Practical Prescribing Guidelines for Rheumatoid Arthritis

188 Pages·2003·2.32 MB·English

by  Hilary Capell

Practical Prescribing Guidelines in Rheumatoid Arthritis
Practical Prescribing Guidelines in
Rheumatoid Arthritis
Edited by
Hilary Capell, MD, FRCP
Rajan Madhok, MD, FRCP
Iain B.McInnes, phD, MRCP
Centre for Rheumatic Diseases
Glasgow Royal Infirmary
Scotland, UK
LONDON AND NEW YORK
© 2003 Martin Dunitz, an imprint of the Taylor & Francis Group
First published in the United Kingdom in 2003
by Martin Dunitz, an imprint of the Taylor & Francis Group, 11 New Fetter Lane,
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iv
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Composition by Wearset Ltd, Boldon, Tyne and Wear
Contents
Contributors vi
1 Introduction 1
2 NSAIDs 9
3 3DMARDs 19
■ Hydroxychloroquine 20
■ Sulphasalazine 28
■ Methotrexate 45
■ Sodium aurothiomalate 57
■ Auranofin 68
■ Penicillamine 78
■ Leflunomide 86
■ Minocycline 95
■ Azathioprine 101
■ Chlorambucil 114
■ Cyclosporin 120
■ Oral cyclophosphamide 128
■ Cytokine-targeting therapies 136
■ Combination therapy: conventional DMARDs 152
4 Corticosteroids 155
References 162
Index 176
Contributors
The editors are grateful to a number of colleagues for their contributions to this text.
Peter Brooks wrote the introductory section on NSAIDs.
Maciej Brzeski wrote the section on cyclophosphamide.
WW Buchanan wrote the introductory section on history, epidemiology and assessment of response.
Max Field wrote the section on hydroxychloroquine.
John Hunter co-wrote the sections on azathioprine and chlorambucil.
Sarah Irvine co-wrote the section on sodium aurothiomalate.
David Kane wrote the section on cyclosporin.
John Larkin co-wrote the introductory section on NSAIDs.
Dorothy Mason was the Pharmacy Advisor.
David McCarey wrote the section on minocycline.
Anne McEntegart wrote the section on leflunomide.
Lisa McKenzie co-wrote the sections on azathioprine and chlorambucil.
Elaine Morrison wrote the chapter on corticosteroids.
Robin Munro wrote the section on penicillamine.
Duncan Porter wrote the section on methotrexate.
Tom Pullar wrote the section on auranofin.
Roger Sturrock co-wrote the section on sodium aurothiomalate.
1
INTRODUCTION
Is there no balm in Gilead?
Is there no physician there?
Jeremiah VIII, 22
The balm of Gilead and the electuaries, mithridatium and therica, testify to the antiquity of therapeutics. The
Biblical balm of Gilead was a resin extracted from the balsam tree and used as a counter-irritant to relieve
pain (Rosner 1993). Mithridatium is ascribed to King Mithridates VI of Pontus in Asia Minor in the first
century BC, and therica was the invention of Andromachus, physician to the Emperor Nero a century later
(Watson 1993). Both these remedies became so popular that they were regarded as virtual panaceas. It was
William Heberden, the Elder (1710–1801) of digital joint node fame, who was the first to denounce the
“farago” of nonsense in a reasoned attack published as a short essay in 1745 (Heberden 1929). However, it
was not until 1788 that these concoctions were removed from the London Pharmacopoeia, and not until
1884 from the last of the European Pharmacopoeias, that of France. Heberden, however, introduced his own
form of therica, known as Mistura Ferri Aromatica and popularly as Heberden’s ink, which remained in the
British Pharmacopoeia until 1890 (Buchanan and Kean 1987).
It might be thought that such therapies were of the forgotten past, but the reverse is the case. During the past
decades there has been a continuing rise in complementary medicine. In a 1997 survey in the United States
42% of 2055 adult responders reported using some type of alternative therapy during the previous year
(Eisenberg et al. 1998). Such therapy has been shown to contain various contaminants, which may be
harmful (Goldman and Myerson 1991; Shaw 1998; Ernst 1998).
There is an urgent need to codify information regarding herbal medicines, and if not to evaluate their
benefits clinically at least to indicate their side-effects and potential interactions with conventional drugs.
Patients who are receiving the disease-modifying antirheumatic drug methotrexate require to be warned that
herbal supplements or other preparations they might take could, like ethanol, lead to liver damage.
Most orthodox physicians consider complementary medicines as merely placebos (Joyce 1994).
However, some have been shown to be therapeutically effective, one classic example being oral extract of
white willow bark (Salix alba). This has recently been shown in a randomized double-blind trial to be
effective in treating exacerbations of low back pain (Chrubasik et al. 2000). This would be ascribed to
salicin, which is biotransformed to salicylic acid (Schmid et al. 2001), but the daily doses of the
administered willow bark were of the order of 120 mg and 240 mg salicin, which is equivalent to only 25
mg and 50 mg of acetylsalicylic acid. This amount of salicin cannot explain the results, and there
is evidence that other analgesic and anti-inflammatory agents may be responsible (Rice-Evans et al. 1995;
Rohnert et al. 1998; Guyatt et al. 1990).
2 PRACTICAL PRESCRIBING GUIDELINES
▇ ASSESSMENT OF EFFICACY AND TOXICITY OF ANTIRHEUMATIC
DRUGS
