected proteins.
• Clinical indications that might be related to tuberculosis or re-emergence of latent tuberculosis.
• Indications of chronic heart failure or exacerbations of previously mild disease.
• Exacerbations or new symptoms suggestive of demyelinating disease.
• Potential withdrawal of treatment if new malignancies or investigations suggestive of malignancies present.
• Blood monitoring for abnormalities.
• The avoidance of pregnancy or breastfeeding whilst being treated with biologic therapies.
• Care with immunization - live vaccines should not be administered and treatment with other vaccines may be suboptima.
• Planned management of patients receiving surgery to ensure adequate withdrawal prior to surgery and recommencement of therapy when wounds are free of infection.
________
Some side effects seen in patients treated with anti-TNFa are only partially explained in research trials and subsequent clinical practice. These include reports of exacerbations of chronic heart failure and demyelinating diseases.
Allergic Response to Anti-TNFa Therapies (see also Anakinra and Infliximab sections)
As all the anti-TNFa therapies consist of foreign proteins (immunoglobulins) there is a small risk of allergic reactions. Serious allergic reactions have been reported in post-marketing surveillance for all biologic therapies - adalimumab, anakinra, etanercept and infliximab. Treatment should be withheld and appropriate treatment administered.
Infusion or Injection Site Reactions
There is the potential for any foreign injected protein to cause an immune-mediated response. The most common reactions for the therapies administered subcutaneously are injection site reactions (approximately 20%-36% in treated groups compared to 9-14% in control groups). These are usually mild and self-limiting and resolve without treatment. Some patients may benefit from topical hydrocortisone cream if the rash is symptomatic or discomfort persists.
A guidance document and training package for subcutaneous administration of biologic therapies and patient self-administration of anti-TNFa therapies has been developed by the Royal College of Nursing (RCN, 2003) as well as by the specific patient education material prepared by the pharmaceutical companies. In the management of the patient it should be remembered that some patients may also be co-prescribed methotrexate either orally or as a subcutaneous injection (by once-a-week injection) and care needs to be taken in ensuring that injection sites are rotated.
Autoantibodies
Auto-antibodies can develop at any time during an individual’s lifetime without receiving biologic therapies; however they can also develop during treatment with biologic therapies. The co-prescribing of a DMARD (particularly methotrexate) may reduce the potential of auto-antibodies developing in individuals treated with an anti-TNFa therapy (Weber, 2004) The presence of auto-antibodies may in rare cases result in the individual developing lupus-like symptoms, which usually resolve on cessation of treatment (Furst et al., 2005). The presence of antibodies increases the risk of infusion/injection sites reactions.
Blood Monitoring
Many patients receiving biologic therapies will also be co-prescribed a DMARD requiring regular blood monitoring (BSR, 2006). However, it is important to note that research evidence from anti-TNFa therapies has occasionally included abnormal haematological findings. These include rare cases of pancytopenia and very rare cases of aplastic anaemia (in very rare cases resulting in fatal outcomes) and abnormal hepatic dysfunction (Furst et al., 2005). The severity and incidence of haematological problems varies between each of the therapies although this can be a complex picture with the patient group, co-morbidities, level of disease activity and previous immunosuppression (or current treatment) with disease-mofying drugs. However, clinical practice should include screening prior to starting treatment and regular monitoring, assessment and review of individuals treated with an anti-TNFa even if treatment is not co-prescribed with a DMARD such as methotrexate.
Cardiac
Clinical examination and history taking should evaluate cardiac status. Treatment with anti-TNFa therapies should not be considered for individuals with a New York
Heart Classification (NYHC) III/IV. Clinical trials and post-marketing surveillance have identified a risk of mortality for individuals with NYHC III/IV (Bozkurt, 2000). For individuals with NYHC I/II treatment should be considered with caution (Abbott Laboratories Ltd, 2005; Schering Plough, 2005; Wyeth Pharmaceuticals, 2005).
Infections Including Tuberculosis
Tuberculosis
All anti-TNFa therapies have the potential to increase the risk of infections, including the re-emergence of latent tuberculosis (TB) (Furst et al., 2005).
All patients should be closely questioned and examined for possible TB infections prior to starting treatment. This should include detailed questioning of those who travel to areas of high prevalence of TB or who have had close contact with relatives who travel to areas with a high prevalence of TB (BTS, 2005). Referral to a respiratory or immunology physician may be required for those who have close contact with TB or relatives with TB or have previously been infected with TB (treated or partially treated), and those who have symptoms suggestive of TB (fever, weight loss). Further assessment and possible prophylactic regimes to treat previously untreated or latent tuberculosis may be required well before the patient can commence anti-TNFa. The British Thoracic Society (BTS) have developed guidelines specifically to address these issues (BTS, 2005).
Reactivation of TB is at its highest in the first 12 months of treatment although for individuals treated with infliximab the majority of cases occurred within 3 cycles of treatment (median range approximately 12 weeks) (BTS, 2005).
Practitioners undertaking assessments and screening of patients prior to starting treatment and during regular monitoring and review should bear in mind the risks of infections including TB, and be vigilant in getting prompt treatment for infections.
Other Infections
A rigorous approach for all patients treated with anti-TNFa should be applied when screening and reviewing patients, particularly in relation to the risk of opportunistic infections. As TNFa is implicated in the regulating of temperature the normal immune response may be compromised and the usual signs of infection may not be present; for example, one of the classical signs of infection such as a raised temperature may be absent. The co-prescribing of additional immunosuppressant therapies (such as steroids or DMARDs) compounds this problem.
Preliminary data from the BSR Biologics Register show that infection rates are broadly similar across all anti-TNFa therapies and broadly similar to the control groups with active disease (treated with DMARDs) but not receiving biologic therapies (Dixon, 2005).
Serious infections (including bacterial, mycobacterium, viral and fungal) have been identified, with some fatalities occurring with all anti-TNFa therapies. A range of infections have been seen including:
• Upper and lower respiratory infections, including rarely pneumonia.
• Tuberculosis (chiefly although not completely related to re-emergence of latent tuberculosis).
• Sepsis/septic arthritis, cellulitis, fungal dermatitis.
• Varicella.
• Reactivation of hepatitis B (in chronic carriers).
For an extensive list and detailed data on the risks related to infections the reader should refer to the summary of product characteristics for each of the therapies (Abbott Laboratories, 2005; Schering Plough, 2005; Wyeth, 2005).
Treatment should not be started in the presence of a serious infection. If serious infections occur, treatment should be discontinued and only recommenced once the infection has been adequately treated and the infection has resolved (BSR, 2005).
There remains uncertainty about the effects of treating individuals who have HIV with anti-TNFa and therefore therapy should not be recommenced if HIV is identified until additional evidence is available.
Lymphomas and Malignancy
There is a theoretical risk of malignancy (as yet unproven) as a result of tumour necrosis factor alpha blockade. Observational studies (such as the BSR Biologics Register) will provide important evidence of the long-term risks of patients receiving biologic therapies, and preliminary data published in 2006 do not indicate any major influence on mortality in the early years after first anti-TNFa use (Watson et al., 2002). The RA population who have severe disease have a two- to threefold increase in the risk of malignancy as a result of their condition and traditional (non-biological) medications (Askling et al., 2005a, 2005b).
As there is limited evidence at present, treatment with anti-TNFa should not be commenced where malignancy is suspected until appropriate investigations have been carried out. In addition those with pre-existing malignancies or previous history of malignancy (within the last 10 years) should only be treated with caution and following a review of the potential risks and benefits to the individual (BSR, 2005).
Neurological
Treatment with anti-TNFa therapies has exacerbated demyelinating diseases (such as multiple sclerosis) (Robinson et al., 2001). Treatment for individuals with a strong family history, pre-existing or recent onset central nervous system or demyelinating disorders should be considered with caution (BSR, 2005). If neurological symptoms develop, treatment should be stopped and investigations undertaken.
PREGNANCY AND BREASTFEEDING
As clinical trials on humans have not been carried out to evaluate the potential risks related the pregnancy or the unborn child none of the biologic therapies should be prescribed if attempting to conceive (or father) a child. The co-prescription of a DMARD such as methotrexate should mean that individuals prior to starting treatment with a biologic should already have been using an effective contraception (adequate contraception should be continued for at least six months after stopping biologic therapy). Preliminary observational data shows that there are no major congenital malformations or evidence of maternal harm in patients treated with all biologic therapies (Hyrich et al., 2005).
Immunoglobulins can be excreted in human milk and therefore a biologic should not be administered to mothers who are breastfeeding. In some circumstances the clinician together with the patient may need to make a careful risk-benefit analysis for both mother and child to decide the best option for management (either stop the biologic or advise that the child is bottle-fed).
For individuals who have been prescribed methotrexate it is recommended that at least a six-month period should elapse before attempting conception; the same length of time is recommended for infliximab (which is co-prescribed with methotrexate). Five months free of treatment is recommended on cessation of adalimumab (personal communication, Abbott Laboratories, December 2005). Withdrawal of methotrexate co-prescription must also be considered and manufacturer advice varies on the length of time from withdrawal of methotrexate before attempting to conceive (between three and six months).
IMMUNIZATION
Live vaccines must not be administered to individuals receiving anti-TNFa therapies (with or without methotrexate or another DMARD) (BSR, 2002). It is therefore useful, if patients are well enough, that time should be allowed to review and plan any necessary immunizations at least four weeks before starting treatment. One study suggests that pneumococcal vaccinations may result in a poor response (BSR, 2005) and others have demonstrated anti-TNFa treated patients to have similar response to controls following vaccination with pneumococcal vaccination although methotrexate does seem to reduce immune response.
If immunizations are to be given they should ideally be administered four weeks prior to starting treatment or at least six months after the last infusion of infliximab or two to three weeks after the last dose of etanercept (BSR, 2005). There is no current advice for adalimumab on the time to elapse before it is safe to administer a vaccine. Additional guidance can be sought from the centre for disease control and prevention for those who are immunosuppressed (www.cdc.gov or www.dh.gov.uk).
Specific guidance on immunization for TB is included in a guidance document produced by the BTS (2005).
SPECIFIC INFORMATION ON ANTI-TNFa
Adalimumab (Humira)
Adalimumab is a recombinant human monoclonal antibody and works by binding specifically to TNFa and preventing the normal TNFa function of locking into p55 and p75 cell surface receptors. The bioavailability following a 40 mg subcutaneous dose was 64%. Absorption and distribution is slow with a peak serum concentration reached at approximately 5 days after administration and a half life for adalimumab of approximately 12-14 days (Abbott Laboratories, 2005).
Indication for Use
Adalimumab is indicated for the treatment of adults with moderate to severe RA following inadequate response to DMARDs and for active and progressive psoriatic arthritis (PsA) when previous response to DMARDs has been inadequate.
