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women who are breast-feeding. arthritis, psoriasis, and inflammatory bowel disease. It
Gold should be used cautiously in patients receiving acts by blocking the transcriptional activation of many
drugs that can also cause nephrotoxicity. Interactions genes involved in the first phase of T cell activation.
between gold compounds and penicillamine may result Cyclophosphamide (Cytoxan) is an alkylating agent
in severe hematological and renal side effects. that was used in severe rheumatoid in the past but is
seldom used today because of its severe bladder toxic-
ity, bone marrow toxicity, and carcinogenicity.
Other Drugs for Rheumatoid Arthritis
Therapy
Minocycline
The following drugs are not commonly used as first-line
The tetracycline antibiotic minocycline (Minocin) is
treatments of rheumatoid arthritis, either because they
modestly effective in the treatment of rheumatoid
lack the efficacy of other drugs or because they pro-
arthritis and is generally well tolerated. Radiographic
duce more serious side effects or both. They do, how-
evidence of its efficacy as a DMARD is lacking, al-
ever, remain useful in specific clinical situations and in
though clinical symptoms do abate. It can be useful in
individuals in whom more conservative therapies have
the treatment of early, mild disease.A more detailed de-
failed.
scription of the pharmacology and clinical uses of
minocycline is found in Chapter 47.
Corticosteroids
Penicillamine
Serious adverse effects are produced by long-term,
high-dose exposure to the corticosteroids; therefore, Penicillamine (Cuprimine) can be used to treat acute,
these drugs are not agents of choice for the treatment of severe rheumatoid arthritis, producing reductions in
rheumatic disease. In general, the use of low-dose corti- joint pain, edema, and stiffness. The response to penicil-
costeroids avoids significant side effects (e.g. fluid re- lamine is usually delayed (4 12 weeks), and remissions
tention, osteoporosis, GI bleeding, immunosuppression) can last several months after withdrawal of treatment.
but does not completely control the disease. However, Radiographic evidence of this drug s efficacy is limited;
for patients whose disease is refractory to other agents thus, penicillamine is seldom used to treat rheumatoid
or who cannot tolerate the side effects of other arthritis. The mechanism of action of penicillamine is
DMARDs, a corticosteroid such as prednisone may be unknown, but some evidence suggests that it may in-
used to control symptoms. Low-dose corticosteroids volve the inhibition of angiogenesis, synovial fibroblast
may also be used as an alternative to more toxic proliferation, or transcriptional activation. Because
DMARDs in pregnant, elderly, or debilitated individu- penicillamine can chelate copper and promote its ex-
als. Intraarticular injection of corticosteroids can con- cretion, it is used to treat Wilson s disease (hepatolen-
trol acute inflammation of a specific joint without caus- ticular degeneration) and has also been used in mercury
ing systemic side effects. High-dose steroids can control and lead intoxication.
severe systemic manifestations of autoimmune disease, Penicillamine is readily absorbed from the GI tract
such as iritis, pericarditis, nephritis, or vasculitis. and is rapidly excreted in the urine, largely as the intact
Following discontinuation of corticosteroid treatment, molecule. Gradually increasing its dose minimizes side
rebound joint deterioration is common. effects, which necessitate discontinuance of penicil-
A detailed discussion of the pharmacodynamics, lamine therapy in perhaps one-third of patients. The
mechanism of action, and adverse effects of the corti- most common side effects are maculopapular pruritic
costeroids and their role in therapeutics can be found in dermatitis, GI upset, loss of taste sensation, mild to oc-
Chapter 60. casionally severe thrombocytopenia and leukopenia,
438 V THERAPEUTIC ASPECTS OF INFLAMMATORY AND SELECTED OTHER CLINICAL DISORDERS
and mild proteinuria, which at times may progress to singly and sequentially for periods of up to 6 months be-
the nephritic syndrome. Discontinuance of therapy usu- fore clinicians could determine their efficacy and switch
ally results in a rapid disappearance of side effects. to a new drug if necessary.
The most recent treatment paradigm calls for earlier,
more aggressive treatment of rheumatoid arthritis.
DMARDs are frequently employed along with NSAIDs
NEW APPROACHES TO THE
in the initial treatment of the disease. The COX-2 in-
TREATMENT OF RHEUMATOID
hibitors are often used because they are less likely to
ARTHRITIS
cause serious GI toxicity than are the nonspecific COX
In previous decades, a pyramid model dominated the inhibitors. The usual DMARD of choice for patients
treatment of rheumatoid arthritis. Early in the course of with mild rheumatoid arthritis is hydroxychloroquine or
the disease, salicylates were used to control pain and sulfasalazine; methotrexate is used for those with mod-
stiffness. If salicylates were poorly tolerated or began to erate to serious disease. Other DMARDs are used if
lose efficacy, they were discontinued and a different these agents are poorly tolerated or do not produce suf-
NSAID was used. As the efficacy of NSAID therapy ficient response. Combination therapy of methotrexate
waned and joint deterioration progressed, treatment and another agent is also used to treat disease that is not
with a DMARD was added. DMARDs were employed responsive to individual DMARDs.
Study Questi ons
1. A man aged 74 has moderate hypertension con- the course of 6 months, as the pain worsens, she in-
trolled with hydrochlorothiazide 12.5 mg once daily creases her dosage to a high level (600 mg four
and losartan 50 mg once daily. He is prescribed ro- times daily). What toxicity is most likely to occur,
fecoxib 50 mg once daily to control osteoarthritis and why?
pain. After 3 months of this therapy, his blood pres- (A) Abnormal heart rhythms; alcohol induces cy-
sure begins to rise. This increase in blood pressure is tochrome P450 isozymes that convert ibuprofen to
most likely due to a cardiotoxic free radical metabolite
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