With the ever-increasing number of new antirheumatic drugs, and the appreciation that clinical impressions
can be misleading, the randomized placebo controlled clinical therapeutic trial has gained acceptance as the
most powerful design for assessing effectiveness of therapy. The quality of many therapeutic trials of
antirheumatic drugs leaves little ground for complacency, hence an outline of design and statistical
interpretation seems appropriate.
There are nine basic components to a clinical trial, namely: research objective; trial design; sample size
calculation; patient selection; randomization and stratification; intervention, co-intervention, contamination
and compliance; outcome assessment; statistical analysis; and interpretation.
Research objective
Although there is a great temptation to seek answers to multiple questions and to dredge data a posteriori,
the best trials are those that are designed to answer one or at the most two questions.
Trial design
There are five types of trial design: randomized parallel; randomized crossover; sequential; nonrandomized
comparative group; and one-group noncomparative open design. Parallel groups generally require larger
numbers of patients than crossover studies, but the latter often present difficulties with carry-over effects,
especially with drugs with a long plasma half-life. The n-of-1 trial is a variation of the crossover method,
and useful in evaluating a single patient response to a short-acting agent (Guyatt et al. 1990).
Nonrandomized comparative group designs and one-group noncomparative open designs lack the rigour of
the randomized parallel, crossover and sequential trial designs. The use of a placebo prevents the outcome:
drug A=drug B=0.
Patient selection
Patients are selected ideally from a single diagnostic group. Selection, however, implies that certain patients
will be excluded, with the consequence that conclusions can be made only on patients with the
characteristics chosen for the study. Patients tend to be a homogeneous group whose disease is considered
responsive to treatment and whose compliance is high.
Calculation of sample size
This can be done from publisbed standard formulae. Several factors, however, are important, especially: the
trial design, the magnitude of type I and type II errors, the variability within and between the patient groups,
and the magnitude of the minimum difference (i.e. the delta) between the treatment groups and placebo
controls. These complexities and standard formulae for calculating sample size are discussed in standard
textbooks (Lee et al. 1973). The greatest difficulty is in defining the delta and standard deviation, the
former often being arrived at by guesswork.
INTRODUCTION 3
Randomization and stratification
Randomization is a statistical method of attempting to increase the probability that undefined variables of
potential prognostic importance are evenly distributed between the study groups. There are, however, no
guarantees that such undefined variables are evenly distributed. Stratification on, the other hand, does allow
for defined variables to be equally distributed. The most important variable in determining the response to
an analgesic drug is the severity of pain present at baseline. Patients with severe pain will respond
dramatically to an anti-inflammatory analgesic, whereas patients with mild or moderate pain will respond
only to a small degree (Lee et al. 1973).
Despite randomization and stratification important prognostic variables can be overlooked in statistical
analysis. Two alternative methods of assigning patients to treatment groups have been described to overcome
such difficulties. These are minimization (Taves 1974) and self-adjusting randomization (Nordle and
Brantmark 1977). Clinicians tend to be in awe of statisticians, failing to realize that clinical common sense
is still superior to any statistical manoeuvre.
Intervention
This term refers to the specific treatment in the study. Doses of a drug may be fixed or titrated, the latter
more closely following clinical practice. Washout periods, especially prior to the start of trials with
nonsteroidal anti-inflammatory analgesics, ensure that patients can respond to treatment.
Co-intervention
Co-intervention is administration of another treatment, which may interfere with the results of a trial. This
treatment may take many forms, which may not be drugs (e.g. physiotherapy). Acetaminophen or
paracetamol is a common co-intervention in trials of nonsteroidal anti-inflammatory drugs, and its
consumption is often used as a surrogate measure of pain control.
Contamination
Contamination occurs in patients in a trial being given inappropriate medication.
Compliance
Compliance is the extent to which a patient adheres to a treatment protocol. The degree of noncompliance
that is clinically important remains to be determined.
The development of electronic monitoring devices has revealed gross over-estimates of compliance as
measured by patient report, either verbal or diary, returned tablet counts and measurement of drug
concentrations or traces or a drug contaminant (e.g. phenobarbitone in blood or urine) (Urquhart 2000).
Patients with continuous severe pain, as in rheumatoid arthritis, have been found to be extremely compliant
in taking analgesics.