Administration
Adalimumab is administered by subcutaneously pre-filled syringe in a dose of 40 mg every other week. Adalimumab can be prescribed as monotherapy but for optimal benefit should be prescribed with methotrexate (for RA patients). Those individuals already receiving methotrexate should continue with their treatment when prescribed adalimumab. For individuals with RA on monotherapy an increase in dose to 40 mg every week may be indicated (Abbott Laboratories, 2005).
Specific Additional Comments
For those with renal or hepatic impairment, there is no specific guidance for individuals receiving adalimumab. If co-prescribed with methotrexate guidance from the British Society for Rheumatology monitoring guidance (2006) and advice from the National Patient Safety Agency should be reviewed (National Patient Safety Agency, 2005).
Etanercept (Enbrel)
Etanercept is a human TNFa receptor p75 fusion protein using recombinant deoxyribonucleic acid (DNA) technology. Etanercept is slowly absorbed following subcutaneous injection reaching maximum concentration approximately 48 hours after a single dose. The half life is approximately 70 hours (Wyeth Pharmaceuticals, 2005).
Indication for Use
Etanercept can be prescribed as monotherapy or in combination with methotrexate for the treatment of adults with active RA who have failed to respond adequately to DMARDs and PsA who have failed or are contraindicated/intolerant of DMARDs. It can also be prescribed for adults with RA who have active and progressive disease not previously treated with methotrexate.
Contraindications
See Table 2.6 and for further information refer to Summary of Product Characteristics and BSR Guidelines (2005).
Administration
Etanercept 50 mg is administered by subcutaneous injection once weekly in 1 ml of water. For moderate to severe plaque psoriasis the usual dose is 25 mg twice weekly or if needed etanercept can be administered at a dose of 50 mg twice weekly for up to 12 weeks reducing to 25 mg twice weekly.
Specific Additional Comments
For those with renal or hepatic impairment, there is no specific guidance for individuals receiving adalimumab. If co-prescribed with methotrexate guidance from the National Patient Safety Agency should be reviewed (National Patient Safety Agency, 2005).
Infliximab (Remicade)
Infliximab is a monoclonal antibody that binds with high affinity to both soluble and trans-membrane TNFa inhibiting the normal activity of TNFa (Figure 2.1). Infliximab is administered by intravenous infusion usually over a two-hour period. The median terminal half life at 3, 5 and 10mg/kg doses ranged from 8-9. 5 days. In most patients infliximab can be detected in the serum for at least 8 weeks after a single dose of 3 mg/kg. It may be that repeated treatments with infliximab might increase this time frame, although the data was studying Crohn’s disease with doses of 5 mg/kg with infliximab detected in serum for 12 weeks after administration (Schering Plough, 2005).
Indication for Use
Infliximab is indicated in the treatment of active RA when the response to DMARDs (including methotrexate) has been inadequate and for severe progressive RA not previously treated with DMARDs. For those with RA, infliximab should be prescribed in combination with methotrexate. It is also indicated for the treatment of PsA when the disease is active and progressive and has failed to respond adequately to DMARDs and in the treatment of AS for those who have axial symptoms and have failed to respond adequately to conventional therapy. It is also licensed for the treatment of Crohn’s disease.
Contraindications
Evidence of hypersensitivity to mouse or mouse dander. See Table 2.6 and for further information refer to Summary of Product Characteristics and BSR Guidelines (2005).
Administration
Infliximab is administered by intravenous infusion initially, usually over a two-hour period at a dose of 3 mg/kg of body weight for RA and 5 mg/kg body weight for AS and PsA. Infusions are administered following the first infliximab treatment at two and six weeks and then every eight weeks thereafter.
Side Effects that Should Be Considered for All Anti-TNFa Treatments
The long half life of infliximab means that monitoring of side effects or re-emergence of latent TB should be continued for up to six months after cessation of treatment.
Infusion Reactions (see also Reactions)
Infliximab is administered intravenously usually by infusion over a two-hour period. Infusion-related reactions (non-specific symptoms such as fever, chills) are reported as ranging from 5-15% (Cheifetz etal, 2003; Schering Plough, 2005; Shergy et al, 2002). Serious infusion reactions (chest pain, hypertension, hypotension or dyspnea) occur in less than 1% of patients treated with infliximab (personal communication, Schering Plough, 2005).
Sany et al. (2005) studied infusion-related reactions and found that pre-medication with betamethasone provided no additional benefit in reducing infusion-related reactions. Infusion-related reactions are more common on the third and fourth infusion and approximately 3% of patients discontinued treatment due to infusion reactions. Individuals receiving a diphenhydramine as a pre-medication had a higher rate of infusion-related reactions (Wasserman et al., 2004).
Although the majority of infusion reactions are mild and do not result in discontinuation of treatment, a small percentage (<1%) can be severe and include anaphylactic reactions that will require emergency treatment including adrenaline, antihistamines and corticosteroids (Schering Plough, 2005). (see Table 2.8).
If patients are re-treated after a prolonged period of time they should be monitored carefully. The episodic treatment (rather than regular maintenance treatment) with infliximab appears to exacerbate the risk of infusion-related reactions (Cheifetz et al., 2003). The risk is reduced if patients continue their DMARDs therapy (Schering Plough, 2005).
It is recommended that infliximab is administered particularly in the first year of treatment, usually over a two-hour period and post-infusion observations continue for one to two hours. There are some differing infusion regimes evolving with developing clinical expertise. Shortened infusion and observation times have been used for those who are established on treatment, and for those who do not have a history of atopy or have experienced a previous infusion reaction. Buch et al. (2004)suggests that the risks of infusion-related reactions were high up to and including the fifth infusion and as a result subsequent infusions can be administered at a faster rate.
Delayed hypersensitivity reactions (myalgia, arthralgia fever, rash or facial oedema, dysphagia) are uncommon and appear to be exacerbated by increasing drug free intervals of less than a year (Schering Plough, 2005).
Auto-antibodies (see also general section on auto-antibodies)
When methotrexate is co-prescribed with infliximab the risk of antibodies against the infliximab monoclonal antibody (human anti-chimeric antibodies, HACA) is reduced. Infusion-related reactions are seen more frequently in individuals who have developed antibodies to infliximab.
Rituximab (Mabthera) B Cell CD 20 Depletion
Mode of Action
Rituximab is a genetically engineered anti-CD20 monoclonal antibody that acts by selectively depleting the number of circulating pre B and mature B cells. B cells expressing CD20 antigen develop during a specific phase of the B cells’ maturity. This means that the overall integrity of the immune system is not compromised and is designed to sustain remission.
A number of research studies have focused on the role of B cells as a key player in the immunopathogenesis of RA (Shaw et al., 2003). Apart from producing immunoglobulins, B cells may have additional stimulatory effects in inflammatory arthritis and may include:
• Acting as antigen-presenting cells and encouraging co-stimulation of T cells.
• Activating T cells.
• Secreting pro-inflammatory cytokines and chemokines.
• Producing rheumatoid factor (RF). Positive RF is linked to aggressive disease and may be implicated in enhancing stimulus to T cells.
Indication for Use
Rituximab has been used to treat non-Hodgkin’s lymphoma (NHL) (Roche, 2005) for a number of years but it is possible that this licence could be extended to include the treatment of RA in patients who have failed anti-TNFa and are RF-positive. Although as yet unlicensed at time of going to press rituximab is being used for patients with severe RA that has failed to respond to anti-TNFa, and therefore it is important for practitioners to be aware of this treatment option.
Treatment with ritixumab should always be given with a pre-medication (pain reliever and anti-histamine). Steroids should also be prescribed if rituximab is not administered as a combination with cyclophosphamide, doxorubicin hydrochloride; oncovin (vincristine) and prednisolone (CHOP) or cyclophosphamide, vincristine and prednisolene (CVP) chemotherapy.
Rituximab has a long half life (up to 152.6 hours) after the first infusion and has been detected for three to six months following treatment (Roche, 2005).
Contraindications
Hypersensitivity to any component of rituximab or murine proteins.
Administration
An intravenous infusion of methylprednisolone (100 mg), paracetamol and antihistamine should be administered before each treatment of an intravenous infusion of rituximab of a fixed dose of 1000 mg rituximab. Treatment usually consists of 2 infusions administered 2 weeks apart (day 1 and day 15). A brief course of oral glucocorticoids should also be prescribed between first and second infusion (British National Formulary (BNF, 2004; Cohen et al., 2006).
Side Effects and Cautions
The research and clinical experience of rituximab is extensive in the field of NHL although clinical experience in the treatment of RA and other inflammatory arthritidies is in its early years to date. Early studies appear to show that there are a reduced number of adverse events compared to those seen in patients with NHL (36% of RA-treated patient compared to 75% of those with NHL) for their first infusion and 10% during the second infusion. It remains to be seen, with greater clinical experience, if the wider aspects of the side effects profile for RA will vary from NHL (Emery et al., 2006).
Cardiovascular
In clinical trials 18.8% of patients’ cardiovascular events were reported with the most frequent reports related to hypotension and hypertension. Individuals treated with anti-hypertensives may need to have their treatment withheld for 12 hours prior to infusion. Rixutimab should be used in caution in individuals treated with cardiotoxic chemotherapy or who have cardiovascular disease as exacerbations of angina, arrhythmia and heart failure have been seen (BNF, 2004).
Haematological/Immunoglobulin
Haematological abnormalities (e.g. thrombocytopenia, neutropenia, anaemia) occurred in a minority of patients and were usually mild and reversible. Blood monitoring should be undertaken and if neutrophils are below 1.5 x10.9/l or platelet counts are below 75 x 10.9/l treatment should be withheld until a medical opinion/review is undertaken.
Autoantibodies
There is a theoretical risk that human anti-chimeric antibodies (HACA) may develop from the biologically engineered rituximab, made up of human/mouse chimeric antibody. To date the incidence is low (< 1%) and rarely associated with any clinical symptoms (Stahl et al., 2004).
Infections
Bacterial, viral and to a lesser extent fungal infections have been identified in patients receiving rituximab, with severe infections occurring in 3.9% of patients in clinical trials. Some of these infections occurred during the treatment period (1.4%) and others presented during the follow-up period (2.5%) (Roche Products Ltd, 2005).
Very rare cases of hepatitis B reactivation have been reported in individuals who were also receiving cytotoxic chemotherapy whilst being treated with rituximab (Roche Products Ltd).
Infusion-related reactions (see also adverse reactions in general section)
The most common adverse events during or following rituximab treatment are mild to moderate infusion reactions (occurring in approximately 9% of patients) and are related to the rate of the infusion, usually occurring within two hours of the initial infusion (Hainsworth, 2003).
