An Update on Methotrexate Pharmacogenetics in Rheumatoid Arthritis

Prabha Ranganathan

Disclosures

Pharmacogenomics. 2008;9(4):439-451. 

In This Article

Abstract and Introduction

Rheumatoid arthritis (RA) is a systemic inflammatory disorder that mainly affects the joints. When left untreated, the disease can result in irreversible joint damage with high morbidity and mortality. Disease-modifying antirheumatic drugs are the cornerstones of treatment in RA. Disease-modifying antirheumatic drugs not only ameliorate the clinical signs and symptoms of disease, but also prevent the radiographic progression of joint damage. Methotrexate is one such disease-modifying antirheumatic drug that has been used in the treatment of RA for over two decades with excellent long-term efficacy and safety. However, there is significant variability in patients' response to methotrexate, both in terms of efficacy and toxicity. At the present time, there are no reliable means of predicting, a priori, an individual patient's response to methotrexate. In this review, recent published literature on the pharmacogenetics of methotrexate in RA is highlighted. Pharmacogenetics may be a powerful tool for optimizing methotrexate therapy in patients with RA.

Rheumatoid arthritis (RA) affects 0.5-1% of the population worldwide. Over half of these patients with RA are being treated with methotrexate (MTX), making this the most commonly used disease-modifying antirheumatic drug (DMARD). More recently, newer biologic therapies such as the TNF-blocking agents have been introduced for the treatment of RA. Despite the availability of the TNF-blocking agents, MTX retains a central role in the treatment of RA. This is because MTX is relatively inexpensive, broad experience with its use exists, and it is widely used in combination regimens with other DMARDs, including the biologic DMARDs.[1,2,3,4]

The efficacy of MTX in RA is variable, with response as defined by the American College of Rheumatology (ACR) 20 criteria varying from 46-65%.[5,6] There are no reliable clinical or molecular markers of response to therapy. Serum levels of MTX are of little use in defining efficacy, as the drug is eliminated from the serum within 24 h of administration, which is shorter than the standard weekly dosing interval in RA.[7] While circulating intracellular levels of MTX polyglutamates (MTXPG) in erythrocytes and polymorphonuclear cells correlate with clinical efficacy, the assay is technically difficult and not available in most clinical facilities.[8] Levels of proinflammatory cytokines and mediators, such as TNF, IL-10[9] serum matrix metalloproteinase (MMP)-3, IL-6,[10] and tissue inhibitor of metalloproteinase (TIMP)-1[11] may correlate with MTX efficacy, but rapid clinical assays to measure them are not readily available. Serum levels of chemokines, such as regulated upon activation, normal T-cell expressed, and secreted (RANTES) and growth regulated peptide (GRO)-α may predict the effect of MTX on radiographic erosions, but are not easily measurable.[12] Hence, although several cytokine and enzyme assays may be useful in assessing response to MTX, these are expensive and not available in most clinical settings, limiting their utility in the clinical management of individual patients.

Toxicity also limits the use of MTX. Approximately 10-30% of patients with RA discontinue MTX because of toxicity.[13] A spectrum of toxicities have been reported including nodulosis (8%),[14] hypersensitivity pneumonitis (2-5%),[15] CNS toxicity (1-35%),[16] post-dosing reactions (10%),[17] gastrointestinal (GI) symptoms, such as nausea, vomiting, abdominal pain and diarrhea (60%)[18,19] hepatitis with elevated transaminases (20-58%),[20] hematologic abnormalities (1-2%),[21] rash (1-2%),[10] alopecia (5%)[10] and osteopathy (rare).[22] Serum MTX levels have not been useful in predicting GI toxicity and myelosuppression.[23] Hence, in clinical practice, toxicity monitoring is performed routinely with blood counts and liver function tests. Not surprisingly, therefore, MTX has the highest monitoring costs among the nonbiologic DMARDs, although the drug itself is inexpensive.[24]

The significant variability in clinical response and unpredictable toxicity in patients on MTX coupled with the presence of effective but expensive alternative biologic therapies,[25] has suggested the need for screening patients prior to initiation of MTX. Such screening approaches may help decrease the morbidity associated with side effects, reduce the need for laboratory tests to monitor toxicity, and help select patients more likely to respond to the drug. The rapidly growing field of pharmacogenetics may make such screening methods feasible and available for use in clinical practice. The goal of this article is to review the pharmacogenetics of MTX in RA by highlighting major, relevant publications over the last year, and describe the potential implications of this field for future research and clinical care. As evident from the contents of this review, pharmacogenetics is a rapidly advancing area of research, holding promise for tailoring therapy based on a patient's genetics in the near future.

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