Page 1213 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Immunomodulating Pharmaceuticals

Gideon P. Smith, Edwin S.L. Chan

Excitement over biologic agents and their capacity to regulate proliferation (Table 87.1). These actions are dependent on
immunological reactions that significantly impact on such inhibition of dihydrofolate reductase; hence toxicities arising
immunologically mediated diseases, such as rheumatoid arthritis from high-dose methotrexate therapy can be treated with folic
(RA) and inflammatory bowel disease (IBD), has overshadowed acid derivatives, such as leucovorin. However, folic or folinic
the older, small-molecule therapeutic agents. Nonetheless, when acid, which are often given in conjunction with methotrexate
tested head-to-head, some small-molecule agents (most notably in inflammatory diseases to reduce the incidence of mucositis
methotrexate) have proven to be almost as effective as biologics; and bone marrow suppression, do little to inhibit its antiinflam-
moreover, combining small-molecule therapies with biological matory efficacy. Decreases in purine and pyrimidine concentra-
agents generally leads to significantly better outcomes than use tions in the serum have been observed following a single dose
1
of either agent alone. Thus it is likely that small-molecule of methotrexate, along with decreased proliferation of antigen-
immunomodulatory drugs will continue to be in wide use. Here, stimulated lymphocytes. However, these changes are transient
we review the most widely accepted and commonly used immu- and insufficient to explain the antiinflammatory effectiveness
nomodulators currently in clinical use. of once-weekly dosing. This, as well as the low doses of methotrex-
ate required to produce an antiinflammatory effect, suggests
METHOTREXATE that the antiinflammatory actions are mediated via different
mechanisms.
Methotrexate (Fig. 87.1) was employed in the treatment of RA Methotrexate also blocks intracellular transmethylation reac-
as early as 1951, but its popularity with regard to RA did not tions and inhibits production of S-adenosylmethionine. Since
come until the 1980s. Over the years, extensive experience with S-adenosylmethionine is necessary for formation of the toxic
its use in inflammatory diseases as diverse as RA (Chapter 52), polyamine metabolites spermine and spermidine, their accumula-
psoriasis (Chapter 64), and IBD (Chapter 75) has taught us a tion at the inflammatory site is prevented. This inhibition of
great deal about its safety, efficacy, and toxicity, as well as its transmethylation is associated with an impairment of monocyte
antiinflammatory mechanisms of action. In this respect, metho- and lymphocyte function and thus potentially the synthesis of
trexate, much as corticosteroids, can be justly regarded as a reactive oxygen species. However, diminution of transmethylation
cornerstone of immunomodulatory therapy. by the use of the S-adenosylhomocysteine hydrolase inhibitor,
deaza-adenosine, has failed to produce any beneficial clinical
Pharmacokinetics of Methotrexate effects in RA.
As an antiinflammatory agent, methotrexate is administered at Methotrexate and its long-acting polyglutamate metabolites
low doses (usually 10–25 mg/week) once weekly, usually orally, also exert antiinflammatory effects by releasing the endog-
3
but it can also be given subcutaneously or intramuscularly. enous autocoid adenosine. As potent inhibitors of the enzyme
At these doses, oral bioavailability is high (60–70%), and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)
although transporters are responsible for its absorption from the transformylase, methotrexate polyglutamates promote accumula-
gastrointestinal (GI) tract, saturation effect does not occur. A small tion of AICAR in tissues. Since AICAR inhibits catabolizing
portion of methotrexate is metabolized by hydroxylation into enzymes for both adenosine and adenosine monophosphate
7-hydroxymethotrexate. Both compounds have a serum half-life (AMP), which can be dephosphorylated to adenosine, the net
of no more than 8 hours. The much longer antiinflammatory effect is intracellular and extracellular increases in adenosine
action, which allows for once-weekly dosing, must therefore be levels. These metabolic pathways are pharmacologically relevant,
mediated by other longer-lasting metabolites, such as polygluta- since aminoimidazole carboxamide and adenosine have been
mates. Excretion occurs principally via the urinary tract but also shown to be increased in urine following low-dose methotrexate
4
via the biliary tract. Therefore renal function is an important treatment in patients with psoriasis. Adenosine causes diminution
consideration in methotrexate dosing, and any medication that of neutrophil accumulation, adhesion, phagocytosis and genera-
impairs glomerular filtration may also potentiate methotrexate’s tion of reactive oxygen species, inhibition of adhesion molecule
effectiveness and toxicity. 2 expression, suppression of proinflammatory cytokines, and
induction of antiinflammatory cytokines, as well as modulation
Mechanisms of Action for Methotrexate of macrophage and endothelial function. Indeed, blockade of
2
As an analogue of folic acid, methotrexate is an inhibitor of adenosine receptors reversed the antiinflammatory effects of
purine and pyrimidine synthesis and thereby suppresses cellular methotrexate on animal models. It has also been suggested that

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