Patients with HACA titres may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies. Data in the treatment of NHL state that the incidence of infusion-related reactions are seen in approximately 50% (Roche Products Ltd, 2005). However, this data may not reflect the RA experience as some reactions seen in NHL are related to tumour lysis syndrome (TLS) and cytokine release syndrome (CRS), which may be specific to NHL and the specific tumour burden.
Infusion reactions include fever, chills, rigors and sometimes hypotension and dyspnoea and generally resolve quickly although in post-marking surveillance some fatal outcomes have been reported for those with severe reactions (Roche Products Ltd, 2005). It is therefore essential that full resuscitation support is readily available.
See Table 2.8 for general advice on the management of infusion-related reactions.
Drug Interactions
No data are currently available on drug interactions and the knowledge of agents capable of causing depletion of normal B Cells is as yet not known.
Pregnancy and Breastfeeding
Women (and men) of childbearing potential should use an effective method of contraceptive during treatment and up to 12 months from cessation of treatment as rituximab has a long half life (although proportional to the dose administered).
Women should not breastfeed whilst on rituximab.
Immunization
B cell depletion typically lasts for several months following treatment and it is therefore important to consider the immunization status of individuals prior to commencing treatment with rituximab and to complete all immunizations at least four weeks prior to the first administration of rituximab (Roche products, personal communication, 2005). Live vaccines should not be administered.
BIOLOGIC THERAPIES - PATIENT ISSUES
Patients should have had the opportunity to discuss all aspects of their treatment and be able, where appropriate, to select the treatment that best suits their needs. Risks and benefits should be explained and consent should be documented. All advice and information provided should be supported by written information and clear guidance on when to stop treatment and seek urgent medical advice.
The RCN guidance on training patients in the self-administration of subcutaneous therapies and detailed information on the management of patients prior to infusions will be a useful tool for practitioners (RCN, 2003). Additional guidance on management of rituximab infusions can be seen in Table 2.8.
Individuals treated with anti-TNFa therapies should be easily identified and treated promptly for infections. As a result specific patient alert cards have been developed for the patient to use to inform healthcare professionals and other care workers or dentists to inform them of key issues related to anti-TNFa therapies. These alert cards can be accessed easily (Arthritis and Research Campaign, 2005).
Biologic therapies will play an increasingly important role in the treatment of a range of autoimmune conditions and as such it is imperative that practitioners in all care settings have the expertise to support the patient in the assessment, management and ongoing monitoring of biologic therapies.
Corticosteroid drugs are synthetic derivatives of the body’s naturally occurring corticosteroid hormones, which are produced in the cortex of the adrenal glands. The principal corticosteroid of the human adrenal cortex is cortisol (hydrocortisone) derived from the hydroxylation of cortisone. The adrenal gland production of corticosteroids is controlled by the hypothalamus and the pituitary gland via a negative feedback system. Corticosteroids consist of androgenics, mineralocorticoids and glucocorticoids.
GLUCOCORTICOIDS
These are responsible for:
• carbohydrate, protein and fat metabolism;
• the maintenance of blood sugar levels;
• the body’s response to both physical and psychological stress;
• the suppression of inflammation and the immune response (Christiansen and Krane, 1993).
Much research has taken place to isolate the glucocorticoid that possesses precise anti-inflammatory and immunosuppressive properties but to date it remains elusive.
Therefore, the role of systemic steroids in the management of rheumatological disorders is complex because, whilst they are very effective anti-inflammatory and immunosuppressive agents, they are also associated with potentially serious side effects even with relatively low doses, which may cause significant morbidity.
Systemic steroids currently prescribed in the treatment of rheumatological disorders include hydrocortisone (cortisol), prednisolone, cortisone and methyl prednisolone.
Mode of Action
Corticosteroids act by binding to specific cytoplasmic receptors which then enter the nucleus where they cause the production of certain mRNAs (ribonucleic acid) coding for various proteins. The beneficial effects of systemic steroids are partly related to increased production of lipocortin and decreased production of the inflammatory response - for example, cytokines, prostaglandins and leukotrienes. The exact effects on the lymphocyte function are still poorly understood. It is not yet possible to separate different corticosteroid effects by using different corticosteroid analogs, indicating that their actions are similar and their relative potencies relate to their structure and plasma half life (Kirwan, 1994) (see Table 2.9).
THE USE OF STEROIDS IN RHEUMATOID ARTHRITIS
In a review of clinical trials of corticosteroids in RA it was concluded that in both short- and long-time studies corticosteroids are effective inflammatory agents, significantly better than placebos and NSAIDs in the relief of pain and stiffness (George and Kirwan, 1990). Work by Kirwan (1995) has demonstrated that patients with early RA who received prednisolone 7.5 mg daily for two years experienced less radiological joint damage (in the hands) than did those individuals receiving placebos. A systematic review from the Cochrane database concluded that prednisolone in doses of less than 15 mg daily may be used intermittantly in patients with RA, especially if the condition could not be controlled by other drugs (Gotzsche and Johansen, 2005). The review highlighted that the lower the dose of steroid the less risk of adverse side effects. Bone protection therapy should be commenced at the initiation of treatment with steroids.
Table 2.9 Half life of commonly used corticosteroids.
Short-acting: 8-12 hours
Cortisone
Cortisol
Intermediate acting: 12-36 hours
Prednisolone
Prednisone
Methylprednisolone
Triamcinolone
Long acting: 36-72 hours
Paramethasone
Dexamethasone
Betamethasone
_____________________
However, the problem with using steroids for control of synovitis is that benefits are not sustained unless increasing doses are employed. This increases the risk of steroid side effects and it often becomes very difficult to decrease or stop the steroids.
CORTICOSTEROID SPARING AGENTS
This term is used to describe drugs which are prescribed in order to make it easier to reduce the corticosteroid dose, while at the same time controlling the underlying disease. Azathioprine, cyclophosphamide and methotrexate can all be used for this purpose.
ADVERSE EFFECTS OF CORTICOSTEROIDS (SEE TABLE 2.10)
The Immune System
Corticosteroids are powerful immunosuppressants, which affect both humoral and cell-mediated immune responses. Although corticosteroids can be valuable in the treatment of autoimmune diseases they can also be potentially life-threatening because high levels of corticosteroids will also reduce the formation of antibodies and the white cell count of patients, therefore permitting the invasion of bacteria or viruses and the spread of infection. Patients on long-term corticosteroids may also be predisposed to staphylococcal, gram-negative, tuberculous and listeria infections (Christiansen and Krane, 1993; Kirwan, 1994).
Table 2.10 Adverse effects of corticosteroids.
Metabolic: a) obesity: changes due to fat redistrubution result in cushingoid features such as a moon face; b) glucose protein metabolism: hypergylcemia and insulin resistance occur.
Decreased resistance to infection: due to immunosuppression. Candida and herpes zoster infection can occur along with a variety of bacterial infections.
Musculoskeletal: a) muscule wastage due to protein catabolism; b) tendon rupture occurs with direct injection into a tendon; c) osteoporosis due to a reduction in calcium absorption into the bones and increase in calcium excretion. Vertebral wedge and crush fractures are a frequent complication of treatment; d) corticosteroid withdrawal syndrome occurs with long-term use of steropids and as a result of too rapid a withdrawal. Symptoms include myalgia, fatigue, malaise, anorexia, nausea and weight loss.
Gastrointestinal: a) peptic ulceration due to the inhibition of gastric prostaglandins which maintain the integrity of the gastric mucosa; b) pancreatitis.
Ophthalmic including cataracts and glaucoma
Central nervous system: psychosis, euphoria and depression
Skin including acne, striae, alopecia, bruising and skin atrophy
Growth retardation
Adrenal suppression
_________________________
Glucose Metabolism
The problem of glucose intolerance with patients receiving corticosteroids was initally highlighted in the late 1940s. The suggested mechanisms of glucose intolerance are as follows:
• decreased insulin secretion;
• increased hepatic glucose production;
• impaired peripheral glucose metabolism.
Methods of Administration
• orally;
• intravenous pulses;
• intra-articular injection;
• intra-muscular injection;
• soft tissue injection.
Pharmacokinetics
Following oral administration of prednisolone, absorption takes place quickly within the gastrointestinal tract and is rapidly metabolized within the liver, with excretion via the urine. Its action on the tissues is of a much longer duration than its presence in the blood (George and Kirwan, 1990).
Treatment Regimen
The factors that dictate the treatment regimen include the actual disease, its severity and the clinical response. Kirwan (1994) divides the treatment regime into three dose-related ranges:
• Low daily doses (up to 15 mg) to treat polymyalgia and symptomatic RA.
• High daily doses 20-60 mg for serious disease - for example, temporal arteritis, dermatomyositis, lupus erythematosus.
• Very high doses (pulsed methylprednisolone) for acute or life-threatening crisis.
THE USE OF CORTICOSTEROIDS IN OTHER RHEUMATOLOGICAL CONDITIONS
The symptoms of PMR and temporal arteritis (TA) often overlap. No controlled trials have been conducted to provide guidance on the best treatment dosage with corticosteroids (Kirwan, 1994). Although practice will differ, PMR is often treated with an initial dose of 15 mg prednisolone daily reducing slowly over 18-24 months governed by blood inflammatory parameters and clinical symptoms. One potential problem is to commence too high a dose of prednisolone accompanied by too rapid a reduction in dosage overtime. This will often result in an exacerbation of original symptoms.
The treatment of TA requires a much higher dose of steroid, usually 60-100 mg daily.
Collagenosis
The use of steroids will be largely determined by the nature of the collagenosis complication rather than by the collagenosis itself - for example, in the case of SLE many individuals with mild disease manifestations may not require steroids.
Inflammatory Muscle Diseases
Dermatomysitis and polymyositis patients are treated with medium to high daily dose steroids initally. This will often be accompanied with a cytotoxic agent such as azathioprine or methotrexate.
Vasculitis
Management of vasculitis involving major organs (e.g. Wegener’s granulomatosis, rheumatoid vasculitis, polyarteritis nodosa) will necessitate the use of high dose steroids orally or intravenous pulse therapy.
BONE MINERAL METABOLISM
Studies have revealed that cytoplasmic glucocorticoid receptors are present in bone cells, which appear to influence calcium intake and excretion and the factors that regulate hormones, cytokines and growth factors. Therefore, prolonged steroid therapy possesses multifaceted adverse effects on bone mineral metabolism which precipitate growth retardation in children, osteoporosis, long bone and vertebral fractures. The adverse effects of steroids that affect bone material metabolism include their effects on:
• Osteoblasts: steriod therapy has been shown to reduce circulating osteocalcin levels which affect osteoblast activity thus inhibiting bone formation. Studies have also revealed that bone matrix synthesis is affected within 24 hours of the administration of steroids (Godschalk and Downs, 1988; Reid et al., 1986).
