Page 1219 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 87 Immunomodulating Pharmaceuticals 1183

thymidylate synthetase, blocking the conversion of deoxyuridine CONCLUSIONS
monophosphate to deoxythymidine monophosphate, which is
essential to DNA synthesis. It may also increase expression of p53, The field of small molecule immunomodulators contains both
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a frequently mutated gene in nonmelanoma skin cancers. It can traditional and new molecules. The traditional molecules come
be administered topically, intramuscularly, or intravenously. In with a long history of efficacy and side-effect data, and this
topical form, its main uses are to treat actinic keratosis, superficial allows us to safely and accurately utilize these therapies. Despite
basal cell carcinoma, Bowen disease, keratoacanthoma, porokera- the introduction of biologics, traditional small-molecule agents,
tosis, and verruca vulgaris. However, intravenous treatment of such as methotrexate and cyclosporine, are both clinically effica-
recalcitrant psoriasis, mycosis fungoides, and scleroderma has cious and cost-effective and thus remain the workhorses of our
also been reported. modern pharmaceutical armamentarium. However, as our
understanding of the pathways involved in inflammation evolve,
Adverse Effects our therapeutics are also refined, allowing the production now,
Topical application is associated with an irritant dermatitis, but for example, of topically effective calcineurin inhibitors, such as
this is also seen as a marker of clinical efficacy. Parenteral tacrolimus and pimecrolimus, which avoid the adverse effects
administration for inflammatory conditions is not widespread; of systemic cyclosporine or topical steroids, and sirolimus, which
adverse effects from parenteral administration are more severe reduces toxicity profiles of systemic FKBP2 signaling. In addition,
and include clinically significant bone marrow suppression, GI newer agents, such as glatiramer and fingolimod, allow treatment
toxicity, and cutaneous reactions. of MS, a disease recalcitrant to more traditional therapies, and,
although not currently being used in other inflammatory dis-
GLATIRAMER orders, have shown promise in animal models. The field of
small-molecule immunomodulators therefore remains one of
Glatiramer acetate is a random polymer of glutamic acid, lysine, both current clinical relevance and continuing, exciting new
tyrosine, and alanine, the four amino acids found in myelin developments.
basic protein (MBP). The mechanism of action for glatiramer
is unknown, but its similarity in structure to MBP may allow it ON tHE HOrIZON
to act as a decoy for immune targeting of myelin. It may also
induce expression of glatiramer acetate–specific suppressor T Refinement of our understanding of the pathways and actions of receptors
cells, and these have been shown to be present in animal models. targeted by our current medications is the key to producing more
elegant therapies.
In contrast to imiquimod, glatiramer shifts the population of T Separating therapeutic effects from the pathways leading to side effects
cells from proinflammatory Th1 cells to regulatory Th2 cells would enable much safer and more tolerable small-molecule
that suppress the inflammatory response. It is FDA approved medications.
for the treatment of adults with relapsing–remitting multiple Better understanding of the dysregulation that occurs in inflammatory
sclerosis (MS), even after only one event. conditions, and the activation of the immune system will be essential
to ensuring the efficacy of such new modalities.
Adverse Effects
Absolute contraindications include allergy to glatiramer or to The challenge in the next 5–10 years is to continue this
mannitol. It is pregnancy Category B, but it is unknown if the refinement in the targeting of small molecules. Many of the
drug is secreted in breast milk. The drug is given via subcutaneous agents we currently use target early parts of pathways or indis-
injection, and the most common adverse effects are injection criminately trigger multiple receptors. This leads to a greater
site reaction, flushing, rash, dyspnea, and transient chest pain. range of side effects and thus limits our ability to reach adequate
dosing levels. A prime example of this is methotrexate, which
FINGOLIMOD (FTY720) leads to increased adenosine levels and thus triggers all four
adenosine receptors. By developing more selective molecules
Fingolimod is a relatively new immunomodulator for treating targeting, for instance, just the adenosine A 2A receptor, not only
MS. It is a structural analogue of sphingosine and is phosphory- would we avoid the side effects attributable to other adenosine
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lated intracellularly by sphingosine kinases. Signaling via one receptors, we might also avoid the effects of methotrexate on
of the sphingosine 1 phosphate receptors, S1PR1, it is believed bone marrow and mucous membranes via inhibition of dihy-
to prevent migration of lymphocytes by halting their ability to drofolate reductase. In other medications, more specific targeting
leave lymph nodes. However, fingolimod has also been reported of pathways may similarly reduce side effects and make for more
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to act as a cPLA2 inhibitor, a cannabinoid receptor antagonist, effective therapeutics. This will require a better understanding
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and a ceramide synthase inhibitor. So far, the FDA has only of the immune system and its dysregulation in disease, as well
approved it for use in MS. However, it has also shown promise as development and application of these medications to clinically
in murine models of SLE and RA, with reduced mortality from relevant models
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lupus nephritis and improvement in arthritis, respectively. It
also has a potential role in the treatment of cutaneous inflam- Please check your eBook at https://expertconsult.inkling.com/
matory conditions, such as psoriasis and atopic dermatitis. 35 for self-assessment questions. See inside cover for registration
details.
Adverse Effects
The most common side effects are minor and include headache REFERENCES
and fatigue. However, fingolimod has also been associated with
serious infections, an increased rate of skin cancers, bradycardia, 1. Pincus T, Furer V, Sokka T. Underestimation of the efficacy, effectiveness,
and one case of focal hemorrhagic encephalitis. tolerability, and safety of weekly low-dose methotrexate in information