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Precision medicine aims to personalize treatment for both effectiveness and safety. As a critical component of this emerging initiative, pharmacogenomics seeks to guide drug treatment based on genetics. In this review article, we give an overview of pharmacogenomics in the setting of an immunosuppressant frequently prescribed by rheumatologists, azathioprine. Azathioprine has a narrow therapeutic index and a high risk of adverse events. By applying candidate gene analysis and unbiased approaches, researchers have identified multiple variants associated with an increased risk for adverse events associated with azathioprine, particularly bone marrow suppression. Variants in two genes, TPMT and NUDT15, are widely recognized, leading drug regulatory agencies and professional organizations to adopt recommendations for testing before initiation of azathioprine therapy. As more gene-drug interactions are discovered, our field will continue to face the challenge of balancing benefits and costs associated with genetic testing. However, novel approaches in genomics and the integration of clinical and genetic factors into risk scores offer unprecedented opportunities for the application of pharmacogenomics in routine practice. Key Points • Pharmacogenomics can help us understand how individuals' genetics may impact their response to medications. • Azathioprine is a success story for the clinical implementation of pharmacogenomics, particularly the effects of TPMT and NUDT15 variants on myelosuppression. • As our knowledge advances, testing and dosing recommendations will continue to evolve, with our field striving to balance costs and benefits to patients. • As we aim toward the goals of precision medicine, future research may integrate increasingly individualized traits-including clinical and genetic characteristics-to predict the safety and efficacy of particular medications for individual patients.

Patients with severely elevated creatine kinase (CK) concentrations are commonly referred to rheumatologists to evaluate for the presence of an idiopathic inflammatory myopathy (IIM). However, no studies have evaluated the frequency with which IIMs are encountered in this clinical scenario. The Vanderbilt Synthetic Derivative, a de-identified copy of over 2 million patient records, was searched to identify adult patients with a CK greater than 1000 IU/L who had been evaluated by a rheumatologist. Each patient was assigned a diagnosis using a pre-determined algorithm. The records were then reviewed for pertinent demographic data and clinical characteristics. A total of 192 patients were included for analysis. Of these patients, 105 (55 %) were diagnosed with an IIM. The non-IIM causes were drug/toxin exposure (n = 16, 8 %), infection (n = 12, 6 %), trauma (n = 10, 5 %), myocardial injury (n = 5, 3 %), hypothyroidism (n = 4, 2 %), muscular dystrophy (n = 4, 2 %), neuropsychiatric disorder (n = 3, 2 %), metabolic myopathy (n = 2, 1 %), idiopathic CK elevation (n = 11, 6 %), and other diagnoses (n = 20, 10 %). Several characteristics were found to be significantly different between IIM and non-IIM cases. In particular, patients with an IIM were more likely to be female, have a positive ANA, have interstitial lung disease, and have proximal, symmetric weakness. This study found that approximately half of patients referred to our division of rheumatology with a CK greater than 1000 IU/L were diagnosed with an IIM. Given the importance of prompt diagnosis and treatment of these disorders, rapid assessment by the consulting rheumatologist for these patients is recommended.

OBJECTIVE: Hypertension is highly prevalent in patients with rheumatoid arthritis (RA). In other populations, high sodium (Na(+)) and low potassium (K(+)) intake are associated with an increased risk of hypertension, and in animal models a high salt intake exacerbated arthritis. Patients with RA have many comorbidities associated with salt-sensitivity, but their salt intake and its relationship to blood pressure and inflammation is unknown. METHODS: Using the Kawasaki formula, Na(+) and K(+) urinary excretion (reflecting intake) was estimated in 166 patients with RA and 92 controls, frequency matched for age, sex, and race. Inflammatory markers and disease activity were measured in RA patients. We tested the associations between blood pressure and Na(+) and K(+) excretion. RESULTS: Estimated 24 hour Na(+) excretion was similarly high in both RA (median [IQR] 5.1 g, [3.9 g–6.6 g]) and controls (4.9 g, [4.0 g–6.5 g]), p=0.9; despite higher rates of hypertension in RA (54% vs. 39%, p=0.03). The Na(+):K(+) excretion ratio was significantly higher in RA (2.0 [1.6–2.4]) vs. 1.7 [1.5–2.1]), p=0.02] compared to controls. In RA, a lower K(+) excretion was inversely correlated with diastolic blood pressure (adjusted-β= -1.79, p=0.04). There was no significant association between Na(+) or K(+) excretion and inflammatory markers. CONCLUSIONS: Despite a similar Na(+) excretion, patients with RA had higher rates of hypertension than controls, a finding compatible with increased salt sensitivity. Patients with RA had a lower Na(+):K(+) excretion ratio than controls, and lower K(+) excretion was associated with higher diastolic blood pressure in RA.