• Osteoclasts: steriod therapy is thought to have a dual accelerating effect of bone reabsorption (1) by directly stimulating osteoclasts or (2) indirectly under the influence of parathyroid hormone (PTH).
• Gastrointestinal absportion of calcium: the consensus of opinion is that steroids suppress the intestinal absorption of calcium although the reason remains unclear.
• Excretion of calcium: a decrease in the reabsorption of calcium within the kidneys has been shown to occur in patients. Although glucocorticoid receptors are present in the kidney their precise mode of action on calcium reabsorption/excretion is unclear (Fuller and Funder, 1976).
• Vitamin D: extensive research regarding the effects of steroids and 25- hydroxyvitamin D levels has revealed conflicting evidence; hence the suggested osteopenic effects of steroids in relation to 25-hydroxyvitamin D levels remains controversial.
• Parathyroid hormone (PTH): PTH-regulated blood phosphorus and calcium levels via its actions on the intestines, bone tissue and kidneys. A normal concentration of calcium (2.2-2/6mmol/1) is essential for normal physiology. However, numerous studies have demonstrated that steroids stimulate the parathyroid glands and increase PTH levels, which stimulate osteoclasts to accelerate bone resorption (Cosman et al., 1992; Gray et al., 1991).
• Growth retardation: since the early 1950s growth retardation in children has been a recognized side effect of long-term steroid therapy, although the precise mechanisms remain elusive. It is suggested that steroid therapy has a direct effect and an indirect consequence on both the osteoblast and cartilage cells, which consequently suppresses the growth of linear bone and impedes epiphyseal closure (Loeb, 1976). The prevention of growth retardation is helped by prescribing an alternate-day regimen (Clarke and Fitzgerald, 1984; Guest and Broyer, 1991; Polito et al, 1986).
Studies of bone loss in adults treated with cortisteroids do not clearly suggest a threshold dose below which osteoporosis can be avoided (Kirwan, 1994), although there does appear to be a consistent relationship between doses above 7.5 mg daily and the rate of bone loss.
PEPTIC ULCERATION
Evidence from controlled studies of corticosteroid therapy suggests that the increased risk of peptic ulceration is considerably lower than is widely believed (Cooper and Kirwan, 1990). However, corticosteroids may exacerbate the ulcer- genic properties of NSAIDs (Piper et al., 1991).
ATHEROSCLEROSIS
Prolonged corticosteroid therapy may accelerate the development of atherosclerosis (Cooper and Kirwan, 1990), with lower limb atherosclerosis occuring in as many as 60% of corticosteroid-treated patients with RA. The evidence linking corticosteroid therapy with atherosclerosis is still considered controversial but, in time, even a small effect could have considerable clinical significance.
REDUCING THE DOSE OF CORTICOSTEROIDS
High doses of corticosteroids are often used for only short periods and can be reduced rapidly with little adverse effect. The exact mode of reduction will depend on the control of the clinical situation. Patients treated with moderate to low doses of corticosteroid over a longer duration of time may develop a corticosteroid withdrawal syndrome when their treatment is reduced. This can include the symptoms of myalgia, fatigue and nausea and has been reported in as many as 70% of patients treated with 30 mg prednisolone daily for longer than three months (Dixon and Christy, 1980).
One approach to try and avoid this is to reduce the corticosteroid treatment very slowly, often by as little as 2.5 mg daily every two months down to 7.5 mg daily, then introduce further graduated reductions of l.0 mg daily or by 1.0 mg on alternate days.
The administration of exognous steroids may result in the suppression of the body’s own (endogenous) steroid production. Therefore, when exogenous steroids are withdrawn, the adrenal gland may fail to produce adequate cortisol, resulting in a steroid crisis with a failure of cortisol production. This in turn results in hypotension, hypoglycaemia and electrolyte imbalance. All patients on steroid treatment should carry a steroid card with them.
The withdrawal of steroids can lead to a marked flair in symptoms of the disease process, which may necessitate the patient being recommenced on steroids.
PULSED CORTICOSTEROIDS
Pulse therapy involves the intravenous infusion of a large dose of corticosteroid (usually 500 mg-1 g of methylprednisolone) over 30-60 minutes. There are many different treatment regimens in practice but most include a course of three pulses on alternate days, followed by a resting phase of around six weeks (Kirwan and the Arthritis and Rheumatism Council Low Dose Glucocorticoid Study Group, 1995). It may be used to bridge the time interval between initiation and response to DMARDs or, when a patient has an acute flare of their RA, to induce remission. A review of the use of pulsed methylprednisolone (Weusten, Jacobs and Bijlsma, 1993) shows few or minor side effects. Those who have experienced severe adverse effects of the cardiovascular system, or experienced infection, had existing compromised cardiovascular and immune systems as a result of their disease or due to concomitant drug therapy (Kirwan, 1995).
INTRAMUSCULAR CORTICOSTEROIDS
Intramuscular injections of corticosteroid may be used to reduce the symptoms of a flare in RA, or be administered prior to the initiation of DMARD where it is known that these medications take many months before benefit can be assessed. It is important to give the injection deep into the muscle to prevent muscular atrophy occurring. Choy et al. (1993) found that intramuscular methylprednisolone was superior to equivalent oral doses in their study of corticosteroids and gold therapy.
INTRA-ARTICULAR/SOFT TISSUE INJECTIONS OF CORTICOSTEROIDS
Intra-articular and soft tissue injections are interventions used in the management of rheumatology disorders that offer an effective supplement to systemic therapies in the control of inflammatory joint disease. In comparison to oral corticosteroids, they are well tolerated and safe if administered appropriately. The Royal College of Nursing Rheumatology Forum has produced guidelines on the use and administration of intra-articular injections, including contraindications for the administration (see Appendix 2.B).
Gout is caused by inflammation induced by microcrystalline uric acid in the form of monosodium urate monohydrate in joints and soft tissues. A usual but not essential prerequisite for the condition is a raised plasma level of urate, which is derived from endogenous and dietary nucleoproteins (Snaith and Adebajo, 2004).
HYPERURICAEMIA
Uric acid is the product of purine metabolism and hyperuricaemia can occur either from an overproduction of uric acid (20-25% patients) or when the kidneys fail to excrete uric acid (75% of patients). Excessive hyperuricaemia may then result in the formation of uric acid crystals, which are deposited in various parts of the body, more commonly in the joints of the foot, hand and knee. However, uric acid crystals may also form torphi in soft tissues or as stones in the kidney.
Prevalence
The prevalence of gout is 5-10 per 1000 adults in the United Kindom. It can occur in young men with a family history of gout, middle-aged men with hypertension, obesity and cardiovascualr disease and in older men and women secondary to diuretic use (Snaith and Adebajo, 2004).
Clinical Features
70% of patients present with an acute attack of gout, which is typically characterized by a sudden onset of podagra (an acute, red, painful swelling at the metatarsophalangeal joint of the great toe), although both the knee and hand may also be affected. Patients with acute attacks may also present with a raised erythrocyte sedimentation rate, pyrexia and leucocytosis.
Precipitating Factors
• A sudden raised level of uric acid (greater than 430 umol/1 resulting either from an oversecretion from the liver or impaired kidney excretion).
• Obesity.
• Alcohol.
• Hypertension.
• Severe dietary restriction.
• Diuretics.
• A sudden fall of uric acid levels following the administration of allopurinol or uricosuric drugs.
• Trauma.
• Surgery.
• Severe systemic illness.
If episodes of acute gout reoccur and remain untreated, gout develops into a chronic condition in which erosions of both cartilage and bone may occur along with deposits of trophi. Trophi are composed of sodium biurate and appear as small hard chalky or cheesy deposits which may discharge and ulcerate. Consequently, chronic gout may result in joint deformities and subsequent functional impairment.
Diagnosis
The examination of synovial fluid by polarized light microscopy is used to identify monosodium uric acid crystals. The identification of these crystals provides the clinician with a definite diagnosis of gout, thus excluding either sepsis or pseudogout.
The crystals present in pseudogout are calcium pyrophosphate. The correct diagnosis is paramount to ensure that patients are not prescribed treatment unnecessarily (Currey, 1988).
Diagnosis Features
• Hyperuricaemia (although not all patients with hyperuricaemia have gout).
• X-rays in early acute attacks are unremarkable. However, the appearance of classic ‘punched out’ erosions (radiolucent urate tophi) appear later with chronic gout.
• Following susbequent episodes of gout, examination of the patient may reveal tophaceous deposits in the helix of the ear, bursae, tendon sheaths and kidney parenchyma.
Treatment
The management of gout is planned in two stages: initially the management of the acute inflammatory joint symptoms, and secondly the long-term management of persistent hyperuricaemia.
First-Stage Treatment
The aim of initial therapy is to suppress the inflammatory process induced by the deposit of uric acid crystals, which may be present in and around joints, tendons and in the kidney parenchyma. Hence, non-steroidal anti-inflammatory drugs are the first line of treatment. The NSAID prescribed will depend on both the patient’s tolerance and the clinician’s preference. The initial dose required is usually twice the normal maintenance dose for three days, reverting to the maintainance dose until resolution is achieved (Snaith and Adebajo, 2004), usually by 14 days.
In those patients for whom NSAIDs are contraindicated, colchicine is prescribed but is often not tolerared at its full dose. Oral or parental steroids are also effective but septic arthritis must be excluded before their use. If using oral prednisolone it can be prescribed at 30 mg daily tapering to zero over 10 days (Snaith and Adebajo, 2004).
Colchicine
Derived from the autumn crocus colchicum autumnale, colchicine is an ancient remedy which has been prescribed since the eighteenth century for the treatment of gout (Emmerson, 1994).
Mode of Action
Colchicine is an alkaloid that halts both the inflammatory response and the deposit of uric acid crystals, although its precise mode of action is complicated and not entirely understood.
Pharmacokinetics
Following administration, colchicine is absorbed through the upper small bowel, metabolized by the liver and then excreted both in the bile and intestinal secretions. As 20% is excreted unchanged in the urine, the dose of colchicine should be adjusted accordingly for those patients who have pre-existing renal disease (Emmerson, 1994).
Treatment Regimen
Initially patients are prescribed 1mg, followed by 0.5 mg every 2 hours which usually has an effect within 24 hours of commencement of therapy. However, because the therapeutic regimen may mirror the toxic dose, dosage continues until either:
• The maximum total dose is attained (10mg).
• The gout subsides.
• Side effects are experienced (diarrhoea and vomiting).
