Clinical Pharmacology and Therapeutics

170 ANTI-INFLAMMATORY DRUGS AND THE TREATMENT OF ARTHRITIS
inflammatory process in inflammatory arthritis. Their mechanisms
are generally poorly understood. They are used in
patients with progressive disease. Response (though unpredictable)
is usually maximal in four to ten weeks. Unlike
NSAIDs, DMARDs reduce inflammatory markers (historically,
it was this effect that led to them being referred to as ‘diseasemodifying’).
It is difficult to prove that a drug influences the
natural history of a relapsing/remitting and unpredictably progressing
disease, such as rheumatoid arthritis, but immunosuppressants
retard the radiological progression of bony
erosions. DMARDs are toxic, necessitating careful patient monitoring,
and are best used by physicians experienced in rheumatology.
Rheumatologists use them earlier than in the past, with
close monitoring for toxicity, with the patient fully informed
about toxic, as well as desired, effects. This is especially important
since many of these drugs are licensed for quite different
indications to arthritis. In terms of efficacy, methotrexate, gold,
D-penicillamine, azathioprine and sulfasalazine are similar,
and are all more potent than hydroxychloroquine. Methotrexate
(Chapter 48) is better tolerated than the other DMARDs, and is
usually the first choice. Sulfasalazine (Chapter 34) is the second
choice. Alternative DMARDs, and some of their adverse effects,
are summarized in Table 26.1.
GOLD SALTS
Use
Gold was originally introduced to treat tuberculosis. Although
ineffective, it was found to have antirheumatic properties and
has been used to treat patients with rheumatoid arthritis since
the 1920s. Sodium aurothiomalate is administered weekly by
deep intramuscular injection. About 75% of patients improve,
with a reduction in joint swelling, disappearance of rheumatoid
nodules and a fall in C-reactive protein (CRP) levels. Urine
must be tested for protein and full blood count (with platelet
count and differential white cell count) performed before each
injection. Auranofin is an oral gold preparation with less toxicity,
but less efficacy than aurothiomalate. Treatment should
be stopped if there is no response within six months.
Mechanism of action
The precise mechanism of gold salts is unknown. Several
effects could contribute. Gold–albumin complexes are phagocytosed
by macrophages and polymorphonuclear leukocytes
and concentrated in their lysosomes, where gold inhibits lysosomal
enzymes that have been implicated in causing joint
damage. Gold binds to sulphhydryl groups and inhibits
sulphhydryl–disulphide interchange in immunoglobulin and
complement, which could influence immune processes.
Adverse effects
Adverse effects are common and severe:
• Rashes are an indication to stop treatment, as they can
progress to exfoliation.
• Photosensitive eruptions and urticaria are often preceded
by itching.
• Glomerular injury can cause nephrotic syndrome.
Treatment must be withheld if more than a trace of
proteinuria is present, and should not be resumed until
the urine is protein free.
• Blood dyscrasias (e.g. neutropenia) can develop rapidly.
Table 26.1: Disease-modifying antirheumatic drugs (DMARDs)
Drug Adverse effects Comments
Immunosuppressants: Blood dyscrasias, carcinogenesis, Methotrexate is usually the first-choice
azathioprine, methotrexate, opportunistic infection, alopecia, DMARD
ciclosporin
nausea; methotrexate also causes
mucositis and cirrhosis; ciclosporin
causes nephrotoxicity, hypertension
and hyperkalaemia
Sulfasalazine Blood dyscrasias, nausea, rashes, First introduced for arthritis, now used
colours urine/tears orange
mainly in inflammatory bowel disease
(Chapter 34)
Gold salts Rashes, nephrotic syndrome, Oral preparation (auranofin) more
blood dyscrasias, stomatitis,
convenient, less toxic, but less effective than
diarrhoea
intramuscular aurothiomalate
Penicillamine
Blood dyscrasias, proteinuria,
urticaria
Antimalarials: chloroquine, Retinopathy, nausea, diarrhoea, See Chapter 47
hydroxychloroquine
rashes, pigmentation of palate,
bleaching of hair