A personal journey from the joint to the heart

Predicting complications of diseases such as rheumatoid arthritis (RA) as well as the efficacy and toxicity of drugs used to treat the disease based on an understanding of genetic differences is leading to the development of highly individualized, personal medicine. The prevention of cardiovascular complications of RA has assumed greater importance as our ability to treat the underlying joint disease has improved and it may be possible to predict which patients with RA are at greatest risk of developing cardiovascular disease.

With the availability of increased information about the role of common genetic polymorphisms in disease suscep tibility, response to therapy and toxicity of therapies, the prospect of increasingly personalized medicine is becoming a reality. Palomino-Morales and colleagues [1] report the novel observation that a common polymorphism in the gene for methylene tetrahydrofolate reductase (MTHFR) that markedly reduces enzyme activity (by as much as 65% in homozygotes) may predispose to the development of atherosclerotic cardiovascular disease (ASCVD) in patients with rheumatoid arthritis (RA).
Although RA primarily aff ects the joints, it is a systemic disease that clearly contributes to a marked increase in the risk for development of ASCVD (for example, [2]). Th e increased risk of developing ASCVD has been attributed to generalized infl ammation that enhances development of atherosclerosis, the use of steroids, changes in lipid profi les and other unknown mechanisms.
Elevated homocysteine levels have long been associated with ASCVD (for example, [3]) and homo cysteine is a direct toxin for the vascular endo thelium. Low dose methotrexate therapy, by inhibiting MTHFR, diminishes recycling of homocysteine to methio nine, leading to increases in plasma homocysteine, although folic acid supplementation abrogates the increase in homocysteine levels in methotrexate-treated patients with RA [4]. One potential contributor to homo cysteine elevation is genetic alterations in MTHFR; two common poly morphisms in this enzyme have previously been reported to alter MTHFR activity (C677T and A1298C).
Th e A1298C polymorphism is quite common and is present in as many normal individuals (40% were AC heterozygotes and 10% were homozygous CC) as RA patients (41% were heterozygotes and 10% were homo zygous for the C allele). Th e striking fi nding by Palomino-Morales and colleagues was that RA patients with cardiovascular events were more likely to have the C allele of A1298C than those without (62% versus 50%, respectively) and the accumulated risk increased over time was strongly associated with the C allele of the A1298C polymorphism. It is interesting to note that the polymorphism associated with more marked declines in MTHFR activity, the C677T polymorphism, was not associated with a greater risk for cardiovascular disease. Th e numbers were probably too small to determine whether there was an interaction between these two common polymorphisms that further contributed to risk.
In some of the patients with RA the authors were able to directly probe the health of the endothelium by measuring the fl ow-dependent forearm vasodilatation and found that the RA patients with the minority A1298C allele in MTHFR had diminished vasodilatory responses, consistent with a less healthy vascular endothelium.
Patients with the C677T polymorphism, but not the A1298C polymorphism, are at greater risk for developing complications of methotrexate therapy and methotrexate therapy may ameliorate the risk of ASCVD in patients with RA [5,6]. Th us, it would be interesting to determine whether methotrexate therapy aff ected the frequency of cardiovascular events in this population and whether there was any interaction between methotrexate and genetic risk for cardiovascular disease in this population. Moreover, it would be important to know how many of these patients were taking folic acid supplements since folic acid supplementation has previously been shown to lower homocysteine levels in patients taking methotrexate [4,[7][8][9], presumably by providing higher levels of

Abstract
Predicting complications of diseases such as rheumatoid arthritis (RA) as well as the effi cacy and toxicity of drugs used to treat the disease based on an understanding of genetic diff erences is leading to the development of highly individualized, personal medicine. The prevention of cardiovascular complications of RA has assumed greater importance as our ability to treat the underlying joint disease has improved and it may be possible to predict which patients with RA are at greatest risk of developing cardiovascular disease. substrate for the enzyme, and it is possible that folic acid supplementation in this group might have had a greater eff ect in the patients with the polymorphism on reducing risk of cardiovascular events.
More often than not, candidate genetic association studies, such as that described here, are not reproducible [10] and it is possible that this study may share the fate common to so many of these types of candidate gene studies. Nonetheless, Palmino-Morales and colleagues have made an interesting observation that may suggest a contributing factor to the development of cardiovascular disease in patients with RA. Moreover, this study provides an even greater rationale for the addition of folic acid to the therapy for RA, prevention of cardiovascular disease.

Competing interests
BNC holds or has fi led applications for patents on the use of adenosine A 2A receptor agonists to promote wound healing and use of A 2A receptor antagonists to inhibit fi brosis; use of adenosine A 1 receptor antagonists to treat osteoporosis and other diseases of bone; the use of adenosine A 1 and A 2B receptor antagonists to treat fatty liver; and the use of adenosine A 2A receptor agonists to prevent prosthesis loosening. Consultant (within the past 2 years) King Pharmaceutical (licensee of patents on wound healing and fi brosis above). CanFite Biopharmaceuticals, Savient Pharmaceuticals, Bristol-Myers Squibb, Roche Pharmaceuticals, Cellzome, Tap (Takeda) Pharmaceuticals, Prometheus Laboratories, Regeneron (Westat, DSMB), Sepracor, Amgen, Endocyte, Protalex, Allos, Inc., Combinatorx, Kyowa Hakka. Honoraria/Speakers' Bureaus: Tap (Takeda) Pharmaceuticals. Stock: CanFite Biopharmaceuticals received for membership in Scientifi c Advisory Board.