NB: colchicine 0.5 mg 2-3 times daily may also be prescribed concurrently with initial long-term treatment of hypouricaemic drugs to prevent further attack of acute gout. Adverse effects are shown in Table 2.11.
Drug Interactions
Ciclosporin: increased plasma levels - therefore possible risk of both nephroxity and myotoxicity.
Second-Stage Therapy: Long-Term Treatment
The aim of long-term treatment of gout is to prevent the possible consequences of further episodes of acute gout (joint deformity, loss of joint function, and kidney damage).
Table 2.11 Adverse effects of colchicine.
Nausea/vomiting
Abdominal pain
Gastrointestinal haemorrhage
Rashes
Renal and hepatic impairment
Peripheral neuritis
Myopathy
Blood disorders (with prolonged therapy)
_________________________
The hypouricaemic drug most commonly prescribed is allopurinol, which is a xanthine-oxidase inhibitor which acts to inhibit the production of uric acid. Other hypouricaemic drugs include probenecid and sulfinpyrazone, which are both uricosuric drugs that block the tubular reabsorption of filtered urate in the kidneys and therefore increase the excretion of uric acid via the kidneys. Second-stage therapy, therefore, is prescribed to prevent recurring acute attacks of gout by maintaining uric acid levels that fall within normal blood plasma parameters.
Indications for the prescription of second-stage therapy:
• Hyperuricaemia with recurrent episodes of acute gout.
• Visible tophi and/or erosions revealed by radiological examination.
• Associated renal impairment.
Allopurinol
Allopurinol acts by inhibiting xanthine oxidase, the product that enables the conversion of xanthine and hypoxanthine to uric acid (Edwards and Boucher, 1991). Because of its low incidence of side effects, allopurinol is the most widely used drug for the long-term prophylaxis of gout. Its added advantage is that it can also be prescribed for those patients with renal impairment or those who have kidney stones (which are conditions contraindicated for treatment with uricosuric drugs).
Treatment Regimen
A dose of 100 mg once daily initially for one week (initial dose for both the elderly and patients with renal dysfunction should be reduced to 50 mg to prevent toxicity; Gibson, 1988), increasing over two to three weeks to a maintenance dose (dependent on either blood plasma or urinary uric levels) of 200-600 mg daily in divided doses. Tablets should be taken after food.
Uricosuric Drugs
Probenecid
Treatment Regimen
• Week one: 250 mg twice daily.
• Week two: 500 mg twice daily.
• Maintenance dose up to 2 g daily in divided doses according to uric acid levels. Tablets are to be taken after food.
Sulfinpyrazone
Treatment Regimen
Initially 100mg-200mg daily, increasing over two to three weeks to 600 mg daily.
Maintenance dose (when uric acid blood plasma falls within normal levels) may be possible to reduce to 200 mg daily. Tablets to be taken with either food or milk.
Compliance of long-term therapy is dependent on patient education regarding the differing actions of both initial and long-term therapies. To prevent further attacks of gout, patients should receive health promotion regarding the risk factors that can precipitate an acute episode of gout.
Benzbromarone is more potent than probenecid or sulfinpyrazone and it can be used in patients with renal impairment and in conjunction with allopurinol. It does increase the risk of stone formation so a high fluid intake is important (Snaith and Adebajo, 2004).
Diet and Lifestyle
Dietary advice can prevent futher attacks of gout.
• Weight reduction.
• Saturated fats replaced with unsaturated fats.
• Relative increase in protein intake.
• Many beers contain guanosine which is converted into uric acid by gut bacteria.
• Alcohol taken without food is catabolized to lactate and other ketones that compete with urate for excretion via the renal tubule.
• Alcohol also decreases the conversion of allopurinol to the effective metabolite oxipurinol.
• Fortified wines may contain oxalates, which contribute to the formation of stones.
• Coffee and tea are diuretics and can interfere with assays for urate (Snaith and Adebajo, 2004).
For more information on gout contact: www.ukgoutsociety.org
The Crown Report on Prescribing, Supply and Administration of Medicines (DoH, 1999) provided the framework for the development of prescribing for nurses. The report describes two types of nurse prescribers.
• Independent prescribers who diagnose patients and then prescribe an appropriate medication.
• Supplementary prescribers who are responsible for the care of the patient once the diagnosis and treatment plan has been determined by an independent prescriber. For example, a patient with inflammatory symptoms will be reviewed by the rheumatologist. Once a diagnosis of RA has been established and the need for DMARDs established the rheumatologist could refer the patient to a rheumatology nurse for the instigation of a DMARD and the necessary ongoing surveillance.
The recommendations of the Crown Report were implemented in three stages.
• Patient group directions (PGDs) for the supply and administrations of medicines (DoH, 2000a). (Appendix 2.C contains an example of a PGD that enables nurses to administer intramuscular Depomedrone to patients with rheumatoid arthritis.)
• Independent prescribing for nurses (DoH, 2000b).
• Supplementary prescribing for pharmacists and nurses (DoH, 2002).
WHO SHOULD PRESCRIBE?
The National Prescribing Centre (NCP) (2005) have suggested the following criteria that may help to identify nurses who would benefit from becoming prescribers. These include nurses who:
• Run their own clinics or services, which would include most rheumatology clinical nurse specialists.
• Work in isolation from other prescribers (although to a lesser extent with supplementary prescribers who need to work in partnership with an independent prescriber).
• Could complete episodes of care if they were able to prescribe.
• Are likely to be able to prescribe for more than one medical condition.
• Hold additional qualifications whereby their professional expertise would facilitate prescribing for specified medical conditions.
INDEPENDENT PRESCRIBING
The first extended nurse prescribers qualified in 2002. The main goal was to have competent nurse prescribers who could treat patients in four specific areas:
• minor illness;
• minor injuries;
• health promotion;
• palliative care.
These areas were chosen as they represent the commonest reasons for patients requiring input from their GPs and the introduction of the extended nurse prescribers (ENPs) formulary was to enable nurses to prescribe in these four domains, in a safe, quick and effective manner to benefit the patients and free up GP time. Consequently the initial nurse prescribing courses were aimed at nurses working in walk-in centres or running minor injury clinics. The ENPs formulary is a list that contains over 70 symptoms and specific conditions for which the nurse prescriber can prescribe (see www.nurse-prescriber.co.uk).
Acute musculoskeletal conditions for which an ENP can prescribe include:
• acute chronic back pain (uncomplicated);
• neck pain (uncomplicated);
• soft tissue injury;
• sprains;
• low back pain;
• knee pain;
• osteoarthritis;
• rheumatoid arthritis.
Independent prescribing is appropriate in the following circumstance:
• The nurse works remotely from a doctor, seeing patients independently for those conditions listed in the nurse prescriber extended formulary (NPEF).
• The doctor could see and treat other patients while the nurse sees some patients.
• The nurse is competent to assess, diagnose and make treatment decisions for the patient.
It is not suitable for prescribing for complex medical conditions or for patients with several co-morbidities (Department of Health Medicines and Healthcare Products Regulatory Agency, 2005a).
From spring 2006, qualified extended formulary nurse prescribers and pharmacists who are independent prescribers will be able to prescribe any licensed medicine (except controlled drugs) for any medical condition. Extended formulary nurse prescribers will be known as nurse independent prescribers (NIPs) and supplementary prescribers as nurse supplementary prescribers (NSPs).
SUPPLEMENTARY PRESCRIBING
The Department of Health define supplementary prescribing as a voluntary prescribing partnership between an independent prescriber and a supplementary prescriber to implement an agreed, patient-specific, clinical management plan with the patient’s agreement (Hennell, 2004).
Once the patient has been diagnosed by the independent prescriber (who in this situation has to be a doctor) a clinical management plan (CMP) is required that has to involve both the independent and supplementary prescriber (in this case a rheumatology nurse).
The Department of Health (2002) state that the CMP should:
• Be patient-specific.
• Be agreed by both the independent and supplementary prescribers before supplementary prescribing begins and supported by the intended recipient.
• Specify the range and circumstances within which the supplementary prescriber can vary the dose, frequency and formulation of the medicines identified.
• Specify when to refer from supplemntary prescriber to independent prescriber.
• Contain relevant warnings about known sensitivities of the patient to particular medicines, and include arrangements for notification of adverse drug reactions.
• Contain the date of commencement of the arrangment and a date for review (not normally longer than one year for patients with chronic conditions).
Supplementary prescribers can prescribe all medications currently prescribed by doctors with the exception of unlicensed medicines (except in specific circumstances) - see Department of Health web site: www.doh.gov.uk/ supplementaryprescribing/plan.htm.
Supplementary prescribing is appropriate in the following circumstances:
• Patients with long-term conditions, who can be managed by a nurse or pharmacist and some allied health professionals (AHPs) between reviews by the doctor.
• Nurses or pharmacists (and some AHPs) who are competent to manage the patient’s condition.
• There is a close working partnership between the independent prescriber (doctor) and the supplementary prescriber, who have access to the same patient record.
Supplementary prescribing is not suited to an urgent prescribing situation because an agreed CMP is required before prescribing can begin (DoH, 2005a).
EDUCATIONAL PREPARATION
Potential nurse prescribers must undertake a Nurse and Midwifery Council (NMC) approved course at level three (first degree level) consisting of at least 26 taught days plus 12 days learning and assessment in practice working with a designated medical practitioner.
PROFESSIONAL RESPONSIBILITIES
As with all areas of practice, nurse prescribers must act within their own level and area of competence acknowledging the scope and limitations of their role. In order to promote safe and effective practice there must be clearly defined policies, support mechanisms and audit systems (Cully, 2005). The National Prescribing Centre (2002) have produced a useful resource reminding nurses of their legal and professional accountability and duty of care.
EVALUATION OF PRESCRIBING
National research evaluating the first two years of extended formulary prescribing demonstrated that it was well received by nurses, patients and doctors and had a positive impact on patient care because of improved access (Latter, 2005). Nurse prescribers felt that:
• they were confident in their prescribing practice;
• extended prescribing had a positive impact on patient care and enabled nurses to make better use of their skills;
• the limited nursing formulary imposed unhelpful limitations on their practice;
• they had received support from their medical practitioner (Latter, 2005).
An audit of the prescribing practice of rheumatology nurses in one rheumatology department over a 10-month period demonstrated that the majority of patients requiring a prescription were patients with RA (81%) and the commonest drug prescribed was methotrexate (35%) (Hennell, 2005). All patients were satisfied with specialist nurses issuing a prescription. The specialist nurses have a greater sense of job satisfaction and are autonomously able to complete episodes of care. It also provides medical staff with more time to manage patients with complex medical needs (Hennell, 2004).