Differences in quality of care may contribute to health disparities in systemic lupus erythematosus (SLE). Studies show low physician adherence rates to the SLE quality indicators but do not assess physician perception of SLE quality indicators or quality improvement. Using a cross-sectional survey of rheumatologists in the southeastern USA, we assessed the perception and involvement of rheumatologists in quality improvement and the SLE quality indicators. Using electronic mail, an online survey of 32 questions was delivered to 568 rheumatologists. With a response rate of 19% (n = 106), the majority of participants were male, Caucasian, with over 20 years of experience, and seeing adult patients in an academic setting. Participants had a positive perception toward quality improvement (81%) with a majority responding that the SLE quality indicators would significantly impact quality of care (54%). While 66% of respondents were familiar with the SLE quality indicators, only 18% of respondents reported using them in everyday practice. The most commonly reported barrier to involvement in quality improvement and the SLE quality indicators was time. Rheumatologists had a positive perception of the SLE quality indicators and agreed that use of the quality indicators could improve quality of care in SLE; however, they identified time as a barrier to implementation. Future studies should investigate methods to increase use of the SLE quality indicators.

Oxidative stress is thought to play a role in the pathogenesis of fibromyalgia. We examined the hypothesis that oxidative stress was increased in patients with fibromyalgia and related to the severity of symptoms. Urinary F(2)-isoprostane excretion was measured in 48 patients with fibromyalgia and compared to those of 96 control subjects. In patients, we examined the association between oxidative stress and symptoms. Patients with fibromyalgia were significantly more symptomatic than control subjects, but urinary F(2)-isoprostane excretion did not differ significantly (2.3+/-1.9 vs. 2.8+/-2.2 ng/mg creatinine, p=0.16). In patients with fibromyalgia, F(2)-isoprostane excretion was associated with fatigue visual analog scale (rho=0.30, p=0.04) but not with pain, quality of life, functional capacity, depression, number of tender points, or overall impact of fibromyalgia. Oxidative stress is not increased in patients with fibromyalgia, but as was previously found in patients with systemic lupus erythematosus, oxidative stress was associated with fatigue.

Patients with systemic lupus erythematosus (SLE) have accelerated atherosclerosis, but the underlying mechanisms are unclear. The size and number of lipoprotein particles may be better predictors of atherosclerosis than conventional cholesterol measurements. We measured lipoprotein subclasses by nuclear magnetic resonance spectroscopy (NMR), coronary artery calcification by electron beam computed tomography, and insulin resistance by homeostasis model assessment in 105 patients with SLE and 77 control subjects. VLDL particles were larger (50.0 ± 8.5 versus 47.7 ± 8.5 nm, P = 0.01) and concentrations of large high-density lipoprotein (HDL) particles lower (10.1 ± 5.3 versus 11.3 ± 5.1 nmol/L, P = 0.03) in patients with SLE than controls. In patients with SLE, small LDL concentration was associated with body mass index (rho = 0.27), insulin resistance (rho = 0.34), C-reactive protein (CRP; rho = 0.30), and erythrocyte sedimentation rate (ESR; rho = 0.20); all P

Cardiovascular disease is a major health care problem and the most common cause of death among individuals from developed nations. Our understanding of atherosclerosis has evolved from a passive process resulting in narrowing of the lumen and consequent myocardial ischemia to a dynamic process that involves inflammation. The study of atherosclerosis in patients with chronic inflammation, such as rheumatoid arthritis (RA), will provide insights into the relationship between inflammation and atherosclerosis. We review the relationship between atherosclerosis and inflammation within the context of RA, providing evidence that patients with RA have increased cardiovascular morbidity and mortality and accelerated coronary and extra-coronary atherosclerosis. In addition, traditional and novel cardiovascular risk factors are discussed. Finally, actions that a rheumatologist can take to better control this cardiovascular morbidity are suggested. These can be summarized as follows: (1) careful assessment and treatment of cardiovascular risk, (2) better control of inflammation, and (3) individual risk–benefit evaluation of need for cyclo-oxygenase-2 inhibitors, nonsteroidal anti-inflammatory drugs, and high doses of corticosteroids.