Clinical Management Plan
Name of patient: Mrs B. Davenpot
Patient identification e.g. ID number, date of birth: 04/04/1944
Patient medication sensitivities/allergies: penicillamine
Current medication: diclofenac 75mg BD; co-codamol.
Medical history: Hypertension
Independent prescriber: Dr H.
Contact details: tel./e-mail/address
Supplementary prescriber: Nurse X.
Contact details: tel./e-mail/address
Condition(s) to be treated: active rheumatoid arthritis
Aim of treatment: to suppress disease activity
Treatment plan:
• Commence methotrexate 7.5 mg weekly for eight weeks.
• After eight weeks increase methotrexate by increments of 2.5 mg every fortnight until a dose of 15 mg in reached.
• Commence folic acid 5 mg daily.
• Observe full blood count (FBC), AST and ALT weekly for the first month and then monthly.
• Observe for dry cough or breathlessness.
Indication: methotrexate
Preparation: oral
Dose schedule: as above
When and who to refer to: Dr H. if change, no improvement (after four months) or if adverse event occurs.
Guidelines supporting treatment plan:
• Inhouse protocols (January 2006).
• Current BNF (September 2005).
• Oxford Handbook of Rheumatology (Hakim and Clunie, 2002).
Review and monitoring requirements: weekly for the first month and then monthly.
Process for reporting adverse drug reactions (ADRs): yellow card.
Documentation and record keeping: hospital case notes and patient’s computerized record.
Name and agreement of independent prescriber/supplementary prescriber, date, date agreed with patient.
There are various useful websites for nurse prescribers including:
• Department of Health: www.dh.gov.uk
• NHS Modernisation Agency: www.modern.nhs.uk/cwp
• Medicines and Healthcare Products Regulatory Agency: www.mhra.gov.uk
• National Prescribing Centre: www.npc.co.uk
• Prescribing News: www.nurse-prescriber.co.uk
• Prodigy: www.prodigy.nhs
• Royal Pharmaceutical Society of Great Britain: www.rpsgb.org.uk.
If the treatment of RA is to be effective, patients must have the ability to adjust drug administration according to the changing activity of their disease (Hill et al., 1991). It is vital in patients with chronic inflammatory conditions who take medications for a long period of time as there is a clear need to assess both the safety and efficacy of the drug regime (Hopkins, 1990), especially as it is the patient who will be responsible for administering prescribed medications at home. Healthcare professionals can no longer assume that people are passive recipients of care, and patients will require information to administer medicines safely and effectively (Kennedy, 1981).
Beardsley, Anderson Johnson and Kabat (1983) define drug self-administration procedures as specific education strategies that contain the necessary knowledge and behavioural components to effect better compliancy. (The whole area of adherence is discussed in further depth in Chapter 4.)
THE CASE FOR SELF-MEDICATION
The conventional system of drug administration from a ward trolley often neglects to address the need for individual education nor does it seek to prepare patients to administer drugs within their own home environment following discharge. All the nurse has to do is to administer and sign that the prescribed drug has been given. This is despite the fact that health education has become a major part of the nurse’s role (Bird, 1990). This traditional system frequently provides dosages at incorrect times and unfortunately is not error-free (Johnson and Giles, 1993). It should no longer be acceptable to the profession and we should aim to provide patients with a personal pharmacy (Corrigan, 1989). Webb (1990) states that the traditional approach of batch processing suits staff convenience rather than being governed by patient need; whereas a holistic humanitarian approach to nursing care necessitates considering people as individuals and providing care in partnership with them.
An important but often neglected area of discharge planning is whether a patient is being discharged home without adequate knowledge of their tablets or with containers that they cannot open. The NMC has recommended that selfadministration projects be established during a hospital stay to provide patients with the necessary knowledge and confidence to continue with a high degree of compliancy on discharge (Sutherland, Morgan and Sample, 1991).
Many patients, particularly those in the older age group, are taking medications when they are admitted to hospital. Quilligan (1990) offers a framework for ensuring that older patients are given enough support in learning about their tablets. It follows the structure of the nursing process:
Patient Assessment
• Does the patient understand their condition and the purpose of their medications?
• Does the patient want to learn more about their medications and are they able to do so?
• Can the family be involved in the process?
Planning and Implementation
• Use realistic joint goals on agreed topics and if possible conduct the sessions when the family can be present.
• Limit the teaching to 3 topics in a 15-minute-maximum session.
• Discuss the patient’s worries and check previous knowledge.
Evaluation
• Ongoing assessment of managing tablets and the teaching programme is required.
ADVANTAGES OF SELF-MEDICATION
Patients have the chance to familiarize themselves with their medications and the opening of the containers/packaging. They would be able to discuss any needs or concerns whilst the nurse would have the opportunity to assess patient knowledge, evaluate previous teaching and identify those patients who will need ongoing support from the community services.
A programme of self-medication may help to reduce the number of drug errors as it would incorporate extensive patient education and provide the opportunity for supervised practice of drug administration. Nurses reported that those patients who had self-medicated in hospital had a better understanding of all aspects of their drug regime (Bird, 1990). Work by Scrivin and Bryan (1987) found that patients were very appreciative of a self-medication programme and medication errors reduced from 17.9% to 6.9% after the programme had been introduced. Also, if patients experience accidental overdoses it is safer for this to occur in the hospital rather than the home environment.
Self-medication returns control to the patient, promoting comfort and demonstrating trust (Bird, 1990). A self-medicating patient will not be woken at 6 a.m. or stay awake until after midnight for sedation, or seek out a nurse for analgesia. Corrigan (1989) found that patients would question if the tablets looked different and were likely to refuse steroids until after breakfast. Webb (1990) found that most patients took in the process of self-medication very quickly, feeling unrushed over administration and enjoyed having something positive to do.
STAGES IN THE IMPLEMENTATION OF SELF-MEDICATION
• Planning - this is often considered the most important stage and cannot be rushed. It is vital to the overall success of the programme to gain the cooperation and support of all those involved including the ward staff, doctors and (crucially) the pharmacist.
• Assessment - in some units this will be a dual process involving both the pharmacist and the nursing staff. The patient will be assessed on their understanding as to the purpose of their medications, their safety in administration (i.e. timing and dosage), potential side effects to report and their psychomotor skills in the handling and reading of their medications. It is at this stage that the nurse will enter into a therapeutic partnership with the patient, offering support and education on an individualized basis to both the patient and their family as required. Table 2.12 lists the information that patients will require to know about their medications. An assessment document is often used to highlight any perceived problems and to determine the level of supervision required.
• Accountability can be a major concern to nurses when they consider implementing a self-medication programme. It can generate concerns of losing control over drug administration whilst still holding the same degree of responsibility. In fact, the nurse is not losing any element of control but is able to utilize the skills of educator, guide and supporter in a more constructive manner to ensure that patients are safely and knowledgeably administering their tablets. It could be argued that there are more concerns about accountability in the traditional system of drug administration as nurses could be engaging in the provision of medicines without ascertaining the patient’s knowledge and understanding of the therapy. Bird (1990) states that the anticipated problems that nurses fear of patients forgetting to take their tablets, taking too many tablets or gaining access to other people’s drugs seldom occurs in practice.
Table 2.12 What patients need to know about their medication (Quilligan, 1990).
The name of the drug
How it is taken
Its intended action
What dosage to take
The side effects
The time of day it is to be taken
How many tablets to take and how often
Whether to take it with food
What to do if a dose is omitted
Check the expiry date
Not to stop essential medicines without first contacting the doctor
Whether any special storage is required
Can you drive?
Not to take any non-prescription drugs without first consulting the doctor
__________________________
• Implementation - in some units a staging process is used. The assessment process will determine the level the patients enter the programme and what degree ofsupervision is required - for example:
• Level One - the nurse administers the medicines providing full explanation.
• Level Two - the patient administers the medicines with nurse supervision.
• Level Three - the patient administers the medicines without supervision (Sutherland, Morgan and Sample, 1991).
Some areas have introduced memory aids in the form of calendar cards, which have been shown to lead to fewer errors when compared with written or verbal instructions (Wandless and Davie, 1997).
• Evaluation -various degrees of supervision have been used, generally including at least daily discussions and observations of the patient’s progress. Evaluation should include the obtainment of both the patient’s and the nurse’s views on progress.
Alternative and complementary medicine is the aggregate of diagnostic and therapeutic practices and systems that are separate from, and in contrast to, conventional scientific medicines (Champion, 1994). Table 2.13 demonstrates the different types of complementary medicines available today.
A third to almost 100% of patients with RA admit to using some form of complementary therapies (Ernst, 1998). Reasons for using complementary therapies include dissatisfaction with conventional medicines and the need for psychological support (Moore, 2000; Jacobs, Kraaimaat and Bijlsma, 2001). Many nurse practitioners actively recommend complementary treatments to patients (Sohn and Cook, 2002).
Table 2.13 Complementary therapies.
Acupuncture
Aromatherapy
Chinese medicine
Diet
Herbalism
Holistic medicine
Homeopathy
Massage
Naturopathy
Osteopathy
Reflexology
Spiritualism
Yoga
______________
DIET
The extensive research into dietary treatments of RA has been reviewed by Buchanan et al. (1991) and the results remain inconclusive. Individual dietary manipulation may be beneficial to selected patients (Darlington et al., 1986; Panush et al., 1983) but it is difficult to generalize from these findings and further study with sound methodological design is required.
Patients are extremely interested in this area and invest both time and money, striving to obtain relief from their symptoms. Dozens of publications vie with each other to suggest yet another method of ridding sufferers of pain and inflammation - often contradicting each other. Trials have shown that the green-lipped mussel extract (Seatone) does not work but its sales continue (Champion, 1994).
Surveys have found that many patients with RA consume diets that are marginally inadequate in several essential nutrients (Kowsari et al., 1983; see Table 2.14). There is no sound evidence that the pharmacologic doses of vitamins used to treat arthritis have definite therapeutic efficacy. However, there is work to suggest that vitamin C, and perhaps vitamin E as an oxidant, could slow the progression of osteoarthritis (Champion, 1994).
RA is associated with moderate hypochromic normocytic anaemia, which is caused by a reduction in endogenous iron metabolism rather than dietary deficiency (Smith, Driscoll and Coniff, 1985). Abnormalities in iron metabolism tend to be corrected as disease activity is suppressed.
Diets rich in fish oil containing N-3 fatty acids, along with a reduction of N-6 fatty acid intakes, have been associated with improvements in pain and stiffness. Some authors claim that fish oils will help inflammation by reducing arachidonic acid and leukotrienes production (Chaitow, 1997). Dietary fish oils may prove to be more effective when used in combination with specific anti-inflammatory agents (Champion, 1994).
Dietary Advice for Patients
For patients with OA:
• Reduce carbohydrates and fats.
• Keep weight down.
• Exercise regularly.
For patients with RA:
• Eat a well-balanced diet that contains minerals and vitamins.
• Eat more fruit and vegetables.
• If weight loss is experienced, increase carbohydrate intake.
• Seek advice regarding drug therapy.
For patients with gout:
• Advice on weight management.
• Reduction of high purine foods.
• Reduction in alcohol intake.
For patients with osteoporosis, see Chapter 3.
MASSAGE
Body massage is a method of manually manipulating the tissues of the body by either stroking, percussion or applying pressure. These actions increase the circulation of blood and lymph, and induce relaxation by soothing sensory nerve endings in the skin (Goldberg, 1991). There have been verbal reports from patients with RA and fibromyalgia that this form of intervention reduces pain and enhances sleep but evaluation from a critical perspective remains limited.
Table 2.14 Nutrients that can be lacking in the diet of patients with RA.
Calcium
Carbohydrates
Folacin
Magnesium
Pantothenic acid
Vitamin B6
______________
AROMATHERAPY
Aromatherapy is the use of essential oils to promote healing in both a physical and a psychological manner. Methods of application include massage, bathing, compresses and steam inhalations. Aromatherapy professes to provide pain relief, reduce inflammation and to maintain joint mobility in patients with RA (Worwood, 1993). Advice must be sought from a qualified aromatherapist before treatment can be instigated.
REFLEXOLOGY
Reflexology is a form of massage applied to the reflex areas present in both the feet and hands. It is suggested that these reflex areas correspond with a specific area of the body and can stimulate the natural healing powers of the body (Dougans and Ellis, 1992).
Reflex areas suggested to ease the symptoms of RA include:
• The diaphram to reduce muscle tension.
• The shoulder and arm to enhance circulation and nerve conduction.
• The hip and leg to aid healing.
• The spine to improve flexibility and to balance the nervous system.
• The solar plexus to promote deep breathing and relaxation.
• The parathyroid glands to maintain homeostasis with both calcium and potassium levels.
• The liver to remove toxins from the body.
• The adrenals to stimulate cortisone production, maintain mineral balance and enhance muscle tone (Norman, 1992).
ACUPUNCTURE
Acupuncture is believed to change the vital energy which flows in the body and connects the internal organs with the superficial parts of the body (Beinfield and Korngold, 1992). It is currently used for musculoskeletal conditions by orthodox, complementary and alternative practitioners (Champion, 1994).
HERBAL MEDICINE
Herbal derivatives are widely used in orthodox rheumatology (Champion, 1994) - for example:
• Salicylates (willow bark).
• Colchicine (Autumn crocus).
• Opiates (opium poppy).
• Quinine (cinchana bark).
Controlled trials of other herbal treatments have proved inconclusive. Herbal preparations may be taken as tablets, infusions - such as tea - tinctures or added to baths. Popular herbs for rheumatism include aloe vera, comfrey, devil’s claw, feverfew and evening primrose oil.
NATUROPATHY
This is a mixture of traditional folk wisdom, empiricism and selections of biomedical science. The basic principles (Champion, 1994) are:
• the healing power of nature is fundamental;
• treat the cause rather than the effect;
• ill health results from a lowering of resistance due to diet, stress etc.
HOLISM
Treatment involves a combination of counselling, nutritional advice, herbal medicine and homeopathy remedies.
Biological compounds such as hyaluronans, chrondroitin sulfate and glucosamine are now used routinely in the treatment of osteoarthritis. Although not yet proven these compounds may be potentially chondroprotective, in that they may favourably modify the natural progression and course of OA (Towheed et al., 2005). Glucosamine is a natural substance and a building block of the glycosaminoglycans (CAG) and glycoproteins in the ground substance of the articular cartilage (Towheed et al., 2005). Glucosamine is usually taken in a daily dose of 1500 mg.
Adverse effects are likely to be mild and predominantly affect the GI tract and are reversible on discontinuation of glucosamine. Concerns about glucosamine affecting glucose homeostasis, increasing insulin resistance and/or impairing insulin secretion (Monauni et al., 2000) appear not to be founded. Research by Scroggie, Albright and Harris (2003) and Tannis et al. (2004) found that normal doses of glucosamine supplemetation did not cause glucose intolerance in healthy adults.
Randomized trials comparing glucosamine to NSAIDs suggest that glucosamine produces similar symptomatic benefits as NSAIDs but with fewer adverse effects (Towheed et al., 2005). A meta-analysis (Richy et al., 2003) comparing the structural and symptomatic efficacy of glucosamine in relation to placebo found an improvement in symptoms as well as in joint space narrowing. Two randomized controlled studies (Pavelka et al., 2002; Reginster et al., 2001) have demonstrated that patients prescribed glucosamine had no significant progression of cartilage loss, suggesting that glucosamine may indeed modify the natural radiological progression of OA of the knee.
PATIENT INFORMATION LEAFLET: GLUCOSAMINE
(This is a modified version of the information sheet used in the rheumatology clinic at the Haywood Hospital, Stoke on Trent).
Glucosamine is a dietary supplement that may be effective in the treatment of osteoarthritis.
WHAT HAPPENS IN OSTEOARTHRITIS?
Healthy cartilage covers the ends of your bones within your joints and helps with smooth and pain-free movement. Osteoarthritis occurs when the healthy cartilage starts to wear out causing the bones to rub together. The joint lining may become inflamed, leading to swelling. Cartilage is made up mainly of water, cells called chondrocytes and other substances such as collagen and proteoglycans. These substances give the cartilage its elastic properties and the ability to absorb shock, especially in hips and knees. As we grow older we produce less of these substances and the cartilage wears down.
WHAT DOES GLUCOSAMINE DO?
Glucosamine is a natural substance that helps to provide the building blocks within cartilage. It helps to produce and maintain healthy cartilage. Exactly how it benefits the cartilage in osteoarthrits is unknown.
WHAT ABOUT THE RESEARCH?
Studies have looked at the effect of glucosamine in the treatment of osteoarthritis. It has been found to reduce pain and improve function in some people. There is also some evidence that it may slow the progression of the condition.
DOES IT WORK WITH EVERYONE?
As with other forms of medication and supplements, everyone can respond differently, and there is no guarantee that it will help. There is no proven evidence that glucosamine helps in other types of arthritis.
ARE THERE ANY SIDE EFFECTS?
Glucosamine is generally well tolerated. Common side effects include nausea, diarrhoea and stomach upset which resolve on stopping glucosamine. There is very little information available about whether there are any increased side effects taking it long term. Always read the information provided with glucosamine.
WHAT DOSE DO I NEED?
The current recommended dose is 1500 mg (1.5 g) of glucosamine sulfate per day.
DOES MY DOCTOR NEED TO PRESCRIBE IT?
Some doctors will prescribe it. It is also available over the counter in pharmacists and health food shops.
WHEN WILL I NOTICE A DIFFERENCE?
Benefit can be variable and it is worth taking for at least six months before assessing whether it has been helpful.
Capsaicin (trans-8-methyl-Wvanillyl-6-nonenamide) is the alkaloid which makes chillies hot. Interest has centered on the use of capsaicin as a topical analgesia for a variety of conditions characterized by pain that are not responsive to analgesia or NSAIDs (Zhang and Wan Po, 1994). Local application of capsaicin to the peripheral sensory endings in the skin results in depletion of substance P from the neurone, both peripherally and centrally (Fitzgerald, 1983). One randomized placebo-controlled trial in osteoarthritis has reported an improvement in pain levels (Deal et al, 1991).
CONCLUSION
Drug therapy plays an important role in the management of inflammatory arthritis. It is hoped that this chapter has provided information on the wide-ranging aspects of medications, enabling the nurse to share this knowledge with the patient so that a mutual understanding of care management can evolve.
APPENDIX 2.A WHAT HAPPENS NEXT?
For each scenario, state what, if any, drug intervention you would recommend:
• 45-year-old man with chronic ankylosing spondylitis. Previous bleeding duodenal ulcer. Found to be H. pylori-positive. NSAID stopped and treated with triple therapy. Ulcer healed on gastrocopy. Attends for review appointment. Stiff as a board. Can’t do his exercises. Current treatment: co-codamol only.
• A 74-year-old woman. Chronic generalized osteoarthritis. Now presents with a several-month history of a superimposed inflammatory arthritis which is clinically very active and is causing significant disturbance to her quality of life. PMH: Peptic ulcer 1970; vagotomy and pyloroplasty 1973. Hypertension. Current treatment: atenolol, ramipril, bendrofluazide, hydralazine, co-codamol. ESR 40, C-reactive protein (CRP) 15, X-rays soft tissue swelling ++, no erosions.
• 77-year-old woman with RA for 12 years. Established erosive disease. Joints troublesome - hands, wrists, shoulders. Clinically low grade synovitis in these areas. PMH: chronic obstructive pulmonary disease (COPD) with recurrent infections. Smoker. Treatment: co-codamol, Slo-Phyllin, frusemide, zoton. Salbutamol, seretide and combivent inhalers.
• 81-year-old man with RA and ?mycetoma left lung cavity. Meloxicam was recently changed by GP to celecoxib. PMH: No ischaemic heart disease/cardiovascular disease (IHD/CVD). Previous thoracotomy. Treatment prednisolone 2mg, sulfasalazine 2g, zoton, celecoxib, weekly fosamax.
• 65-year-old man with chronic ankylosing spondylitis. PMH: Gout, asthma, renal stones, bleeding peptic ulcer detected because of anaemia after 15 years on voltarol suppositories. Now asymptomatic from gastrointestinal aspect and haemoglobin (Hb) stable. Treatment: co-codamol and losec. Spine and peripheral joints getting worse.
• 25-year-old male driver. Presents with an eight-month history of a sero-negative inflammatory oligoarthritis affecting knee, forefoot (dactylitis), and sacroiliac joints. Quite symptomatic despite diclofenac slow release 75mg twice daily (bd). PMH : Nil of note. On examination (O/E) synovitis in affected areas. ESR 3 CRP 4. X-rays: suspicion of erosion third and fourth MTPs.
• 35-year-old woman with a 3-month history of inflammatory joint symptoms involving hands, wrists, shoulders and feet. PMH: Nil of note. Non-smoker. Rx: Over-the-counter (OTC) ibuprofen or paracetemol. O/E Synovitis in MCPs, wrists and MTPs. Stiff shoulders. ESR 40, CRP 20, RF-positive. X-rays non-erosive.
Case scenarios kindly provided by Dr A. B. Hassell, Consultant Rheumatologist, Haywood Hospital, Stoke on Trent.
APPENDIX 2.B GUIDELINES FOR NURSES ON THE USE AND ADMINISTRATION OF INTRA-ARTICULAR INJECTIONS
1. What is an expanded role?
Role extension refers to nurses carrying out tasks not included in their normal training for registration. Most of these tasks relate to medical technical interventions usually carried out by doctors (Wright, 1995).
2. Accountability:
The scope of professional practice (UKCC, 1992) acknowledges that nurses are involved in negotiating the boundaries of practice and should be responsive to the needs of patients and clients. The onus is on individual nurses to recognize their own levels of competence and decline any duties or responsibilities unless they are able to perform them in a safe and skilled manner. Nurses are also individually accountable for maintaining and improving their knowledge and should be familiar with the contents of the following documents:
(a) UKCC Exercising Accountability 1989;
(b) UKCC Scope of Professional Practice 1992;
(c) UKCC Code of Professional Practice 1992;
(d) UKCC Standards for the Administration of Medicine 1992.
3. What are intra-articular injections?
These are injections into the synovial joints. Long-acting steroids are generally used for joint injections (and hydrocortisone is used for soft tissue injections).
4. Indications for joint injections:
(a) Relief of pain from localized inflammation of the joint (e.g. Rheumatoid Arthritis);
(b) Relief of pain from soft tissue discomfort;
(c) To aid mobilization;
(d) To assist with rehabilitation (e.g. physiotherapy);
(e) To improve function.
5. Contraindications of joint injections:
(a) Local infection;
(b) Intra-articular fracture;
(c) Anticoagulant therapy;
(d) Bleeding disorders.
6. Preparation the nurse must undertake prior to the administration of intra-articular injections:
The nurse must be able to demonstrate evidence of competency in the administration of intra-articular injections in accordance with the Scope of Professional Practice (UKCC, 1992).
(a) Evidence of competency should indicate that the nurse has knowledge of:
(i) Anatomy and physiology of the joints and soft tissues;
(ii) Drugs used and their effects and side effects;
(iii) Indications and contraindications for intra-articular injections;
(iv) Potential complications;
(v) Aspiration and injection technique.
(b) Evidence of assessment of competency should be available.
(c) The employer must have precise knowledge of the employee’s activities, and agree to them being undertaken by the employee; in accordance with vicarious liability.
7. The nurse’s responsibility when giving intra-articular injections:
(a) Obtain written instructions from the prescribing doctor detailing the drug, dosage and site of administration.
(b) Ensure the patient has given informed consent.
(c) Use an aseptic or no touch technique.
(d) Aspirate the joint if swollen.
(e) Send a sample of synovial fluid for culture if it is very opaque, green or foul-smelling.
(f) If no obvious signs of infection or contraindications are present, administer the prescribed drug into the site stated.
(g) Document the drug, dosage and site of administration in the care records.
(h) Provide the patient with after care advice.
8. After care advice:
The nurse must advise patients that:
(a) The joint may be painful for 24 hours after the injection. Take analgesia if necessary.
(b) It may take several days before benefit is felt.
(c) The injected joint should be rested as much as possible 24-48 hours after the injection.
(d) Short-term facial flushing may be experienced.
(e) Localized skin atrophy may occasionally occur.
(f) They should contact the rheumatology department if they have any concerns.
9. Potential complications following the administration of intra-articular injections:
(a) Infections;
(b) Damage to the articular cartilage;
(c) Tendon rupture;
(d) Skin atrophy.
REFERENCES
Wright S. (1995) The Role of the Nurse: Extended or Expanded? Nursing Standard, May 10, 9 (33), 25 -9.
APPENDIX 2.C: PATIENT GROUP DIRECTION FOR THE ADMINISTRATION OF METHYLPREDNISOLONE INJECTION 40 mg/ml BY INTRAMUSCULAR INJECTION
Reproduced by kind permission of Dr AB Hassell, Consultant Rheumatologist, Haywood Hospital, Stoke on Trent.
1. Reference number:
2. Medicine:
(a) Methylprednisolone (Depomedrone) injection 40 mg/ml.
3. Dose, route and duration:
(a) 120mg methylprednisolone (Depomedrone) intramuscularly, no more frequently than once every four months.
(b) The injection should be administered deeply into the gluteal muscle and aspirate to avoid intravascular administration.
4. Legal status of the medicine:
(a) Prescription only medicine.
5. Date PGD comes into force:
6. Date PGD expires:
7. Health professionals who may supply or administer this medicine:
(a) Registered nurses who will have completed the training programme including the Assessment Exercise.
8. Clinical condition/situation to which the PGD applies:
(a) Active rheumatoid arthritis.
9. Criteria for confirmation of the clinical condition/situation:
(a) Flare of rheumatoid arthritis.
(b) Two out of the following three criteria must be present:
(i) Increased early morning stiffness (over one hour).
(ii) Polyarticular pain with soft tissue swelling.
(iii) Raised serum inflammatory markers - for example, ESR over 30, CRP over 30.
10. Description of the circumstances in which further advice should be sought from a doctor (or dentist) and the arrangement for referral:
(a) Patient is an insulin-dependent diabetic.
(b) Patient has severe osteoporosis.
(c) If the patient is taking ciclosporin or warfarin. Ciclosporin can interact with methylprednisolone causing convulsions and methylprednisolone may increase the anticoagulant effects of warfarin.
(d) Pregnancy.
11. Description of these patients excluded from treatment under the PGD:
(a) Patients with an infection.
(b) Patients who have received more than three intramuscular injections of methylpresdnisolone in the past year.
(c) Patients with a known allergy to methylprednisolone.
12. Details of actions to be taken for patients who do not wish to receive or do not adhere to care under the PGD:
Patients who do not wish to receive intramuscular methylprednisolone will be referred to the rheumatologist’s clinic for a review of their clinical management.
13. Potential adverse reactions:
(a) Facial flushing. This is a transient reaction and will settle within one to two days.
(b) Suppresses reaction to skin tests - for example, Heaf test.
(c) Subcutaneous and cutaneous atrophy.
(d) Anaphylactic and allergic reactions. Refer to the medical guidelines for management of anaphylactic reactions
14. Patient information/advice to be given:
(a) Provide the patient with an information sheet.
(b) Facial flushing may occur 24-48 hours following administration.
(c) Provide the patient with a blue steroid card to monitor accumulative dosages.
PATIENT INFORMATION SHEET ON INTRAMUSCULAR
DEPOMEDRONE
Steroids can be given in many different ways. They can be injected into a muscle, vein or joint or given as tablets. Steroid injections are usually given only occasionally to treat a flare of arthritis. This information sheet deals only with injections in to the muscle.
1. Why am I having a steroid injection?
If your arthritis has recently become more active you may have noticed more joint pain and swelling and an increase in the stiffness of the joints, particularly in the morning. The steroid injection should help to reduce these problems.
2. How long will the injection take to work?
The injection works quickly and you should notice a benefit within a few days.
3. What are the possible side effects?
All drugs including injections can cause side effects. The after effects of the injection can lead to:
(a) facial flushing;
(b) an upset of diabetes.
The side effects listed below are a feature of long-term treatment with steroids and should not occur with occasional injections:
(a) weight gain;
(b) thinning of the bones;
(c) easy bruising;
(d) stomach pain;
(e) thinning of the skin;
(f) muscle weakness;
(g) mood changes;
(h) cataracts.
If you suffer from epilepsy then it is possible that steroids can make this worse. Steroids can reduce reactions to skin tests - for example, Heaf tests.
Warning
If you have not had chicken pox but come in to contact with someone who has chicken pox or herpes zoster or you develop either of these yourself, you should contact your doctor immediately.
What do I do if I experience any problems?
• If you experience any side effects following the injection, contact the Arthritis Helpline. If you develop a fever, contact your own doctor.
• If you have any operations or other illnesses over the next two to three months it is important that you inform the doctor and show your blue card.
ASSESSMENT EXERCISE REGARDING THE ADMINISTRATION OF METHYLPREDNISOLONE INJECTION 40 mg/ml BY INTRAMUSCULAR INJECTION
When you have completed the exercise below you need to have it assessed by the nurse consultant.
1. Which of the following clinical conditions does this PGD apply to?
(a) Psoriatic arthritis.
(b) Ankylosing spondylitis.
(c) Rheumatoid arthritis.
(d) Lupus.
2. Which of the following clinical criteria must be present for a patient to be eligible for a methylprednisolone intramuscular injection?
(a) Widespread pain.
(b) Increased early morning stiffness lasting over one hour.
(c) Increased stiffness after inactivity lasting over one hour.
(d) A hot, painful, swollen joint.
(e) Polyarticular pain with soft tissue swelling.
(f) Raised inflammatory markers.
3. Which of the following conditions/situations would prevent the administration of methylprednisolone?
(a) Hypertension.
(b) Insulin-dependent diabetic.
(c) Renal impairment.
(d) Infection.
(e) Severe osteoporosis.
(f) Osteoarthritis.
(g) Known allergy to methylprednisolone.
4. Name two medications that interact with methylprednisolone.
5. Which of the following are potential adverse reactions to methylprednisolone?
(a) Increased pain.
(b) Facial flushing.
(c) Epistaxsis.
(d) Suppressed reaction to skin tests - for example, Heaf test.
(e) Anaphylactic and allergic reactions.
(f) Mouth ulcers.
(g) Subcutaneous and cutaneous atrophy.
6. What advice would you give to a patient who rings the day after an injection experiencing facial flushing?
7. What action would you take in the event of an anaphylactic reaction following the administration of methylprednisolone?
8. What is the dose and route of administration of methylprednisolone in this PGD?
9. What is the maximum number of injections over a 12-month period of time?
CASE SCENARIOS
WHAT WOULD YOU DO IN THE FOLLOWING SITUATIONS?
• Mrs T. has RA. She is very weepy with a history of widespread pain and stiffness. Her inflammatory markers are stable. She had an intramuscular injection of methylprednisolone six months ago and is requesting another one.
• Mr A. has recently commenced phenylbutazone for his SA. He has back pain and peripheral arthritis with objective swelling. He asks whether anything can be given to help him with his pain and stiffness in the short term as he has been informed that the phenylbutazone will take many months to work.
• Mrs J. has RA with objective evidence of polyarticular pain with soft tissue swelling and raised ESR and CRP. She has developed a cough over the last week. She enquires whether she can have an injection of methylprednisolone.
• Mr W. has RA. Over the last month his early morning stiffness has increased to four hours and his ESR has risen to 60. He also has hypertension and is a long-standing insulin-dependent diabetic. He enquires whether he can have an injection of methylprednisolone.
• Mrs B. has RA with increased early morning stiffness and polyarticular pain and stiffness. She enquires whether she can have an injection of Methylprednisolone.
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